BRPF1-Related Intellectual Disability

Mendelian MONDO:0015022 Pathograph 65 Show in embeddings browser autosomal dominant syndromic intellectual disability

BRPF1-related intellectual disability (intellectual developmental disorder with dysmorphic facies and ptosis, IDDDFP; OMIM 617333) is an autosomal dominant neurodevelopmental disorder caused by heterozygous loss-of-function variants in BRPF1. BRPF1 is not itself an acetyltransferase: it is the multivalent chromatin-reader scaffold that assembles and activates the MYST lysine acetyltransferases KAT6A (MOZ) and KAT6B (MORF) together with ING4/ING5 and MEAF6. Its signature catalytic output is acetylation - and, as later shown, propionylation - of histone H3 at lysine 23 (H3K23), and tested patient variants can impair both acylations, with allele-specific effects. The clinical core is developmental delay with a strikingly consistent speech and language disorder, variable (usually mild-to-moderate, occasionally absent) intellectual disability, infantile hypotonia and feeding difficulty, and a recognizable periocular facial gestalt dominated by ptosis and blepharophimosis with downslanted palpebral fissures and a broad nasal bridge. Ocular involvement beyond the eyelids (strabismus, amblyopia, refractive error, coloboma, subclinical optic neuropathy) supports comprehensive ophthalmological assessment. Corpus callosum abnormalities have also been reported in a subset of imaged patients. Expressivity within families is wide, extending to carriers with normal intellect.

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Classifications

Harrison's Part

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Mappings

MONDO

MONDO:0015022 intellectual developmental disorder with dysmorphic facies and ptosis

Orphanet's record for ORPHA:698090 (Ophthalmological abnormalities-facial dysmorphism-intellectual disability syndrome, synonym "BRPF1-related neurodevelopmental disorder") carries an Exact cross-reference to OMIM:617333, the OMIM phenotype MONDO:0015022 is built on. Orphanet lists BRPF1 (hgnc:14255) as the disease-causing gene, matching this entry.

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Inheritance

Autosomal dominant inheritance HP:0000006

Heterozygous BRPF1 variants act in a dominant, haploinsufficiency mode. Unlike many de-novo-dominant chromatinopathies, a large fraction of reported BRPF1 variants are inherited from a mildly affected or apparently unaffected parent, and recurrence in one reported sibship suggested parental gonadal mosaicism. Expressivity is wide even within a single family.

Autosomal dominant inheritance Expressivity: VARIABLE

Show evidence (3 references)

PMID:27939640 SUPPORT Human Clinical

"Here, we describe an intellectual disability disorder in ten individuals with inherited or de novo monoallelic BRPF1 mutations."

Monoallelic (heterozygous) variants, both inherited and de novo, cause the disorder.

PMID:37946714 SUPPORT Human Clinical

"Both de novo and inherited pathogenic variants have been previously reported in association with this disorder."

Confirms the mixed de novo / inherited origin of pathogenic alleles.

PMID:39837771 SUPPORT Human Clinical

"Familial analysis revealed variability in clinical expression."

The largest cohort documents variable expressivity within families.

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Mechanistic Hypotheses

H3K23 Acetylation Deficiency Branch

h3k23_acetylation_loss CANONICAL

Evidence balance 1 support

The canonical molecular lesion is loss of BRPF1-dependent acetylation of histone H3 at lysine 23. Patient-derived BRPF1 variants impair H3K23 acetylation in functional assays, and the same deficiency is reproduced in Brpf1-knockout mice, making this the best-supported route from gene to chromatin defect.

Pathograph links

Impaired BRPF1-KAT6 Acetyltransferase Complex Function -> Deficient Histone H3K23 Acetylation DIRECT

Deficient Histone H3K23 Acetylation -> Altered Chromatin Accessibility INDIRECT UNKNOWN INTERMEDIATES

Show evidence (1 reference)

PMID:27939640 SUPPORT In Vitro

"Functional assays showed that the resulting BRPF1 variants are pathogenic and impair acetylation of histone H3 at lysine 23, an abundant but poorly characterized epigenetic mark."

Directly establishes impaired H3K23 acetylation as the molecular consequence of patient BRPF1 variants.

H3K23 Propionylation Deficiency Branch

h3k23_propionylation_loss EMERGING

Evidence balance 1 support

A later-recognized, non-redundant arm: the same BRPF1-KAT6 complexes also catalyze H3K23 propionylation, and patient BRPF1 variants impair this acylation as well. Whether the propionylation deficit contributes to the clinical phenotype independently of the acetylation deficit is not established; the two marks are currently inseparable in patient material. This branch nonetheless motivates the pharmacologic acylation-restoration strategy (propionate, butyrate, valproate, vorinostat) that has so far been demonstrated only in cell systems.

Pathograph links

Impaired BRPF1-KAT6 Acetyltransferase Complex Function -> Deficient Histone H3K23 Propionylation DIRECT

Deficient Histone H3K23 Propionylation -> Altered Developmental Transcriptional Programs INDIRECT UNKNOWN INTERMEDIATES

Show evidence (1 reference)

PMID:32010779 SUPPORT In Vitro

"Moreover, we identify BRPF1 variants in 12 previously unidentified cases of syndromic intellectual disability and demonstrate that these cases and known BRPF1 variants impair H3K23 propionylation."

Establishes propionylation loss as a distinct, patient-variant-associated acylation defect.

Discussions and Knowledge Gaps

How do zygosity, affected cell lineage and deletion timing influence the relevance of mouse and stem-cell BRPF1 models to variable human heterozygous disease?

HUMAN MODEL MISMATCH OPEN brpf1_zygosity_and_species_model_mismatch

Attached to

pathophysiology#Aberrant Cortical Neurogenesis pathophysiology#Abnormal Corpus Callosum Development pathophysiology#Impaired Hematopoietic Stem and Progenitor Cell Maintenance pathophysiology#Impaired Learning and Memory

Complete global, early forebrain and hematopoietic loss can cause lethal mouse phenotypes, whereas postnatal CaMKIIa-Cre conditional mice survive and have selective physiological and behavioral effects. Emx1-lineage conditional heterozygotes match human zygosity only within the targeted lineage, not throughout the organism. Human expressivity varies, including a reported individual with normal intellectual development; these observations do not establish normal life expectancy. Human callosal abnormalities are uncommon. Anemia and thrombocytopenia have been reported in a family and in additional individuals in the 2025 cohort, without demonstrating the severe stem-cell failure mechanism of the homozygous hematopoietic mouse model. Global null embryos also have placental and vascular defects with cranial neural tube failure. Zebrafish pharyngeal homeotic transformations establish a developmental role, but have no demonstrated equivalent in human heterozygous craniofacial dysmorphism.

Proposed experiments

BRPF1 zygosity-matched allelic series in human iPSC-derived cortical neurons and organoids

isogenic allelic-series loss-of-function experiment

exp_brpf1_human_allelic_series_organoid

In an isogenic human iPSC background, build a BRPF1 allelic series (heterozygous null, heterozygous patient truncating and missense alleles, homozygous null) and differentiate to cortical neurons and forebrain organoids. Read out H3K23 acetylation and propionylation, chromatin accessibility, intermediate-progenitor (TBR2) abundance, dendritic arborization, and excitatory and inhibitory synaptic physiology. This directly tests whether the heterozygous human state reproduces the null-allele mouse phenotypes and, if so, at what magnitude.

Test for a BRPF1 DNA methylation episignature in patient blood

DNA methylation episignature study

exp_brpf1_episignature

Profile genome-wide DNA methylation in blood from variant-confirmed BRPF1 cases, matched controls and KAT6A/KAT6B cases. A reproducible signature could complement existing patient-cell histone-acylation assays and could be evaluated for variant interpretation. Its diagnostic performance, specificity and sensitivity would require validation; a positive cohort-level result alone would not resolve every variant of uncertain significance.

Show evidence (5 references)

PMID:25568313 SUPPORT Model Organism

"Here, we report that forebrain-specific inactivation of the mouse Brpf1 gene caused early postnatal lethality, neocortical abnormalities, and partial callosal agenesis."

The forebrain model is a conditional null with a lethal phenotype that has no human counterpart.

PMID:24646517 SUPPORT Model Organism

"In support of this, inactivation of the mouse Brpf1 gene causes lethality around embryonic day 9.5."

Complete Brpf1 loss is embryonic-lethal in mouse, unlike human heterozygous disease.

PMID:35243762 SUPPORT Human Clinical

"Here, we describe a patient with normal intellectual development who had congenital ptosis, hypotonia, muscular weakness, atlanto-axial malformation, and pyramidal at the neurological examination."

Documents variable human cognitive expressivity. Mouse behavioral tasks are not equivalent to human intellectual assessment.

+ 2 more references

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Pathophysiology

Heterozygous BRPF1 Loss-of-Function Variation

Mechanism confidence: Established

The initiating lesion is a heterozygous BRPF1 variant, either de novo or inherited. Reported alleles are predominantly protein-truncating (nonsense, frameshift) or whole-gene/partial deletions, with a smaller number of missense and stop-loss alleles; a single 3p25 contiguous deletion can remove BRPF1 together with SETD5.

BRPF1 hgnc:14255

Genetic context BRPF1 hgnc:14255 variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION

Heterozygous BRPF1 truncating, splice, deletion and missense alleles. Recorded as LOSS_OF_FUNCTION (haploinsufficiency).

Downstream

BRPF1 Haploinsufficiency

Show evidence (3 references)

PMID:27939639 SUPPORT Human Clinical

"We performed exome sequencing in a large family affected by an autosomal-dominant form of mild syndromic ID with ptosis, growth retardation, and hypotonia, and we identified an inherited 2 bp deletion causing a frameshift in BRPF1 (c.1052_1053del) in five affected family members."

The founding family establishes a heterozygous frameshift BRPF1 allele segregating with the phenotype.

PMID:27939639 SUPPORT Human Clinical

"We identified BRPF1 deletions or point mutations in six additional individuals with a similar phenotype."

Documents the allelic spectrum as both deletions and point mutations.

PMID:31020800 SUPPORT Human Clinical

"To conclude, BRPF1 haploinsufficiency is an underdiagnosed cause of intellectual disability of variable severity, ptosis and/or blepharophimosis and additional nonspecific features, and should be considered in relevant clinical circumstances."

Multiplex-family study attributing the phenotype to BRPF1 haploinsufficiency.

BRPF1 Haploinsufficiency

Mechanism confidence: Established

Heterozygous loss-of-function variants reduce functional BRPF1 scaffold activity. Haploinsufficiency is supported by clinical genetics and dosage curation, but does not establish an exact halving of protein abundance. The c.1052_1053del transcript undergoes partial nonsense-mediated decay; its residual truncated product has allele-specific defects in stability, localization and partner recruitment in expression assays. Comparison of BRPF1 lesions, SETD5 lesions and deletions spanning both genes implicates BRPF1 dosage particularly in the periocular phenotype.

Downstream

Impaired BRPF1-KAT6 Acetyltransferase Complex Function

Ptosis

Blepharophimosis

Show evidence (1 reference)

PMID:27939639 SUPPORT Human Clinical

"We conclude that both genes contribute to the phenotypic severity of 3p25 deletion syndrome but that some specific features, such as ptosis and blepharophimosis, are mostly driven by BRPF1 haploinsufficiency."

Attributes the discriminating periocular features specifically to BRPF1 dosage loss, separating it from the co-deleted SETD5.

Impaired BRPF1-KAT6 Acetyltransferase Complex Function

Mechanism confidence: Established

BRPF1 is the scaffold subunit of tetrameric MYST acetyltransferase complexes built around KAT6A (MOZ) or KAT6B (MORF) plus ING4/ING5 and MEAF6. Association with KAT7 (HBO1) has also been demonstrated in vitro, but its in-vivo relevance is less clear; KAT7 preferentially associates with BRD1 or BRPF3 in vivo. Patient variants can impair partner recruitment and catalytic stimulation, with effects that depend on the allele. For example, p.Val351GlyfsTer8 retains KAT6A binding but fails to recruit ING5 and MEAF6 in transfected cells. BRPF1-, KAT6A- and KAT6B-related disorders overlap clinically, but their differences do not by themselves establish which additional partners or independent activities account for that overlap.

H3K23 Acetylation Deficiency Branch H3K23 Propionylation Deficiency Branch

histone acetyltransferase activity GO:0004402 ↓ DECREASED

MOZ/MORF histone acetyltransferase complex GO:0070776

Downstream

Deficient Histone H3K23 Acetylation

Deficient Histone H3K23 Propionylation

Show evidence (6 references)

PMID:24646517 SUPPORT Other

"Within these complexes, BRPF1 serves as a scaffold for bridging subunit interaction, stimulating acetyltransferase activity, governing substrate specificity and stimulating gene expression."

Defines normal scaffold functions. The extent to which each function is disrupted requires allele-specific assays.

PMID:36077605 SUPPORT Other

"It functions in the form of a tetrameric complex with a monocytic leukemia zinc finger protein (MOZ or KAT6A), MOZ-related factor (MORF or KAT6B) or HAT bound to ORC1 (HBO1 or KAT7) and two small non-catalytic proteins, the inhibitor of growth 5 (ING5) or the paralog ING4 and..."

Defines the composition of the complexes that BRPF1 scaffolds.

PMID:27939640 SUPPORT Human Clinical

"These clinical features overlap with but are not identical to those reported for persons with KAT6A or KAT6B mutations, suggesting that BRPF1 targets these two acetyltransferases and additional partners in humans."

Documents clinical overlap and differences; the additional-partner explanation is the authors' interpretation.

+ 3 more references

Deficient Histone H3K23 Acetylation

Mechanism confidence: Established

Loss of BRPF1 scaffold activity can lower acetylation of histone H3 lysine 23; the effect depends on the allele and experimental context. In human embryonic stem cells, BRPF1, H3K4me3 and H3K23ac co-occupy open chromatin at stemness genes, linking BRPF1 occupancy with local histone modification. Co-occupancy does not itself establish direct recognition of H3K23ac by BRPF1. Assay context matters: the founding p.Val351GlyfsTer8 study found failure to stimulate H3K23 acetylation in transfected cells, while its patient-fibroblast decrease was not significant. Global H3, H3K9 and H3K14 acetylation were not detectably changed there. In the hESC knockout study, H3K4me3 persisted and H3K14ac was initially preserved before declining with differentiation; direct H3K4me3 recognition by BRPF1 was not biochemically resolved.

H3K23 Acetylation Deficiency Branch

histone H3K23 acetyltransferase activity GO:0043994 ↓ DECREASED

Experimental models

BRPF1 Pro370Ser patient-derived lymphoblastoid cells CELL LINE Tests biochemical response to HDAC inhibition.

Inducible Brpf1-null mouse embryonic fibroblasts PRIMARY CELL CULTURE

BRPF1-null human H1 embryonic stem cells with inducible rescue OTHER

Animal models

Hematopoietic Vav1-iCre Brpf1 conditional knockout mouse Mus musculus measures

Downstream

Altered Chromatin Accessibility

Show evidence (3 references)

PMID:27939640 SUPPORT In Vitro

"Functional assays showed that the resulting BRPF1 variants are pathogenic and impair acetylation of histone H3 at lysine 23, an abundant but poorly characterized epigenetic mark."

Functional assays identify impaired H3K23 acetylation for patient-associated variants; the magnitude and detectability vary with allele and preparation.

PMID:27939640 SUPPORT Model Organism

"We also found a similar deficiency in different lines of Brpf1-knockout mice."

The acetylation deficit is reproduced in an independent in vivo system.

PMID:27939639 SUPPORT In Vitro

"However, unlike wild-type BRPF1, the p.Val351Glyfs∗8 variant failed to stimulate K23 acetylation of histone H3"

The expression assay supports deficient stimulation of H3K23 acetylation. In patient fibroblasts from this study, the H3K23 decrease was slight and not statistically significant, so this is not evidence of a uniform measurable deficit in every patient sample.

Deficient Histone H3K23 Propionylation

Mechanism confidence: Provisional

BRPF1-KAT6 complexes propionylate H3K23. Several patient variants impair this activity, and the mark is reduced in Pro370Ser lymphoblastoid cells and Arg455Ter lymphoblastoid cells and fibroblasts. Complete Brpf1 deletion abolishes detectable H3K23 propionylation in mouse embryos and cultured fibroblasts. Effects are allele- and assay-dependent: Pro76Leu retained stimulation in the biochemical assay, and some truncating products also retained activity. The independent contribution of propionylation loss to the human phenotype is unresolved.

H3K23 Propionylation Deficiency Branch

peptidyl-lysine propionylation GO:0061921 ↓ DECREASED

Experimental models

BRPF1 Pro370Ser patient-derived lymphoblastoid cells CELL LINE Measures the patient-cell propionylation deficit.

BRPF1 Pro370Ser patient-derived lymphoblastoid cells CELL LINE Tests biochemical response to sodium propionate.

Inducible Brpf1-null mouse embryonic fibroblasts PRIMARY CELL CULTURE

Downstream

Altered Developmental Transcriptional Programs

Show evidence (3 references)

PMID:32010779 SUPPORT In Vitro

"Moreover, we identify BRPF1 variants in 12 previously unidentified cases of syndromic intellectual disability and demonstrate that these cases and known BRPF1 variants impair H3K23 propionylation."

Patient variants impair H3K23 propionylation.

PMID:32010779 SUPPORT Model Organism

"Brpf1 deletion obliterates the acylation in mouse embryos and fibroblasts."

In vivo loss of Brpf1 abolishes the acylation, confirming BRPF1 dependence.

PMID:32010779 SUPPORT In Vitro

"The Pro76Leu variant was normally expressed and promoted the expression of ING5 and MEAF6 as wild-type BRPF1"

This variant retained stimulation of H3K23 acylation in the study; its disease relationship remained uncertain. A blanket loss-of-function assertion for every reported variant is inappropriate.

Altered Chromatin Accessibility

Mechanism confidence: Provisional

Complete BRPF1 deletion in human H1 embryonic stem cells reduces ATAC-seq accessibility at stemness genes while increasing accessibility at lineage-associated genes. H3K4me3 remains substantially present despite loss of H3K23ac and pluripotency. Co-occupancy and rescue support BRPF1-dependent chromatin regulation, but the biochemical route from H3K23ac loss to accessibility change and its applicability to heterozygous patient neurons remain unresolved.

chromatin organization GO:0006325 ⚠ ABNORMAL

Experimental models

BRPF1-null human H1 embryonic stem cells with inducible rescue OTHER

Downstream

Altered Developmental Transcriptional Programs

Show evidence (1 reference)

PMID:36711238 SUPPORT In Vitro

"BRPF1 deletion impairs H3K23ac in hESCs and leads to closed chromatin accessibility on stemness genes and hESC differentiation as well."

BRPF1-null H1 embryonic stem cells lose H3K23ac and accessibility at stemness loci. Other lineage-associated regions gain accessibility; this is not uniform genome-wide closure.

Altered Developmental Transcriptional Programs

Mechanism confidence: Provisional

BRPF1 perturbation changes developmental gene expression in a context-dependent manner. Human embryonic stem-cell deletion suppresses stemness genes and activates lineage genes. In mouse hippocampal CA1 tissue, postnatal excitatory-neuron deletion both downregulates selected neural genes and derepresses normally suppressed transcription factors. These are distinct experimental systems; their transcriptomic changes do not identify a universal mediator of the human multisystem phenotype. In zebrafish mutants, anterior Hox expression is initiated normally but subsequently lost in cranial neural crest; this contrasts with elevated Hox expression after mouse forebrain deletion and illustrates tissue-dependent directionality.

regulation of transcription by RNA polymerase II GO:0006357 ⚠ ABNORMAL

Experimental models

Inducible Brpf1-null mouse embryonic fibroblasts PRIMARY CELL CULTURE

BRPF1-null human H1 embryonic stem cells with inducible rescue OTHER

Animal models

Postnatal CaMKIIa-Cre conditional Brpf1 knockout mouse Mus musculus measures

Zebrafish brpf1 pharyngeal-patterning mutants Danio rerio partially recapitulates

Zebrafish brpf1 pharyngeal-patterning mutants Danio rerio rescues

Constitutive Brpf1-null mouse embryo Mus musculus measures

Downstream

Impaired Dendritic Arborization

Reduced Inhibitory Neurotransmission in GABAergic Interneurons

Global Developmental Delay

Speech and Language Disorder

Infantile Hypotonia

Aberrant Cortical Neurogenesis

Impaired Hematopoietic Stem and Progenitor Cell Maintenance

Congenital Cardiac Anomalies

Deregulated Ocular and Periocular Developmental Transcription Factor Programs

Reduced Intrinsic Excitability of MGE-Derived GABAergic Interneurons

Reduced Dendritic Spine Density and Altered Spine Morphology

Impaired Axonal Outgrowth

Reduced Intrinsic Excitability of Hippocampal Pyramidal Neurons

Abnormal Corpus Callosum Development

Show evidence (3 references)

PMID:36711238 SUPPORT In Vitro

"BRPF1 deletion impairs H3K23ac in hESCs and leads to closed chromatin accessibility on stemness genes and hESC differentiation as well."

BRPF1-null H1 embryonic stem cells lose H3K23ac and accessibility at stemness loci. Other lineage-associated regions gain accessibility; this is not uniform genome-wide closure.

PMID:37862219 SUPPORT Model Organism

"The results showed a dual role forBrpf1in regulating gene expression, that is, regulating both gene activation and suppression."

RNA-seq and qPCR in hippocampal CA1 tissue show both directions of transcriptional change after postnatal conditional deletion. No individual transcript was rescued to prove mediation of physiology or behavior.

PMID:18469222 SUPPORT Model Organism

"We conclude that Brpf1 is specifically required for the maintenance, but not for the initiation, of anterior Hox gene expression."

Zebrafish mutants lose maintenance of anterior Hox expression; initiation and neural crest migration were preserved. This is not a demonstrated human craniofacial pathway.

Deregulated Ocular and Periocular Developmental Transcription Factor Programs

Mechanism confidence: Hypothetical

BRPF1-dependent regulation of Pitx2, Hmx1 and Pax6 has been proposed as a route to the ocular and periocular phenotype. The cited clinical cohort extrapolates from developmental-model literature; it does not directly test these transcription factors in human periocular tissue. The connection to ptosis, blepharophimosis and ocular alignment remains hypothetical.

regulation of transcription by RNA polymerase II GO:0006357 ⚠ ABNORMAL

Downstream

Ptosis

Blepharophimosis

Strabismus

Show evidence (3 references)

PMID:39837771 SUPPORT Other

"has been shown to affect the transcriptional regulation of several key transcription factors, including Pitx2, Hmx1 and Pax6, which have been implicated in a wide range of ocular developmental abnormalities"

Names the three transcription factors that constitute this node and links them to ocular developmental abnormality.

PMID:39837771 SUPPORT Other

"This likely accounts for the significant frequency and variability of ocular defects observed in our cohort and reported in the literature."

The authors present the mechanism as a likely explanation rather than a demonstrated one - the basis for the HYPOTHETICAL confidence level.

PMID:27939639 SUPPORT Human Clinical

"some specific features, such as ptosis and blepharophimosis, are mostly driven by BRPF1 haploinsufficiency"

Establishes that the endpoints of this arm are attributable to BRPF1 dosage specifically, independent of the co-deleted SETD5.

Aberrant Cortical Neurogenesis

Mechanism confidence: Provisional

Early forebrain-specific Brpf1 homozygous deletion reduces Tbr2-positive intermediate neuronal progenitors and alters cortical neurogenesis in mice. Developmental transcript changes accompany these abnormalities, but specific transcriptional mediators have not been isolated by rescue. The severe conditional-null model is not equivalent to heterozygous human disease.

neurogenesis GO:0022008 ⚠ ABNORMAL

Animal models

Embryonic Emx1-Cre Brpf1 conditional homozygous mouse Mus musculus measures

Show evidence (1 reference)

PMID:25568313 SUPPORT Model Organism

"With respect to the control, the mutant forebrain contained fewer Tbr2-positive intermediate neuronal progenitors and displayed aberrant neurogenesis."

Identifies depletion of intermediate neuronal progenitors as the cellular basis of the cortical phenotype.

Abnormal Corpus Callosum Development

Mechanism confidence: Provisional

Conditional homozygous Brpf1 loss in the embryonic forebrain produces partial callosal agenesis in mice. Conditional heterozygotes in a separate study have a modest reduction in callosal thickness. These zygosity-dependent anatomical changes provide model evidence, while the route to rare human agenesis or hypoplasia remains unproven.

Animal models

Embryonic Emx1-Cre Brpf1 conditional homozygous mouse Mus musculus measures

Downstream

Agenesis of the Corpus Callosum

Hypoplasia of the Corpus Callosum

Show evidence (1 reference)

PMID:25568313 SUPPORT Model Organism

"Here, we report that forebrain-specific inactivation of the mouse Brpf1 gene caused early postnatal lethality, neocortical abnormalities, and partial callosal agenesis."

The conditional homozygous model has a tissue-level callosal phenotype; it does not establish a universal callosal defect in heterozygous humans.

Impaired Hematopoietic Stem and Progenitor Cell Maintenance

Mechanism confidence: Provisional

Hematopoietic Vav1-iCre Brpf1 homozygous deletion impairs fetal stem/progenitor function and causes progressive postnatal marrow failure in mice. The phenotype includes loss of repopulating capacity despite preserved marrow homing, reduced neonatal LSK proliferation, and increased apoptosis, oxidative stress and senescence. Fetal LSK proliferation is initially preserved. Conditional heterozygotes have unchanged survival and neonatal LSK-cell numbers in the reported tests. Human anemia and thrombocytopenia have been observed without establishing this severe stem-cell failure mechanism.

fetal hematopoietic stem cell CL:0000037 hematopoietic multipotent progenitor cell CL:0000837

hemopoiesis GO:0030097 ↓ DECREASED

Experimental models

Brpf1-null fetal-liver and neonatal marrow colony cultures PRIMARY CELL CULTURE

Animal models

Hematopoietic Vav1-iCre Brpf1 conditional knockout mouse Mus musculus measures

Hematopoietic Vav1-iCre Brpf1 conditional heterozygous mouse Mus musculus measures

Downstream

Anemia

Thrombocytopenia

Show evidence (6 references)

PMID:27500495 SUPPORT Model Organism

"The mutant bone marrow and fetal liver exhibited severe deficiency in HSCs and hematopoietic progenitors, along with elevated reactive oxygen species, senescence, and apoptosis."

Defines the cellular hematopoietic deficit produced by Brpf1 loss.

PMID:27500495 SUPPORT Model Organism

"Furthermore, BRPF1 was required for acetylation of histone H3 at lysine 23, a highly abundant but not well-characterized epigenetic mark."

H3K23ac loss accompanies hematopoietic dysfunction. No mark-specific rescue establishes it as the sole mediator, and H3K9/H3K14 acetylation also decline in this null model.

PMID:27500495 SUPPORT Model Organism

"No significant difference was observed between wild-type and heterozygous LSK cell numbers"

Conditional heterozygotes did not show the neonatal LSK depletion observed after homozygous deletion; this negative comparison limits direct extrapolation to human heterozygosity.

+ 3 more references

Impaired Dendritic Arborization

Mechanism confidence: Provisional

Emx1-lineage conditional Brpf1 heterozygous mice have reduced dendritic branching in dentate granule cells and layer V cortical pyramidal neurons. E16.5 cortical cultures also show shorter and less complex dendrites at DIV14. Conditional homozygous loss produces more severe changes. These observations concern mouse neurons; they do not establish a human neuronal phenotype or a transcriptional mediator.

hippocampal granule cell CL:0001033 cortical pyramidal neuron CL:4023111

dendrite morphogenesis GO:0048813 ⚠ ABNORMAL

Experimental models

Emx1-lineage Brpf1 conditional cortical neuron cultures PRIMARY CELL CULTURE

Animal models

Emx1-lineage conditional Brpf1 heterozygous mouse Mus musculus partially recapitulates

Show evidence (1 reference)

PMID:31213987 SUPPORT Model Organism

"Sholl analysis revealed a significant decrease in the number of intersections in Brpf1 HT and cKO neurons compared with that in WT neurons"

Golgi-stained dentate granule neurons had reduced dendritic complexity; similar changes were measured in layer V cortical neurons. The intervening transcriptional steps remain unresolved.

Reduced Dendritic Spine Density and Altered Spine Morphology

Mechanism confidence: Provisional

Conditional Emx1-lineage Brpf1 heterozygous mice have fewer and longer spines on cortical pyramidal-neuron apical dendrites. Homozygous conditional loss has a more severe effect. Hippocampal CA3 electron microscopy separately shows lower synaptic density, smaller postsynaptic densities and narrower synaptic clefts. Spine and synaptic measurements accompany electrophysiological changes but were not selectively rescued to demonstrate mediation.

cortical pyramidal neuron CL:4023111

dendritic spine development GO:0060996 ⚠ ABNORMAL

Animal models

Emx1-lineage conditional Brpf1 heterozygous mouse Mus musculus partially recapitulates

Downstream

Reduced Excitatory Synaptic Transmission in Forebrain Neurons

Show evidence (2 references)

PMID:31213987 SUPPORT Model Organism

"Brpf1 HTs exhibited a significant reduction in the number of spines compared to that in WT mice."

Spines were counted along secondary apical dendritic branches of adult cortical pyramidal neurons.

PMID:31213987 SUPPORT Model Organism

"Statistical analysis revealed a significant increase in spine length in Brpf1 HT and cKO mice."

Cortical spine length increased alongside a reduction in spine density; the measurements concern conditional mouse genotypes.

Impaired Axonal Outgrowth

Mechanism confidence: Provisional

Primary cortical neurons from E16.5 Emx1-lineage Brpf1 conditional heterozygotes have shorter Tau-positive axons at DIV5; conditional homozygous deletion produces a larger reduction. This culture phenotype does not by itself explain callosal anatomy or human cognitive impairment.

Experimental models

Emx1-lineage Brpf1 conditional cortical neuron cultures PRIMARY CELL CULTURE

Show evidence (1 reference)

PMID:31213987 SUPPORT In Vitro

"axonal elongation in HT cells was impaired, with a 20.3% decrease in length"

Tau-positive axons in E16.5 cortical cultures were measured at DIV5; conditional homozygous neurons had a more severe reduction.

Reduced Intrinsic Excitability of Hippocampal Pyramidal Neurons

Mechanism confidence: Provisional

CA1 pyramidal neurons in acute slices from Emx1-lineage conditional Brpf1 heterozygotes have lower input resistance, a higher current threshold for firing and fewer spikes at selected current steps, while resting membrane potential is unchanged. These effects are distinct from mEPSC changes and were not observed in the separate mild hippocampal shRNA culture study.

hippocampal pyramidal neuron CL:1001571

Animal models

Emx1-lineage conditional Brpf1 heterozygous mouse Mus musculus partially recapitulates

Show evidence (1 reference)

PMID:31213987 SUPPORT Model Organism

"The mean resting potential was comparable between HTs and WTs, while the mean action potential current threshold was significantly higher in the HTs than in the WTs"

Acute CA1 slice current-clamp recordings found increased firing-current threshold with preserved resting membrane potential.

Reduced Excitatory Synaptic Transmission in Forebrain Neurons

Mechanism confidence: Provisional

Brpf1 perturbation reduces mEPSC frequency in several mouse neuronal preparations. Emx1-lineage conditional heterozygotes also have lower mEPSC amplitude in acute CA1 slices, whereas mild shRNA knockdown in hippocampal cultures preserves amplitude and measured arbor morphology. These preparation-specific results do not establish a universal temporal sequence from dendritic change to synaptic dysfunction.

excitatory postsynaptic potential GO:0060079 ↓ DECREASED

Experimental models

Brpf1-knockdown mouse hippocampal neuron cultures PRIMARY CELL CULTURE Measures synaptic currents after partial Brpf1 knockdown.

Animal models

Emx1-lineage conditional Brpf1 heterozygous mouse Mus musculus partially recapitulates

Postnatal CaMKIIa-Cre conditional Brpf1 knockout mouse Mus musculus measures

Downstream

Impaired Learning and Memory

Show evidence (3 references)

PMID:34485298 SUPPORT In Vitro

"We found that mild knockdown of Brpf1 reduced mEPSC frequency of cultured hippocampal neurons, before any significant changes of dendritic morphology showed."

Cultured hippocampal neurons showed reduced mEPSC frequency without significant measured arbor changes at the assessed time point.

PMID:31213987 SUPPORT Model Organism

"Collectively, these data show that Brpf1 haploinsufficiency causes reduced synaptic transmission and decreased cell excitability, which may contribute to abnormal behaviors."

Synaptic and behavioral deficits occur in the conditional heterozygous model, but their causal coupling was not tested by selective rescue.

PMID:37862219 SUPPORT Model Organism

"We found that the frequency but not the amplitude of mEPSCs decreased significantly"

Acute CA1 slices from six-month-old CaMKIIa-Cre conditional homozygous mice showed reduced mEPSC frequency, with amplitude and measured membrane properties preserved.

Reduced Inhibitory Neurotransmission in GABAergic Interneurons

Mechanism confidence: Provisional

Partial Brpf1 knockdown in cultured mouse MGE-derived GABAergic interneurons reduced miniature inhibitory postsynaptic current amplitude without a significant change in frequency. This synaptic readout is distinct from the intrinsic excitability changes measured in the same cultures. Dendritic morphology and transplanted-cell cortical distribution were not significantly altered under the tested conditions. The findings do not establish a human circuit-level excitation/inhibition ratio or a causal route to seizures.

MGE-derived GABAergic interneuron CL:0011005

inhibitory postsynaptic potential GO:0060080 ↓ DECREASED

Experimental models

Brpf1-knockdown mouse MGE-derived interneuron cultures PRIMARY CELL CULTURE Measures inhibitory postsynaptic currents after partial knockdown.

Show evidence (1 reference)

PMID:33744924 SUPPORT In Vitro

"The amplitude but not the frequency of mIPSCs decreased significantly"

Whole-cell recording at DIV15 after AAV-shBrpf1 infection at DIV3 found reduced mIPSC amplitude; frequency did not significantly differ.

Reduced Intrinsic Excitability of MGE-Derived GABAergic Interneurons

Mechanism confidence: Provisional

In cultured mouse MGE-derived interneurons, partial Brpf1 knockdown increased the injected-current threshold required to evoke action potentials and reduced spike counts at selected current steps. Resting membrane potential and maximum evoked firing frequency were unchanged. These cell-intrinsic responses are experimentally distinct from the reduced mIPSC amplitude and have not been tested as a cause of human cognitive or seizure phenotypes.

MGE-derived GABAergic interneuron CL:0011005

Experimental models

Brpf1-knockdown mouse MGE-derived interneuron cultures PRIMARY CELL CULTURE Current-clamp assays measure evoked firing.

Show evidence (1 reference)

PMID:33744924 SUPPORT In Vitro

"The AAV-shBrpf1 group required a larger incident current to induce the evoked APs, with a significant increase in the firing threshold"

Current-clamp recordings demonstrate increased threshold after partial knockdown, without a corresponding change in resting potential or maximum evoked frequency.

Impaired Learning and Memory

Mechanism confidence: Provisional

Behavioral effects vary across mouse preparations and tasks. Embryonic Emx1-lineage heterozygotes show water-maze learning and memory deficits and reduced contextual and cued freezing. Postnatal CaMKIIa-Cre conditional homozygotes show impaired spatial reference and contextual fear memory, with acquisition, cued fear memory and object recognition preserved at two months. Regional shRNA knockdown yielded only a behavioral tendency. These tests are not equivalent to human intellectual disability, which has variable expressivity.

Animal models

Postnatal hippocampal Brpf1 shRNA knockdown mouse Mus musculus measures

Emx1-lineage conditional Brpf1 heterozygous mouse Mus musculus partially recapitulates

Postnatal CaMKIIa-Cre conditional Brpf1 knockout mouse Mus musculus measures

Downstream

Intellectual Disability

Show evidence (3 references)

PMID:31213987 SUPPORT Model Organism

"Brpf1 HTs spent less time in the target quadrant where the platform was previously located"

Conditional heterozygous mice had reduced target-quadrant occupancy after water-maze training; contextual and cued fear-conditioning tests also showed reduced freezing.

PMID:37862219 SUPPORT Model Organism

"forebrain excitatory neuron-specific deletion ofBrpf1led to impaired contextual but not cued fear memory"

At two months, contextual freezing and spatial-reference probe performance were impaired, while cued freezing and acquisition latency were unchanged.

PMID:37862219 SUPPORT Model Organism

"The discrimination ratio of the cKO mice was similar to that of WT mice"

Novel-object recognition was unchanged at two months; the paper also reports preserved locomotion and no detected group difference in sociability or self-grooming.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

Blood 2

Anemia VERY_RARE HP:0001903

Frequency derivation: 1 of 25 patients with haematological data in Colson et al. 2025 had anaemia. 1/25 = 4%, which falls in the VERY_RARE band (<5%). The founding observation was a single Turkish family in which the feature was newly described.

Show evidence (2 references)

PMID:39837771 SUPPORT Human Clinical

"In our cohort, two different patients presented with haematopoietic abnormalities without evidence of bone marrow damage (7%, 1/25 with anaemia and 1/25 with thrombocytopenia)."

Anaemia in 1/25 = 4%, which falls in the VERY_RARE band (<5%).

PMID:37190896 SUPPORT Human Clinical

"Additionally, the patients had hematopoietic disorders such as anemia and thrombocytopenia, which have not been previously described in IDDDFP patients."

Single-family observation explicitly flagged by the authors as not previously described.

Thrombocytopenia VERY_RARE HP:0001873

Frequency derivation: 1 of 25 patients with haematological data in Colson et al. 2025 had thrombocytopenia. 1/25 = 4%, which falls in the VERY_RARE band (<5%).

Show evidence (2 references)

PMID:39837771 SUPPORT Human Clinical

"In our cohort, two different patients presented with haematopoietic abnormalities without evidence of bone marrow damage (7%, 1/25 with anaemia and 1/25 with thrombocytopenia)."

Thrombocytopenia in 1/25 = 4%, which falls in the VERY_RARE band (<5%).

PMID:37190896 SUPPORT Human Clinical

"Additionally, the patients had hematopoietic disorders such as anemia and thrombocytopenia, which have not been previously described in IDDDFP patients."

Same single-family, previously undescribed hematological observation.

Cardiovascular 2

Congenital Cardiac Anomalies VERY_RARE Abnormal heart morphology HP:0001627

The 2025 cohort reports one minor structural heart defect among 25 assessed patients (1/25, 4%). The literature aggregate of 9/49 includes atrioventricular nodal pauses and blocks as well as malformations, so it is not used as a frequency for abnormal heart morphology.

Show evidence (2 references)

PMID:39837771 SUPPORT Human Clinical

"Similarly, we observed one minor heart defect in our cohort (1/25)."

This is the structural finding in the new cohort, separate from the heterogeneous literature aggregate.

PMID:32010779 SUPPORT Human Clinical

"Cardiac anomalies are present in a subset of the cases."

Documents cardiac anomalies in a subset of the 12 newly identified BRPF1 cases.

Atrioventricular Block HP:0001678

Show evidence (1 reference)

PMID:39837771 SUPPORT Human Clinical

"atrioventricular (AV) nodal pauses and blocks"

The clinical literature synthesis identifies conduction findings in addition to structural defects; it does not give a block-specific frequency or establish the cardiac mechanism.

Digestive 3

Feeding Difficulties HP:0011968

Frequency deliberately omitted. Quotable denominators disagree across bands (12% versus 53-57%); the discrepancy most likely reflects ascertainment - earlier reports and the speech/feeding-focused cohort both enrich for oromotor involvement - but no source reconciles them, so no band is claimed.

Show evidence (2 references)

PMID:39837771 SUPPORT Human Clinical

"Feeding problems were observed in 12% of our series (3/26) compared with 57% of patients reported in the literature (24/42)."

Supports the disease-phenotype association and documents the cross-cohort disagreement (12% versus 57%) that is the stated reason no band is assigned.

PMID:38346666 SUPPORT Human Clinical

"Participants had vision impairment (13/15), fine (8/15) and gross motor delay (10/15) which often resolved in later childhood, infant feeding impairment (8/15), and infant hypotonia (9/15)."

Supports the disease-phenotype association; infant feeding impairment in 8 of 15 (53%) is one of the two irreconcilable estimates and is not used to assign a band.

Gastroesophageal Reflux FREQUENT HP:0002020

Frequency derivation: reflux in 9 of 29 patients (31%) in Colson et al. 2025 and 4 of 15 (27%) in the independent Morison cohort. 31% falls in the FREQUENT band (30-79%) at its lower edge; the second estimate sits just below in OCCASIONAL, so the band should be read as borderline.

Show evidence (1 reference)

PMID:39837771 SUPPORT Human Clinical

"oesophageal reflux was a common problem in our series, affecting 9 of 29 patients (31%), compared with 4 of 15 participants (27%) in the report by Morison and collaborators"

9/29 = 31%, which falls in the FREQUENT band (30-79%); the independent 27% estimate is at the OCCASIONAL/FREQUENT boundary.

Constipation OCCASIONAL HP:0002019

Frequency derivation: constipation in 14% of the 29-patient Colson et al. 2025 cohort. 14% falls in the OCCASIONAL band (5-29%).

Show evidence (1 reference)

PMID:39837771 SUPPORT Human Clinical

"A few patients had constipation (14%) and bulimia (14%)."

Constipation at 14% falls in the OCCASIONAL band (5-29%).

Eye 11

Ptosis FREQUENT HP:0000508

Frequency derivation: Colson et al. 2025 report ptosis in 20 of 29 patients. 20/29 = 69%, which falls in the FREQUENT band (30-79%). This is the eponymous feature of IDDDFP and the highest-frequency craniofacial sign in the cohort, but it is not obligate.

Show evidence (3 references)

PMID:39837771 SUPPORT Human Clinical

"Common features associated with IDDDFP included blepharophimosis (10/29; 34%), hypertelorism (14/29; 48%), ptosis (20/29; 69%), and a round face (17/27; 63%)"

Ptosis in 20/29 (69%) falls in the FREQUENT band (30-79%).

PMID:37946714 SUPPORT Human Clinical

"Bromodomain and PHD finger containing 1 (BRPF1)-related neurodevelopmental disorder is characterized by intellectual disability, developmental delay, hypotonia, dysmorphic facial features, ptosis, and blepharophimosis."

Ptosis is listed as a defining characteristic of the disorder.

PMID:40752867 SUPPORT Human Clinical

"We report the case of a 2-year-old girl who presented with drooping of the left upper lid since birth and who was ultimately diagnosed with IDDDFP."

Illustrates congenital, unilateral ptosis as the presenting feature leading to diagnosis.

Strabismus FREQUENT HP:0000486

Colson et al. 2025 report strabismus in 13/27 assessed patients (48%) in the discussion and Table 2, supporting FREQUENT. The denominator is those with recorded strabismus status, not the full 29-patient cohort.

Show evidence (2 references)

PMID:39837771 SUPPORT Human Clinical

"Ophthalmological abnormalities were found in 19 patients (66%), with strabismus present in 13 patients (48%)."

Strabismus in 48% falls in the FREQUENT band (30-79%); ocular abnormalities overall reach 66%.

PMID:38590032 SUPPORT Human Clinical

"The reported ocular involvement includes strabismus, amblyopia, and refraction errors."

Lists strabismus among the established ocular manifestations.

Amblyopia OCCASIONAL HP:0000646

Frequency derivation: amblyopia in 3 of 29 patients in Colson et al. 2025. 3/29 = 10%, which falls in the OCCASIONAL band (5-29%). The same paper describes amblyopia as a sporadic finding in the wider literature.

Show evidence (3 references)

PMID:39837771 SUPPORT Human Clinical

"Our cohort had similar findings: strabismus (13/27), myopia (5/29), hypermetropia (2/29), nystagmus (2/29), amblyopia (3/29) and cataract (1/29)."

Amblyopia in 3/29 = 10%, which falls in the OCCASIONAL band (5-29%).

PMID:38590032 SUPPORT Human Clinical

"The reported ocular involvement includes strabismus, amblyopia, and refraction errors."

Amblyopia is an established component of the ocular phenotype.

PMID:31176769 SUPPORT Human Clinical

"with refraction problems, amblyopia and strabism as other reported ophthalmological features"

Independently confirms amblyopia among reported ophthalmological features.

Iris Coloboma VERY_RARE HP:0000612

Frequency derivation: Colson et al. 2025 describe coloboma among the sporadic ocular findings of the literature and record none in their own 29-patient cohort (their ocular tally lists strabismus, myopia, hypermetropia, nystagmus, amblyopia and cataract, but no coloboma). The author wording "sporadic cases" maps to VERY_RARE (<5%) under the DisMech qualitative mapping.

Show evidence (3 references)

PMID:39837771 SUPPORT Human Clinical

"In the literature, patients (41/53) are mainly reported to have visual impairments including strabismus, hypermetropia and myopia, with sporadic cases of coloboma, microphthalmia, nystagmus and amblyopia"

Author wording "sporadic cases" of coloboma maps to VERY_RARE (<5%) under the DisMech qualitative mapping.

PMID:31176769 SUPPORT Human Clinical

"He presented with ID, bilateral iris colobomas, facial nerve palsy and severe hypoplasia of the corpus callosum."

Reports bilateral iris coloboma in a BRPF1 nonsense-variant carrier.

PMID:31176769 SUPPORT Human Clinical

"indicates coloboma and facial nerve palsy as possible additional features of IDDDFP syndrome"

The authors frame coloboma as a possible, not established, feature.

Subclinical Optic Neuropathy HP:0001138

Frequency deliberately omitted. The only source is a two-patient OCT series with no cohort denominator, and because detection requires OCT the observed rate in any cohort not systematically imaged is uninformative. Colson et al. 2025 note only that two patients with frameshift variants have been described with optic neuropathy.

Show evidence (2 references)

PMID:38590032 SUPPORT Human Clinical

"Having detected a peculiar ocular phenotype in P1, we suggested optical coherence tomography (OCT) for P2; such an exam also detected bilateral subclinical optic neuropathy in this case."

Documents subclinical optic neuropathy in both reported patients, detected by OCT.

PMID:38590032 SUPPORT Human Clinical

"To date, only a few patients with BRPF1 variants have been described, and none were reported to have optic neuropathy."

Makes explicit that this is a novel observation in a very small number of patients.

Hypertelorism FREQUENT HP:0000316

Frequency derivation: hypertelorism in 14 of 29 patients in Colson et al. 2025. 14/29 = 48%, which falls in the FREQUENT band (30-79%).

Show evidence (2 references)

PMID:39837771 SUPPORT Human Clinical

"Common features associated with IDDDFP included blepharophimosis (10/29; 34%), hypertelorism (14/29; 48%), ptosis (20/29; 69%), and a round face (17/27; 63%)"

Hypertelorism in 14/29 (48%) falls in the FREQUENT band (30-79%).

PMID:31020800 SUPPORT Human Clinical

"he showed dysmorphic facial features, most notably bilateral ptosis, hypertelorism and downslanted palpebral fissures"

Independent documentation of hypertelorism in a BRPF1 multiplex family proband.

Visual Impairment VERY_FREQUENT HP:0000505

The frequency describes the small speech-ascertained cohort (13/15), not an unbiased population estimate. The 41/53 literature aggregate is not used as an acuity-deficit denominator because it pools different ocular findings.

Show evidence (1 reference)

PMID:38346666 SUPPORT Human Clinical

"Participants had vision impairment (13/15), fine (8/15) and gross motor delay (10/15) which often resolved in later childhood, infant feeding impairment (8/15), and infant hypotonia (9/15)."

The authors report vision impairment in 13/15 participants; ascertainment and endpoint definitions limit generalization.

Refractive Error OCCASIONAL Abnormality of refraction HP:0000539

Frequency derivation: refractive disorders in seven of 29 patients in Colson et al. 2025. 7/29 = 24%, which falls in the OCCASIONAL band (5-29%), comprising myopia 5/29 and hypermetropia 2/29.

Show evidence (2 references)

PMID:39837771 SUPPORT Human Clinical

"Refractive disorders were found in seven patients (24%)"

Refractive error in 7/29 (24%) falls in the OCCASIONAL band (5-29%).

PMID:38590032 SUPPORT Human Clinical

"The reported ocular involvement includes strabismus, amblyopia, and refraction errors."

Lists refraction errors among the established ocular manifestations.

Myopia OCCASIONAL HP:0000545

Frequencies, where supplied, summarize reported 2025 cohort counts and are subject to ascertainment and incomplete assessment.

Show evidence (1 reference)

PMID:39837771 SUPPORT Human Clinical

"| Myopia | 5/29 (17%) | N/A |"

The source summary table explicitly records this finding; source inconsistencies are retained in the description.

Hypermetropia OCCASIONAL HP:0000540

Frequencies, where supplied, summarize reported 2025 cohort counts and are subject to ascertainment and incomplete assessment.

Show evidence (1 reference)

PMID:39837771 SUPPORT Human Clinical

"| Hypermetropia | 2/29 (7%) | 6 (N/A) |"

The source summary table explicitly records this finding; source inconsistencies are retained in the description.

Horizontal Nystagmus OCCASIONAL HP:0000666

Frequencies, where supplied, summarize reported 2025 cohort counts and are subject to ascertainment and incomplete assessment.

Show evidence (1 reference)

PMID:39837771 SUPPORT Human Clinical

"| Horizontal nystagmus | 2/29 (7%) | 1 (N/A) |"

The source summary table explicitly records this finding; source inconsistencies are retained in the description.

Genitourinary 1

Cryptorchidism HP:0000028

The 2025 summary reports 5/27 across the cohort, not a male-only denominator, and reports a different percentage elsewhere. A male-specific frequency cannot be inferred from this aggregate. Its statement that cryptorchidism had not previously been reported conflicts with the founding 2017 report.

Show evidence (2 references)

PMID:39837771 SUPPORT Human Clinical

"occurring in 5 of 27 patients (19%)."

Reports five affected patients; the aggregate denominator and inconsistent percentages do not establish a male-specific frequency.

PMID:27939639 SUPPORT Human Clinical

"He had surgery for his ptosis and for cryptorchidism."

The founding family already included cryptorchidism requiring surgery, contradicting the later claim of novelty.

Head and Neck 18

Blepharophimosis FREQUENT HP:0000581

Frequency derivation: blepharophimosis in 10 of 29 patients in Colson et al. 2025. 10/29 = 34%, which falls in the FREQUENT band (30-79%), at its lower edge.

Show evidence (3 references)

PMID:39837771 SUPPORT Human Clinical

"Common features associated with IDDDFP included blepharophimosis (10/29; 34%), hypertelorism (14/29; 48%), ptosis (20/29; 69%), and a round face (17/27; 63%)"

Blepharophimosis in 10/29 (34%) falls in the FREQUENT band (30-79%).

PMID:31176769 SUPPORT Human Clinical

"Besides intellectual disability (ID), ptosis and blepharophimosis are frequent findings, with refraction problems, amblyopia and strabism as other reported ophthalmological features."

Describes blepharophimosis as a frequent finding across reported patients.

PMID:39837771 SUPPORT Human Clinical

"characteristic dysmorphic facial features such as ptosis, blepharophimosis and a broad nasal bridge"

The largest cohort lists blepharophimosis among the characteristic facial features.

Downslanted Palpebral Fissures HP:0000494

Frequency deliberately omitted. Colson et al. 2025 tabulate up-slanting (7/29) and narrow (10/29) palpebral fissures but do not report a downslanting count, and the only quotable source here is a four-member single family in which all four were affected - a denominator too small and too ascertainment-biased to support a population band.

Show evidence (1 reference)

PMID:31020800 SUPPORT Human Clinical

"The four affected individuals showed varying degrees of intellectual disability, distinct facial features including downslanted palpebral fissures, ptosis, and/or blepharophimosis."

All four affected family members had downslanted palpebral fissures.

Broad Nasal Bridge Wide nasal bridge HP:0000431

Frequency deliberately omitted. The largest cohort names a broad nasal bridge among the characteristic features but reports a count only for bulbous nose (14/28), not for the nasal bridge itself, so no numerator and denominator exist to derive a band from.

Show evidence (1 reference)

PMID:39837771 SUPPORT Human Clinical

"characteristic dysmorphic facial features such as ptosis, blepharophimosis and a broad nasal bridge"

Names broad nasal bridge as a characteristic facial feature.

Retrognathia FREQUENT HP:0000278

Frequency derivation: retrognathia in 12 of 29 patients in Colson et al. 2025. 12/29 = 41%, which falls in the FREQUENT band (30-79%).

Show evidence (2 references)

PMID:39837771 SUPPORT Human Clinical

"Other notable features included up slanting palpebral fissures (7/29; 24%), epicanthus (12/29; 41%, with epicanthus inversus in 5/29), narrow palpebral fissures (10/29; 34%), palpebral oedema (8/29; 28%), low columella (9/29; 31%), bulbous nose (14/28; 50%), high palate (14/29; 48%), and..."

Retrognathia in 12/29 (41%) falls in the FREQUENT band (30-79%).

PMID:37190896 SUPPORT Human Clinical

"The patients demonstrated classical features of IDDDFP such as intellectual disability, developmental delay, ptosis, micro and retrognathia, and dysmorphic facial features, in addition to the anemia and thrombocytopenia."

Lists retrognathia among the classical IDDDFP features.

Palpebral Edema OCCASIONAL HP:0100540

Frequency derivation: palpebral oedema in 8 of 29 patients in Colson et al. 2025. 8/29 = 28%, which falls in the OCCASIONAL band (5-29%).

Show evidence (2 references)

PMID:39837771 SUPPORT Human Clinical

"palpebral oedema (8/29; 28%)"

Palpebral oedema in 8/29 (28%) falls in the OCCASIONAL band (5-29%).

PMID:39837771 SUPPORT Human Clinical

"New phenotypic features identified include palpebral oedema, laterally elongated eyebrows, low hanging columella and hypertrichosis."

Identifies palpebral oedema as a newly described feature of the disorder.

Facial Nerve Palsy Facial palsy HP:0010628

Frequency deliberately omitted. Single-case evidence with no denominator; the feature is not tabulated in any BRPF1 cohort, including the 29-patient 2025 series.

Show evidence (1 reference)

PMID:31176769 SUPPORT Human Clinical

"indicates coloboma and facial nerve palsy as possible additional features of IDDDFP syndrome"

Proposed by the authors as a possible additional feature on single-case evidence.

Round Face FREQUENT HP:0000311

Frequency derivation: round face in 17 of 27 patients in Colson et al. 2025. 17/27 = 63%, which falls in the FREQUENT band (30-79%).

Show evidence (2 references)

PMID:39837771 SUPPORT Human Clinical

"Common features associated with IDDDFP included blepharophimosis (10/29; 34%), hypertelorism (14/29; 48%), ptosis (20/29; 69%), and a round face (17/27; 63%)"

Round face in 17/27 (63%) falls in the FREQUENT band (30-79%).

ORPHA:698090 SUPPORT Other

"dysmorphic facial features such as ptosis and round face"

Orphanet's definition of the disorder names round face alongside ptosis as the defining dysmorphic features.

Bulbous Nose FREQUENT HP:0000414

Frequency derivation: bulbous nose in 14 of 28 patients in Colson et al. 2025. 14/28 = 50%, which falls in the FREQUENT band (30-79%).

Show evidence (1 reference)

PMID:39837771 SUPPORT Human Clinical

"bulbous nose (14/28; 50%)"

Bulbous nose in 14/28 (50%) falls in the FREQUENT band (30-79%).

High Palate FREQUENT HP:0000218

Frequency derivation: high palate in 14 of 29 patients in Colson et al. 2025. 14/29 = 48%, which falls in the FREQUENT band (30-79%).

Show evidence (1 reference)

PMID:39837771 SUPPORT Human Clinical

"high palate (14/29; 48%)"

High palate in 14/29 (48%) falls in the FREQUENT band (30-79%).

Epicanthus FREQUENT HP:0000286

Frequency derivation: epicanthus in 12 of 29 patients in Colson et al. 2025. 12/29 = 41%, which falls in the FREQUENT band (30-79%). Epicanthus inversus specifically was present in 5/29 (17%, OCCASIONAL).

Show evidence (2 references)

PMID:39837771 SUPPORT Human Clinical

"epicanthus (12/29; 41%, with epicanthus inversus in 5/29)"

Epicanthus in 12/29 (41%) falls in the FREQUENT band (30-79%); the inversus subtype is separately quantified at 5/29.

PMID:32457794 SUPPORT Human Clinical

"epicanthic folds and hypertelorism"

Independent documentation of epicanthal folds in a BRPF1 missense-variant carrier.

Synophrys FREQUENT HP:0000664

Frequency derivation: synophrys in 10 of 28 patients in Colson et al. 2025. 10/28 = 36%, which falls in the FREQUENT band (30-79%).

Show evidence (1 reference)

PMID:39837771 SUPPORT Human Clinical

"synophrys (10/28; 36%)"

Synophrys in 10/28 (36%) falls in the FREQUENT band (30-79%).

Laterally Extended Eyebrows OCCASIONAL HP:0011230

Frequency derivation: laterally extended eyebrows in 8 of 29 patients in Colson et al. 2025. 8/29 = 28%, which falls in the OCCASIONAL band (5-29%).

Show evidence (1 reference)

PMID:39837771 SUPPORT Human Clinical

"laterally extended eyebrows (8/29, 28%)"

Laterally extended eyebrows in 8/29 (28%) fall in the OCCASIONAL band (5-29%).

Low Hanging Columella FREQUENT HP:0009765

Frequency derivation: low columella in 9 of 29 patients in Colson et al. 2025. 9/29 = 31%, which falls in the FREQUENT band (30-79%), at its lower edge.

Show evidence (1 reference)

PMID:39837771 SUPPORT Human Clinical

"low columella (9/29; 31%)"

Low columella in 9/29 (31%) falls in the FREQUENT band (30-79%).

Microcephaly OCCASIONAL HP:0000252

Frequency derivation: two of 29 patients in Colson et al. 2025 had congenital microcephaly and none acquired it. 2/29 = 7%, which falls in the OCCASIONAL band (5-29%). Earlier reports give higher rates, which is consistent with the historical over-representation of contiguous 3p25 deletions.

Show evidence (2 references)

PMID:39837771 SUPPORT Human Clinical

"With the exception of two patients with congenital microcephaly, microcephaly was not observed in the cohort."

2/29 = 7%, which falls in the OCCASIONAL band (5-29%).

PMID:31020800 SUPPORT Human Clinical

"Their data demonstrated that microcephaly and ptosis (either unilateral or bilateral) and/or blepharophimosis were significantly more common in those with BRPF1 disruptions"

Attributes microcephaly within the 3p25 deletion region specifically to BRPF1 dosage rather than to SETD5.

Upslanted Palpebral Fissures OCCASIONAL HP:0000582

Frequencies, where supplied, summarize reported 2025 cohort counts and are subject to ascertainment and incomplete assessment.

Show evidence (1 reference)

PMID:39837771 SUPPORT Human Clinical

"| Upslanted palpebral fissure | 7/29 (24%) | 4 (N/A) |"

The source summary table explicitly records this finding; source inconsistencies are retained in the description.

Plagiocephaly OCCASIONAL HP:0001357

Frequencies, where supplied, summarize reported 2025 cohort counts and are subject to ascertainment and incomplete assessment.

Show evidence (1 reference)

PMID:39837771 SUPPORT Human Clinical

"| Plagiocephaly | 2/28 (7%) | N/A |"

The source summary table explicitly records this finding; source inconsistencies are retained in the description.

Facial Asymmetry OCCASIONAL HP:0000324

Frequency describes the reported cohort, with incomplete assessment and ascertainment limitations.

Show evidence (1 reference)

PMID:39837771 SUPPORT Human Clinical

"| Facial asymmetry | 3/28 (11%) | 3 (N/A) |"

The summary table explicitly records this finding and denominator.

Epicanthus Inversus OCCASIONAL HP:0000537

Frequency describes the reported cohort, with incomplete assessment and ascertainment limitations.

Show evidence (1 reference)

PMID:39837771 SUPPORT Human Clinical

"| Epicanthus inversus | 5/29 (17%) | N/A |"

The summary table explicitly records this finding and denominator.

Immune 1

Recurrent Viral Infections OCCASIONAL HP:0004429

Frequencies, where supplied, summarize reported 2025 cohort counts and are subject to ascertainment and incomplete assessment.

Show evidence (1 reference)

PMID:39837771 SUPPORT Human Clinical

"| Recurrent viral infections | 4/28 (14%) | N/A |"

The source summary table explicitly records this finding; source inconsistencies are retained in the description.

Integument 3

Hypertrichosis FREQUENT HP:0000998

Frequency derivation: hypertrichosis, mostly on the back and arms, in 9 of 29 patients in Colson et al. 2025. 9/29 = 31%, which falls in the FREQUENT band (30-79%), at its lower edge.

Show evidence (2 references)

PMID:39837771 SUPPORT Human Clinical

"Cutaneous abnormalities were observed in approximately one third of the cohort, including laterally extended eyebrows (8/29, 28%), hypertrichosis, mostly on the back and arms (9/29; 31%), synophrys (10/28; 36%), and various hair abnormalities (12/29; 41%), such as fine hair, sparse hair, low..."

Hypertrichosis in 9/29 (31%) falls in the FREQUENT band (30-79%).

PMID:39837771 SUPPORT Human Clinical

"New phenotypic features identified include palpebral oedema, laterally elongated eyebrows, low hanging columella and hypertrichosis."

Names hypertrichosis as a newly recognized feature.

Hair Abnormalities FREQUENT Abnormal hair morphology HP:0001595

Frequency derivation: various hair abnormalities in 12 of 29 patients in Colson et al. 2025. 12/29 = 41%, which falls in the FREQUENT band (30-79%).

Show evidence (1 reference)

PMID:39837771 SUPPORT Human Clinical

"various hair abnormalities (12/29; 41%), such as fine hair, sparse hair, low posterior hairline, and high anterior hairline."

Hair abnormalities in 12/29 (41%) fall in the FREQUENT band (30-79%).

Prominent Fingertip Pads OCCASIONAL HP:0001212

Frequency derivation: prominent fingertip pads in 6 of 27 patients in Colson et al. 2025. 6/27 = 22%, which falls in the OCCASIONAL band (5-29%).

Show evidence (1 reference)

PMID:39837771 SUPPORT Human Clinical

"prominent fingertip pads in six patients (6/27; 22%)"

Prominent fingertip pads in 6/27 (22%) fall in the OCCASIONAL band (5-29%).

Limbs 4

Clinodactyly of the Fifth Finger FREQUENT Clinodactyly of the 5th finger HP:0004209

Frequency derivation: clinodactyly of the fifth digit in 8 of 27 patients in Colson et al. 2025. 8/27 = 30%, which falls in the FREQUENT band (30-79%), exactly at its lower boundary.

Show evidence (1 reference)

PMID:39837771 SUPPORT Human Clinical

"No abnormalities were noted in the extremities, except for clinodactyly of the fifth digit in eight patients (8/27; 30%), prominent fingertip pads in six patients (6/27; 22%), and small hands with a wide hallux in four patients (4/23; 17%)"

Clinodactyly of the fifth digit in 8/27 (30%) falls in the FREQUENT band (30-79%) at its boundary.

Small Hands OCCASIONAL HP:0200055

Frequencies, where supplied, summarize reported 2025 cohort counts and are subject to ascertainment and incomplete assessment.

Show evidence (1 reference)

PMID:39837771 SUPPORT Human Clinical

"| Small hand | 4/27 (15%) | 5/25 (20%) |"

The source summary table explicitly records this finding; source inconsistencies are retained in the description.

Broad Hallux OCCASIONAL HP:0010055

Frequencies, where supplied, summarize reported 2025 cohort counts and are subject to ascertainment and incomplete assessment.

Show evidence (1 reference)

PMID:39837771 SUPPORT Human Clinical

"| Broad hallux | 4/27 (15%) | N/A |"

The source summary table explicitly records this finding; source inconsistencies are retained in the description.

Talipes Equinovarus VERY_RARE HP:0001762

Frequencies, where supplied, summarize reported 2025 cohort counts and are subject to ascertainment and incomplete assessment.

Show evidence (1 reference)

PMID:39837771 SUPPORT Human Clinical

"| Talipes equinovarus | 1/28 (4%) | 3 (N/A) |"

The source summary table explicitly records this finding; source inconsistencies are retained in the description.

Musculoskeletal 4

Infantile Hypotonia FREQUENT HP:0001252

Frequency derivation: two independent cohorts agree on the band - infant hypotonia in 9/15 (60%) in the speech-phenotyping cohort (PMID:38346666) and hypotonia in 11/29 (approximately 38%; reported as 40%) in Colson et al. 2025. Both fall in the FREQUENT band (30-79%).

Show evidence (3 references)

PMID:39837771 SUPPORT Human Clinical

"Hypotonia was observed in 11 patients (40%), including one with neonatal hypotonia."

The paper reports 11/29 with hypotonia and rounds this to 40%. The calculated proportion is approximately 38%; both are FREQUENT.

PMID:38346666 SUPPORT Human Clinical

"Participants had vision impairment (13/15), fine (8/15) and gross motor delay (10/15) which often resolved in later childhood, infant feeding impairment (8/15), and infant hypotonia (9/15)."

Infant hypotonia in 9 of 15 (60%) supports the FREQUENT band.

PMID:27939640 SUPPORT Human Clinical

"Symptoms include infantile hypotonia, global developmental delay, intellectual disability, expressive language impairment, and facial dysmorphisms."

Independently lists infantile hypotonia as a core symptom.

Muscle Weakness HP:0001324

Frequency deliberately omitted. Weakness is named in the founding series and in a single case report but is not tabulated separately from hypotonia in any cohort, so no numerator and denominator exist for it.

Show evidence (1 reference)

PMID:35243762 SUPPORT Human Clinical

"Here, we describe a patient with normal intellectual development who had congenital ptosis, hypotonia, muscular weakness, atlanto-axial malformation, and pyramidal at the neurological examination."

Documents muscular weakness in a BRPF1 variant carrier.

Distal Joint Hypermobility OCCASIONAL HP:0020152

Frequencies, where supplied, summarize reported 2025 cohort counts and are subject to ascertainment and incomplete assessment.

Show evidence (1 reference)

PMID:39837771 SUPPORT Human Clinical

"| Distal joint laxity | 7/27 (26%) | 5 (N/A) |"

The source summary table explicitly records this finding; source inconsistencies are retained in the description.

Scoliosis OCCASIONAL HP:0002650

Frequencies, where supplied, summarize reported 2025 cohort counts and are subject to ascertainment and incomplete assessment.

Show evidence (1 reference)

PMID:39837771 SUPPORT Human Clinical

"| Scoliosis | 2/27 (7%) | N/A |"

The source summary table explicitly records this finding; source inconsistencies are retained in the description.

Nervous System 18

Global Developmental Delay FREQUENT HP:0001263

The two panels of Table 1 in Colson et al. 2025 record global developmental delay as present in 14 patients, absent in nine and unavailable in six. Among the 23 with recorded status, 14/23 is approximately 61%, supporting FREQUENT. This is a derived table count, distinct from the paper's 16/29 intellectual-disability count and its combined ID/DD wording.

Show evidence (4 references)

PMID:39837771 SUPPORT Human Clinical

"| Global developmental delay | N | Y | Y | Y | Y | Y | Y | N | Y | Y | N | Y | Y | N |"

Table 1, panel 1, provides individual global developmental delay status. Across both panels there are 14 Y, nine N and six N/A entries; only the 23 patients with known status form the frequency denominator.

PMID:39837771 SUPPORT Human Clinical

"| Global developmental delay | Y | N | N | Y | N | N | Y | Y | N/A | N | N/A | N/A | N/A | N/A | N/A |"

Table 1, panel 2, provides individual global developmental delay status. Across both panels there are 14 Y, nine N and six N/A entries; only the 23 patients with known status form the frequency denominator.

PMID:27939640 SUPPORT Human Clinical

"Symptoms include infantile hypotonia, global developmental delay, intellectual disability, expressive language impairment, and facial dysmorphisms."

Lists global developmental delay among the core symptoms of the founding ten-individual series.

+ 1 more reference

Intellectual Disability FREQUENT HP:0001249

Frequency derivation: Colson et al. 2025 report ID in 16 of 29 patients with available data (55%), of whom six were mild and 10 moderate. 16/29 = 55%, which falls in the FREQUENT band (30-79%). The band is not OBLIGATE: a speech-ascertained cohort found FSIQ >= 70 in all four formally tested participants (PMID:38346666) and at least one carrier has normal intellect (PMID:35243762).

Show evidence (4 references)

PMID:39837771 SUPPORT Human Clinical

"Of the 29 patients with available data, 16 (55%) presented with ID of varying severity: six patients had mild ID, while 10 patients had moderate ID."

16/29 = 55%, which falls in the FREQUENT band (30-79%), and gives the mild/moderate severity split.

PMID:39837771 SUPPORT Human Clinical

"Neuropsychological assessment reveals a predominance of mild to moderate ID, with cognitive profiles showing variability in verbal and visual processing."

Establishes the mild-to-moderate severity distribution in the largest cohort.

PMID:38346666 SUPPORT Human Clinical

"All those tested for cognitive abilities had a FSIQ ≥70 (4/4)."

Qualifies the claim: in a speech-ascertained cohort, formally tested individuals were not in the intellectual disability range.

+ 1 more reference

Speech and Language Disorder Delayed speech and language development HP:0000750

A single frequency band is not assigned across different endpoints and assessment methods: language disorder was found in 11/12 formally assessed participants in the dedicated study, while delayed speech and language development was reported in 13/28 (46%) in Table 2 of the 2025 cohort. Neither figure establishes universal impairment across all BRPF1 carriers.

Show evidence (3 references)

PMID:39837771 SUPPORT Human Clinical

"Delayed speech and language development were noted in 13 patients (46%)."

Table 2 specifies the denominator as 28: 13/28 is 46%. This concerns delayed speech-language milestones and cannot be equated directly with the formal language-disorder assessment in the separate study.

PMID:38346666 SUPPORT Human Clinical

"Language disorders were common (11/12), and most had mild to moderate deficits across receptive, expressive, written, and social-pragmatic domains."

Language disorder occurred in 11/12 assessed participants in this study; the frequency is specific to this assessment and cohort.

PMID:38346666 SUPPORT Human Clinical

"The universal involvement of speech and language impairment ... relative to the high degree of phenotypic variability in BRPF1-related disorder."

The speech-ascertained study describes widespread involvement; its wording does not establish universal penetrance in an unselected population.

Childhood Apraxia of Speech FREQUENT Speech apraxia HP:0011098

Frequency derivation: childhood apraxia of speech in 3 of 9 formally assessed participants (PMID:38346666). 3/9 = 33%, which falls in the FREQUENT band (30-79%). The denominator is small and speech-ascertained, so the estimate is provisional.

Show evidence (1 reference)

PMID:38346666 SUPPORT Human Clinical

"Speech disorders were frequent (7/9), including phonological delay (6/9) and disorder (3/9), and childhood apraxia of speech (3/9)."

Childhood apraxia of speech in 3 of 9 assessed (33%) falls in the FREQUENT band.

Motor Delay FREQUENT HP:0001270

Frequency derivation: gross motor delay 10/15 (67%) and fine motor delay 8/15 (53%) in the speech-phenotyping cohort (PMID:38346666), and motor delay in 52% of Colson et al. 2025. All three figures fall in the FREQUENT band (30-79%).

Show evidence (2 references)

PMID:39837771 SUPPORT Human Clinical

"Most patients had motor delay (52%)."

52% in the largest cohort, which falls in the FREQUENT band (30-79%).

PMID:38346666 SUPPORT Human Clinical

"Participants had vision impairment (13/15), fine (8/15) and gross motor delay (10/15) which often resolved in later childhood, infant feeding impairment (8/15), and infant hypotonia (9/15)."

Gross motor delay in 10 of 15 (67%) and fine motor delay in 8 of 15 (53%) both fall in the FREQUENT band.

Hypoplasia of the Corpus Callosum HP:0002079

No subtype-specific denominator is available from the cited case report. The historical 5/22 figure concerns all structural brain abnormalities and is not a hypoplasia frequency or an imaging-only denominator.

Show evidence (1 reference)

PMID:31176769 SUPPORT Human Clinical

"He presented with ID, bilateral iris colobomas, facial nerve palsy and severe hypoplasia of the corpus callosum."

Directly identifies severe callosal hypoplasia in the reported patient.

Seizures OCCASIONAL HP:0001250

Frequency derivation: epilepsy documented in 4 of 29 patients in Colson et al. 2025. 4/29 = 14%, which falls in the OCCASIONAL band (5-29%).

Show evidence (2 references)

PMID:39837771 SUPPORT Human Clinical

"Epilepsy was documented in 4 patients (14%) and 18 patients (62%) had behavioural disorders, including attention deficit/hyperactivity (33%), low frustration tolerance (29%), inappropriate laughter (14%), anxiety (21%), agitation (15%) and autistic behaviour (15%)."

Epilepsy in 4/29 (14%) falls in the OCCASIONAL band (5-29%).

PMID:35243762 SUPPORT Human Clinical

"In 2017, Mattiolli et al. and Yan et al. described a series of patients with clinical findings essentially characterized by intellectual disabilities, ptosis, hypotonia, epilepsy, and weakness."

Epilepsy is listed among the findings of the two founding series.

Attention Deficit Hyperactivity Disorder FREQUENT HP:0007018

Frequency derivation: attention deficit/hyperactivity in 33% of the 29-patient Colson et al. 2025 cohort, reported as a component of the 62% with any behavioural disorder. 33% falls in the FREQUENT band (30-79%).

Show evidence (2 references)

PMID:39837771 SUPPORT Human Clinical

"18 patients (62%) had behavioural disorders, including attention deficit/hyperactivity (33%), low frustration tolerance (29%), inappropriate laughter (14%), anxiety (21%), agitation (15%) and autistic behaviour (15%)."

Attention deficit/hyperactivity at 33% falls in the FREQUENT band (30-79%).

PMID:37946714 SUPPORT Human Clinical

"Their history of mild intellectual disability, speech delay, attention deficient hyperactivity disorder (ADHD), and ptosis align with the features previously reported in the literature."

Reports ADHD in two affected sisters and states it aligns with previously reported features.

Behavioural Disorder FREQUENT Atypical behavior HP:0000708

Frequency derivation: 18 of 29 patients (62%) in Colson et al. 2025 had behavioural disorders. 62% falls in the FREQUENT band (30-79%). The HPO term label is "Atypical behavior"; the preferred_term keeps the clinical wording used by the source. The source also reports a combined aggressive/impulsive/violent category (6/27) and labels food-intake behavior as bulimia (4/29), without documenting diagnostic criteria or compensatory purging; these data do not establish bulimia nervosa.

Show evidence (1 reference)

PMID:39837771 SUPPORT Human Clinical

Any behavioural disorder in 62% falls in the FREQUENT band (30-79%), with the component behaviours itemized.

Anxiety OCCASIONAL HP:0000739

Frequency derivation: anxiety in 21% of the 29-patient Colson et al. 2025 cohort. 21% falls in the OCCASIONAL band (5-29%).

Show evidence (1 reference)

PMID:39837771 SUPPORT Human Clinical

"anxiety (21%)"

Anxiety at 21% falls in the OCCASIONAL band (5-29%).

Autistic Behavior OCCASIONAL HP:0000729

Frequency derivation: autistic behaviour in 15% of the 29-patient Colson et al. 2025 cohort. 15% falls in the OCCASIONAL band (5-29%).

Show evidence (2 references)

PMID:39837771 SUPPORT Human Clinical

"autistic behaviour (15%)"

Autistic behaviour at 15% falls in the OCCASIONAL band (5-29%).

PMID:32010779 SUPPORT In Vitro

"These results indicate that BRPF1 dysfunction also contributes to autism spectrum disorder"

Functional support for a BRPF1 contribution to autism, based on a single variant found in an autistic individual; not a frequency claim.

Sleep Disturbance FREQUENT HP:0002360

Frequency derivation: sleep disturbance reported by nine of 29 patients in Colson et al. 2025. 9/29 = 31%, which falls in the FREQUENT band (30-79%), at its lower edge.

Show evidence (1 reference)

PMID:39837771 SUPPORT Human Clinical

"Sleep disturbance was reported by nine patients (31%)."

Sleep disturbance in 9/29 (31%) falls in the FREQUENT band (30-79%).

Chiari Type I Malformation HP:0007099

Frequency deliberately omitted. The largest cohort reports cerebral malformations collectively (13/26 in the literature, 3/17 in their own imaged patients) without breaking out a Chiari-specific count, and the only individually reported case has no denominator.

Show evidence (2 references)

PMID:38590032 SUPPORT Human Clinical

"P1 had a Chiari Malformation type I and a subclinical optic neuropathy, which could not be explained by variations in other genes."

Documents Chiari type I malformation in a BRPF1 variant carrier, with other genetic causes excluded.

PMID:39837771 SUPPORT Human Clinical

"Cerebral malformations are commonly reported in the literature (13/26), including periventricular nodular heterotopia, Arnold-Chiari malformation and abnormalities of the corpus callosum"

Places Arnold-Chiari malformation within the reported spectrum of BRPF1 cerebral malformations, without a Chiari-specific denominator.

Inappropriate Laughter OCCASIONAL HP:0000748

Frequencies, where supplied, summarize reported 2025 cohort counts and are subject to ascertainment and incomplete assessment.

Show evidence (1 reference)

PMID:39837771 SUPPORT Human Clinical

"| Inappropriate laughter | 4/25 (14%) | N/A |"

The source summary table explicitly records this finding; source inconsistencies are retained in the description.

Low Frustration Tolerance OCCASIONAL HP:0000744

Frequencies, where supplied, summarize reported 2025 cohort counts and are subject to ascertainment and incomplete assessment.

Show evidence (1 reference)

PMID:39837771 SUPPORT Human Clinical

"| Low frustration tolerance | 8/28 (29%) | N/A |"

The source summary table explicitly records this finding; source inconsistencies are retained in the description.

Agitation OCCASIONAL HP:0000713

Frequencies, where supplied, summarize reported 2025 cohort counts and are subject to ascertainment and incomplete assessment.

Show evidence (1 reference)

PMID:39837771 SUPPORT Human Clinical

"| Agitation | 4/27 (15%) | N/A |"

The source summary table explicitly records this finding; source inconsistencies are retained in the description.

Impulsivity HP:0100710

Show evidence (1 reference)

PMID:39837771 SUPPORT Human Clinical

"Impulsive behavior, low frustration tolerance"

Individual patient entries in Table 1 explicitly identify impulsive behavior. The combined aggressive/impulsive/violent denominator in Table 2 is not a separate frequency estimate for each behavior.

Agenesis of the Corpus Callosum OCCASIONAL Agenesis of corpus callosum HP:0001274

The 2/17 estimate is restricted to imaged patients and may be influenced by clinical selection. It should not be generalized to all BRPF1 carriers.

Show evidence (1 reference)

PMID:39837771 SUPPORT Human Clinical

"Brain MRI was available for 17 patients, of whom two (12%) had agenesis of the corpus callosum and one had multifocal hyperintensities in the white matter."

The clinical narrative specifies agenesis in two of the seventeen imaged patients; this is not the frequency of hypoplasia or of all brain abnormalities.

Respiratory 2

Laryngomalacia HP:0001601

Frequencies, where supplied, summarize reported 2025 cohort counts and are subject to ascertainment and incomplete assessment.

Show evidence (1 reference)

PMID:39837771 SUPPORT Human Clinical

"| Laryngomalacia | 2/28 (7%) | 5/15 (33%) |"

The source summary table explicitly records this finding; source inconsistencies are retained in the description.

Stridor HP:0010307

Frequencies, where supplied, summarize reported 2025 cohort counts and are subject to ascertainment and incomplete assessment.

Show evidence (1 reference)

PMID:39837771 SUPPORT Human Clinical

"| Stridor | 1/28 (4%) | 2/15 (13%) |"

The source summary table explicitly records this finding; source inconsistencies are retained in the description.

Growth 2

Short Stature HP:0004322

Frequency deliberately omitted. The two quotable denominators straddle bands - 6/29 (21%, OCCASIONAL) in the prospectively phenotyped 2025 cohort versus 17/42 (40%, FREQUENT) in that paper's literature comparison - and no source reconciles them, so no band is claimed.

Show evidence (2 references)

PMID:39837771 SUPPORT Human Clinical

"short stature was noted in three patients (6/29, 21%), whereas short stature is relatively common in IDDDFP patients reported in the literature (17/42, 40%)"

Supports the disease-phenotype association and documents the 21% versus 40% discrepancy that is the stated reason no band is assigned.

PMID:31020800 SUPPORT Human Clinical

"while strabismus and small stature were enriched in this group, however did not reach statistical significance"

Short stature trends with BRPF1 disruption within the 3p25 deletion region but the enrichment was not statistically significant.

Obesity OCCASIONAL HP:0001513

Frequency derivation: four of 28 patients (14%) in Colson et al. 2025 were obese. 14% falls in the OCCASIONAL band (5-29%).

Show evidence (1 reference)

PMID:39837771 SUPPORT Human Clinical

"Weight changes were generally normal across age groups, with only four patients being obese (14%) and no reports of decreased body weight."

Obesity at 14% falls in the OCCASIONAL band (5-29%).

🧬

Genetic Associations

BRPF1 Pathogenic Variants (Causative)

Gene: BRPF1 hgnc:14255 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal dominant inheritance

Show evidence (8 references)

CGDS:HGNC_14255 SUPPORT Other

"BRPF1 | HGNC:14255 | 7862 | 3p25.3 | chr3:9731735-9748015 | 3 - Sufficient Evidence for Haploinsufficiency | 0 - No Evidence for Triplosensitivity | 2023-08-23"

ClinGen's dosage sensitivity curation scores BRPF1 haploinsufficiency at 3 (Sufficient Evidence) and triplosensitivity at 0 (No Evidence), fixing the disease mechanism as loss of one functional copy and locating the gene at 3p25.3.

CGDS:HGNC_14255 SUPPORT Other

"Numerous loss-of-function mutations have been reported in intellectual developmental disorder with dysmorphic facies and ptosis (IDDDFP) patients, and functional analyses support a haploinsufficiency of the BRPF1 gene."

ClinGen's evidence summary states the haploinsufficiency conclusion explicitly and grounds it in both variant spectrum and functional assays.

PMID:27939640 SUPPORT Human Clinical

"These data indicate that aberrations in the chromatin regulator gene BRPF1 cause histone H3 acetylation deficiency and a previously unrecognized intellectual disability syndrome."

Establishes BRPF1 as the causative gene for a distinct intellectual disability syndrome.

+ 5 more references

🔬

Variants

c.1052_1053del (p.Val351GlyfsTer8)

Gene: BRPF1 hgnc:14255 deletion

Founding familial frameshift with partial nonsense-mediated decay. In transfected cells, the truncated protein retains KAT6A interaction but fails to recruit ING5/MEAF6 and fails to stimulate H3K23 acetylation. The decrease in patient-fibroblast H3K23ac was not statistically significant; protein abundance and functional effect should not be generalized across assays. The cited study provides segregation and functional evidence, but an explicit ACMG class for this allele was not established from the cached source; a formal clinical_significance value is therefore not assigned.

Show evidence (2 references)

PMID:27939639 SUPPORT Human Clinical

"we identified an inherited 2 bp deletion causing a frameshift in BRPF1 (c.1052_1053del) in five affected family members."

Identifies the segregating familial frameshift.

PMID:27939639 SUPPORT In Vitro

"Whereas the wild-type was able to bind ING5 and MEAF6, the p.Val351Glyfs∗8 variant failed to do so."

Partner-specific impairment was measured in transfected cells; KAT6A binding was retained.

NM_004634:c.556C>T (p.Gln186Ter) Pathogenic

Gene: BRPF1 hgnc:14255 single nucleotide variant

Truncating allele reported as pathogenic in a multiplex family, inherited from the mother by three affected sons. Cognitive expressivity varied; the mother initially described herself as unaffected. No direct allele-specific RNA or protein assay was reported in this clinical study.

Show evidence (2 references)

PMID:31020800 SUPPORT Human Clinical

"the previously unreported c.556C>T (p.Q186*) truncating mutation on exon 2 of the BRPF1 gene (NM_004634), in the proband and his mother."

Identifies the transcript and familial allele.

PMID:31020800 SUPPORT Human Clinical

"the mutation fully segregated with the disease in the family"

The familial p.Gln186Ter allele segregated with the BRPF1 phenotype. A sibling with Leber hereditary optic neuropathy instead carried an MT-ND1 variant and did not share the BRPF1 phenotype.

c.1054G>C (p.Val352Leu) Uncertain Significance

Gene: BRPF1 hgnc:14255 single nucleotide variant

Reported in one child with a BRPF1-like phenotype and absent from tested parental and sibling blood samples. The paper classifies the allele as uncertain significance. Modeling predicts altered PZP-domain packing; no biochemical or cellular experiment establishes destabilization or acetylation loss.

Show evidence (2 references)

PMID:32457794 SUPPORT Human Clinical

"The variant detected here was classified as variant with unclear significance according to the most recent ACMG guidelines."

The methods explicitly give uncertain significance, despite stronger causal wording in the title and discussion. Structural effects were predicted, not experimentally measured.

PMID:32457794 SUPPORT Human Clinical

"the heterozygous mutation was detected only in the index patient II-3"

Sanger testing found the allele in the proband but not the tested parents or sisters.

c.2420_2433del (p.Gln807LeufsTer27) Pathogenic

Gene: BRPF1 hgnc:14255 deletion

Frameshift reported as pathogenic in two sisters. Negative parental buccal testing suggests parental gonadal mosaicism, but parent-of-origin and gonadal mosaicism were not directly established. The proband also had a partial ARHGAP26 deletion classified as a VUS; that finding should not be conflated with BRPF1 haploinsufficiency.

Show evidence (2 references)

PMID:37946714 SUPPORT Human Clinical

"WES analysis identified a heterozygous pathogenic variant in BRPF1 c.2420_2433del (p.Q807Lfs∗27) in both sisters."

Identifies the shared frameshift and source classification.

PMID:37946714 SUPPORT Human Clinical

"Hence, parent-of-origin could not be determined."

No informative nearby SNPs established the parental allele of origin.

NM_004634.3:c.1433G>A (p.Trp478Ter) Pathogenic

Gene: BRPF1 hgnc:14255 single nucleotide variant

Nonsense allele reported as pathogenic in a family with the BRPF1 phenotype and anemia/thrombocytopenia. No additional genomic change was detected by the reported WES and microarray tests; this does not prove a specific marrow-failure pathway or exclude every other cause of cytopenia.

Show evidence (1 reference)

PMID:37190896 SUPPORT Human Clinical

"a novel heterozygous c.1433G > A; p.W478* (NM_004634.3) pathogenic variant on exon 3 of the BRPF1 gene."

Identifies the reported nonsense variant and source classification.

💊

Medical Actions

Multidisciplinary Supportive and Developmental Care

Category: Therapeutic Action: supportive care Ontology label: Supportive Care NCIT:C15747

Platform: Other

Supportive care can be individualized to developmental, feeding, motor, educational and ocular needs. Coordinating these services is a care-planning inference from the clinical phenotype, not a tested BRPF1-specific program. The cited cohort specifically recommends comprehensive ophthalmological evaluation; other supportive interventions require assessment of the individual patient.

Target Phenotypes: Global developmental delay HP:0001263

Show evidence (1 reference)

PMID:39837771 SUPPORT Human Clinical

"Our findings highlight the diverse clinical manifestations of BRPF1-related disorders and suggest that comprehensive ophthalmological evaluation is essential for the management of these patients."

The cohort explicitly recommends comprehensive ophthalmological evaluation. This snippet does not evaluate multidisciplinary care or establish benefit from the broader supportive program.

Speech and Language Therapy

Category: Therapeutic Action: speech therapy Ontology label: Speech Language Therapy NCIT:C159273

Platform: Behavioral / lifestyle

Speech and language therapy should address the individual speech and language profile, including childhood apraxia of speech where present. The dedicated speech-pathology study supports a formal differential diagnosis. It does not compare treatment effectiveness or establish this as the highest-yield intervention.

Target Phenotypes: Delayed speech and language development HP:0000750 Speech apraxia HP:0011098

Show evidence (2 references)

PMID:38346666 SUPPORT Human Clinical

"We have implicated BRPF1-related disorder as causative for speech and language disorder, including childhood apraxia of speech."

Establishes the specific speech diagnoses that therapy must target.

PMID:37946714 SUPPORT Human Clinical

"Early developmental milestones were reported to be delayed primarily for speech and communication skills, for which she received speech therapy."

Documents speech therapy use in an affected adult, without a controlled estimate of effectiveness.

Ptosis Repair Surgery

Category: Therapeutic Action: ptosis repair surgery Ontology label: Surgical Procedure NCIT:C15329

Platform: Surgery

Several affected individuals in the founding family underwent ptosis surgery. Two adults required repeat operations with limited results. These observations document treatment use and variable outcomes without establishing comparative efficacy, an optimal surgical approach or a syndrome-specific timing recommendation.

Target Phenotypes: Ptosis HP:0000508

Show evidence (1 reference)

PMID:27939639 SUPPORT Human Clinical

"who had surgery twice for her ptosis with limited results"

Describes repeat surgery in an affected adult from the founding family. The text also reports limited results after two operations in her sister; these observations do not establish a general success rate.

Physical Therapy

Category: Therapeutic Action: physical therapy Ontology label: Physical Therapy NCIT:C15302

Platform: Behavioral / lifestyle

Physical therapy is a supportive approach for motor delay and hypotonia, individualized to functional needs. The cited speech-phenotyping cohort documents motor impairment and improvement with age; it does not attribute that improvement to physical therapy or measure treatment efficacy.

Target Phenotypes: Hypotonia HP:0001252 Motor delay HP:0001270

Show evidence (1 reference)

PMID:38346666 SUPPORT Human Clinical

"fine (8/15) and gross motor delay (10/15) which often resolved in later childhood"

Documents motor impairment as a potential supportive-care target; the observed natural history is not evidence of physical-therapy efficacy.

Occupational Therapy

Category: Therapeutic Action: Occupational Therapy NCIT:C121351

Platform: Behavioral / lifestyle

Occupational therapy may address fine-motor and daily-living limitations when present. This is a supportive-care inference from the reported functional impairments; the cited cohort does not test occupational therapy outcomes.

Target Phenotypes: Motor delay HP:0001270

Show evidence (1 reference)

PMID:38346666 SUPPORT Human Clinical

"fine (8/15) and gross motor delay (10/15) which often resolved in later childhood"

Fine-motor impairment provides a potential treatment target, without disorder-specific evidence of occupational-therapy benefit.

Genetic Counseling

Category: Therapeutic Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Platform: Other

Counselling must cover the autosomal dominant 50% recurrence risk for an affected parent, the wide intrafamilial variability (including mildly affected or apparently unaffected carriers, so parental testing and careful parental phenotyping are essential), and the possibility of suspected gonadal mosaicism producing recurrence after an apparently de novo variant.

Show evidence (2 references)

PMID:37946714 SUPPORT Human Clinical

"The absence of the BRPF1 variant in parental buccal samples provides evidence of a de novo frameshift pathogenic variant, most likely as a result of parental gonadal mosaicism, which has not been previously reported."

Sibling recurrence despite negative parental buccal testing supports counselling about possible gonadal mosaicism; it was inferred rather than directly demonstrated.

PMID:39837771 SUPPORT Human Clinical

"Familial analysis revealed variability in clinical expression."

Intrafamilial variability is a key counselling point.

Experimental HDAC Inhibition to Increase H3K23 Acylation

Category: Therapeutic Action: pharmacotherapy Ontology label: Pharmacotherapy NCIT:C15986

Agent: butyrate CHEBI:17968 vorinostat CHEBI:45716 valproic acid CHEBI:39867 trichostatin A CHEBI:46024

Platform: Small molecule

Preclinical biochemical rescue only. Valproate, vorinostat, trichostatin A and butyrate increased H3K23 acetylation and propionylation in HEK293 cells and patient-derived Pro370Ser lymphoblastoid cells. Beta-hydroxybutyrate did not increase the marks in those systems, although it did in Brpf1-null mouse fibroblasts. These culture experiments establish model-dependent biochemical responses, not clinical efficacy or correction of neurodevelopment.

Mechanism Target:

RESTORES Deficient Histone H3K23 Acetylation

RESTORES Deficient Histone H3K23 Propionylation

Show evidence (2 references)

PMID:32010779 SUPPORT In Vitro

"We also tested LCLs from the individual harboring the Pro370Ser variant. As shown in Fig. 6C, all inhibitors except β-hydroxybutyrate enhanced H3K23 acetylation and propionylation."

Patient-derived lymphoblastoid cells show biochemical responses to the tested HDAC inhibitors; beta-hydroxybutyrate is an important negative comparison in this model.

PMID:18469222 SUPPORT Model Organism

"Treatment of mutants from 20–33 hpf rescued hoxa2b expression in CNC"

Trichostatin A restored the measured transcriptional readout in zebrafish; the experiment is preclinical. This separate model supports transcriptional rescue, not the H3K23-specific treatment targets above.

Experimental Propionate Supplementation to Increase H3K23 Propionylation

Category: Therapeutic Action: pharmacotherapy Ontology label: Pharmacotherapy NCIT:C15986

Agent: propionate CHEBI:17272

Platform: Small molecule

In vitro sodium propionate treatment increased H3K23 propionylation in Pro370Ser patient-derived lymphoblastoid cells. It did not increase H3K23 acetylation. The propionylation response was absent in Brpf1-null mouse embryonic fibroblasts, making residual BRPF1 activity and model context relevant. The study does not establish dietary or drug efficacy in patients.

Mechanism Target:

RESTORES Deficient Histone H3K23 Propionylation

Show evidence (3 references)

PMID:32010779 SUPPORT In Vitro

"Propionate treatment stimulated H3K23 propionylation but not acetylation in MEFs"

Separates the propionylation response from acetylation; this source does not support targeting both defects with propionate.

PMID:32010779 SUPPORT In Vitro

"The treatment also enhanced H3K23 propionylation in the patient-derived LCLs"

The patient-derived response was demonstrated for the Pro370Ser lymphoblastoid line.

PMID:32010779 SUPPORT In Vitro

"The enhancement of propionylation in response to propionate treatment was abolished in Brpf1−/− MEFs"

Complete Brpf1 loss prevented this response, unlike the residual-function patient-cell setting.

Behavioural and ADHD Management

Category: Therapeutic Action: behavioural counselling and ADHD management Ontology label: Behavioral Counseling NCIT:C181743

Platform: Behavioral / lifestyle

Behavioral difficulties were reported in 18/29 patients in the 2025 cohort, including attention/hyperactivity, low frustration tolerance, anxiety and agitation; sleep disturbance was also reported. These findings identify potential targets for individualized behavioral assessment and support. The cited cohort does not measure caregiver burden, compare behavioral interventions or evaluate ADHD medications.

Target Phenotypes: Behavioural disorder HP:0000708 Attention deficit hyperactivity disorder HP:0007018 Sleep disturbance HP:0002360

Show evidence (2 references)

PMID:39837771 SUPPORT Human Clinical

Documents behavioral difficulties that may warrant individualized assessment and support; it does not test a counseling intervention or medication.

PMID:39837771 SUPPORT Human Clinical

"Sleep disturbance was reported by nine patients (31%)."

Documents sleep disturbance as an additional care need; it does not test a sleep-management regimen.

🔬

Diagnosis

Whole exome sequencing

Exome sequencing can identify heterozygous BRPF1 sequence variants in patients with a suggestive neurodevelopmental phenotype. Testing has been performed in single individuals and trios, with segregation studies where available.

Whole Exome Sequencing NCIT:C101295

Results: A heterozygous pathogenic or likely pathogenic BRPF1 variant supports a molecular diagnosis in the appropriate clinical context. A variant of uncertain significance does not establish the diagnosis.

Show evidence (2 references)

PMID:31020800 SUPPORT Human Clinical

"Molecular analysis of the family was pursued using whole exome sequencing (WES) and subsequent Sanger sequencing."

Whole exome sequencing with Sanger confirmation is the route to diagnosis.

PMID:39837771 SUPPORT Human Clinical

"In 17 patients, genotyping was conducted by exome sequencing (ES) or genome sequencing (GS) (single or trio) using routine techniques."

The cohort documents both sequencing approaches; it does not separately report their diagnostic yields.

Whole genome sequencing

Genome sequencing is another documented route to identify BRPF1 variants. The 2025 cohort groups exome and genome sequencing together, without providing a genome-specific yield.

Whole Genome Sequencing NCIT:C101294

Show evidence (1 reference)

PMID:39837771 SUPPORT Human Clinical

"In 17 patients, genotyping was conducted by exome sequencing (ES) or genome sequencing (GS) (single or trio) using routine techniques."

The cohort documents both sequencing approaches; it does not separately report their diagnostic yields.

BRPF1 copy-number analysis

Whole-gene BRPF1 deletions and larger 3p25.3 deletions are documented disease-associated variants. Array comparative genomic hybridization detected deletions in the 2025 cohort, with segregation assessed by qPCR. A molecular workup needs to account for copy-number variation and the detection limits of the chosen assay; the source does not establish that every patient requires a separate microarray in addition to copy-number-sensitive sequencing.

chromosomal microarray analysis NCIT:C18477

Results: A heterozygous whole-gene BRPF1 deletion, or a contiguous 3p25.3 deletion encompassing BRPF1 with or without SETD5, supports a molecular diagnosis. Deletions spanning SETD5 and other genes require interpretation as contiguous-gene disorders. Greater severity was observed in the small founding comparison, but it is not a deterministic individual prediction.

Show evidence (3 references)

PMID:39837771 SUPPORT Human Clinical

"Two variants were detected by array CGH, with segregation analysis performed by qPCR in 4 related patients."

In the largest cohort, array CGH - not sequencing - was the modality that found two of the pathogenic alleles, with qPCR used for family segregation.

PMID:27939639 SUPPORT Human Clinical

"We identified BRPF1 deletions or point mutations in six additional individuals with a similar phenotype."

The founding series already reported deletions alongside point mutations, establishing copy-number loss as part of the diagnostic yield.

PMID:37190896 SUPPORT Human Clinical

"Apart from the variant in BRPF1, no additional genomic changes were detected by WES and chromosomal microarray analysis (CMA)."

Illustrates the paired sequencing-plus-CMA workup used to exclude additional or alternative copy-number causes.

Comprehensive ophthalmological evaluation

Detailed ophthalmological assessment can characterize ptosis, blepharophimosis, strabismus, amblyopia, refractive errors and coloboma. Optical coherence tomography identified subclinical optic nerve alterations in a two-case report. These sources support comprehensive assessment but do not establish a BRPF1-specific screening interval or routine OCT schedule.

Eye Examination NCIT:C38060

Results: Identifies treatable amblyogenic factors (ptosis, strabismus, refractive error) and otherwise occult optic nerve involvement.

Show evidence (2 references)

PMID:39837771 SUPPORT Human Clinical

"Our findings highlight the diverse clinical manifestations of BRPF1-related disorders and suggest that comprehensive ophthalmological evaluation is essential for the management of these patients."

The largest cohort explicitly recommends comprehensive ophthalmological evaluation.

PMID:38590032 SUPPORT Human Clinical

"Since subclinical optic nerve alterations can go easily undetected, our experience highlights the importance of a more detailed ophthalmologic evaluation in patients with BRPF1 variant."

Supports adding OCT-level detail to the ophthalmological workup.

📊

Prevalence

Worldwide

Point Prevalence ≤0.1 per 100,000 <1 in 1,000,000

Orphanet records a validated worldwide point-prevalence class of <1 / 1 000 000 for ORPHA:698090, i.e. fewer than 0.1 cases per 100,000. Only the upper bound is recorded (rate_high) because the source gives an open-below class, not a point estimate.

Show evidence (1 reference)

ORPHA:698090 SUPPORT Other

"<1 / 1 000 000 | Worldwide | Point prevalence | ORPHANET"

Orphanet's epidemiology table gives a worldwide point-prevalence class of <1 / 1 000 000, which maps to PrevalenceClassEnum BELOW_1_IN_1000000.

Worldwide

Cases In Literature Ultra Rare

These are dated literature counts, not a population prevalence or a deduplicated cumulative census. The 2020 study stated that BRPF1 variants had been reported in 40 cases of syndromic intellectual disability. The 2025 study described 29 new patients from 20 families and compared them with published cases. A total near 100 is not established by these citations. The cached Orphadata cases/families record provides no numerical count.

Show evidence (2 references)

PMID:32010779 SUPPORT Human Clinical

"BRPF1 variants are present in 40 cases of syndromic intellectual disability"

Gives a cumulative published case count of 40 as of 2020.

PMID:39837771 SUPPORT Human Clinical

"This study expands the clinical and molecular spectrum of IDDDFP by analysing 29 new patients from 20 families with confirmed BRPF1 variants."

Describes 29 new patients from 20 families; it does not establish a deduplicated cumulative total near 100.

🔀

Differential Diagnoses

Conditions with similar clinical presentations that must be differentiated from BRPF1-Related Intellectual Disability:

Arboleda-Tham syndrome (KAT6A) MONDO:0014558

Overlapping Features KAT6A encodes an acetyltransferase scaffolded by BRPF1, creating mechanistic and phenotypic overlap. Both disorders can include developmental and speech impairment, hypotonia and congenital anomalies. BRPF1 families show wide variation in intellectual function and often prominent ptosis or blepharophimosis. Phenotype can guide testing, but the overlap requires gene-level molecular distinction; KAT6A clinical findings should not be assigned to BRPF1 solely because the proteins share a complex.

Show evidence (1 reference)

PMID:27939640 SUPPORT Human Clinical

Explicitly separates the BRPF1 entity from KAT6A/KAT6B disorders despite the shared complex.

Say-Barber-Biesecker-Young-Simpson syndrome (KAT6B) MONDO:0011365

Overlapping Features SBBYS is the other blepharophimosis-plus-intellectual-disability chromatinopathy in the same complex and is the most confusable clinical neighbour, since it too features blepharophimosis, ptosis and hypotonia. Discriminators favouring SBBYS are a mask-like immobile face, long thumbs and great toes, patellar hypoplasia or agenesis, dental anomalies, hypothyroidism and lacrimal duct anomalies, with generally more severe intellectual disability; SBBYS variants are almost always de novo truncating KAT6B alleles.

Show evidence (1 reference)

PMID:27939640 SUPPORT Human Clinical

The same source separates BRPF1 disease from the KAT6B disorders.

Genitopatellar syndrome (KAT6B) MONDO:0011640

Overlapping Features An allelic KAT6B disorder with a characteristic combination of patellar agenesis or hypoplasia, contractures, genital abnormalities and other developmental findings. Genital abnormalities alone do not distinguish it from BRPF1-related disorder, because cryptorchidism is documented in BRPF1 cases. The combined phenotype and molecular diagnosis are more informative than an absolute absence claim.

Show evidence (2 references)

PMID:36077605 SUPPORT Other

"BRPF1, KAT6A and KAT6B mutations were identified as the cause of neurodevelopmental disorders, leukemia, medulloblastoma and other types of cancer, with germline mutations associated with neurodevelopmental disorders displaying intellectual disability, and somatic variants associated with..."

Establishes KAT6B as a separate cause of intellectual-disability syndromes within the same complex, making its phenotypes differentials rather than the same entity.

PMID:27939639 SUPPORT Human Clinical

"He had surgery for his ptosis and for cryptorchidism."

The founding family already included cryptorchidism requiring surgery, contradicting the later claim of novelty.

SETD5 haploinsufficiency intellectual disability MONDO:0014336

Overlapping Features The critical co-located confounder. SETD5 is immediately adjacent to BRPF1 at 3p25, and before BRPF1 was characterized most of the 3p25 deletion phenotype was attributed to SETD5. Isolated SETD5 haploinsufficiency causes intellectual disability with facial dysmorphism but does not preferentially produce ptosis and blepharophimosis; those features track with BRPF1 loss.

Show evidence (2 references)

PMID:27939639 SUPPORT Human Clinical

"Deletions of the 3p25 region, containing BRPF1 and SETD5, cause a defined ID syndrome where most of the clinical features are attributed to SETD5 deficiency."

States the historical attribution of the 3p25 phenotype to SETD5, the reason BRPF1 was recognized late.

PMID:27939639 SUPPORT Human Clinical

"We compared the clinical symptoms of individuals carrying mutations or small deletions of BRPF1 alone or SETD5 alone with those of individuals with deletions encompassing both BRPF1 and SETD5."

The direct comparison that separates the two adjacent genes' contributions.

3p25.3 microdeletion syndrome Not Yet Curated MONDO:0018564

Overlapping Features A contiguous gene deletion that can encompass both BRPF1 and SETD5. It should be considered whenever the phenotype is more severe than expected for an isolated BRPF1 variant; chromosomal microarray distinguishes it from a single-nucleotide BRPF1 variant.

Show evidence (1 reference)

PMID:27939639 SUPPORT Human Clinical

"We conclude that both genes contribute to the phenotypic severity of 3p25 deletion syndrome"

Establishes the two-gene contiguous-deletion entity as distinct from single-gene BRPF1 disease.

Noonan syndrome and other RASopathies MONDO:0018997

Overlapping Features Facial dysmorphism, short stature and developmental delay can prompt a clinical Noonan diagnosis. In a series of clinically diagnosed patients with negative RASopathy panels, exome sequencing established BRPF1 among the alternative diagnoses. The overlap supports molecular evaluation; the cited report does not establish absolute absence of individual RASopathy-associated features in BRPF1-related disease.

Show evidence (1 reference)

PMID:41137536 SUPPORT Human Clinical

"In six cases, alternative genetic diagnoses were established due to variants in SETD5, BRPF1, DPH1, ACTB, CREBBP, and GATA4, genes associated with syndromes presenting overlapping phenotypes with NS."

Documents BRPF1 being found in patients carrying a clinical Noonan diagnosis, making Noonan a real differential.

Blepharophimosis, ptosis, and epicanthus inversus syndrome MONDO:0007201

Overlapping Features FOXL2-related BPES overlaps the eyelid phenotype of BRPF1-related disorder, including epicanthus inversus. Congenital eyelid malformation and age-related primary ovarian insufficiency characterize BPES, while the broader neurodevelopmental phenotype can favor BRPF1 or a contiguous-gene deletion. Molecular testing distinguishes these causes.

Distinguishing Features

The eyelid malformation is present at birth in every affected individual in BPES, whereas ptosis is present in 20/29 (69%) of BRPF1 patients.
Age-related primary ovarian insufficiency in affected females is a defining BPES feature in the cited GeneReviews chapter; the BRPF1 cohorts cited here do not establish a comparable association.
Additional neurodevelopmental findings in BPES warrant consideration of a contiguous deletion involving FOXL2 and neighboring genes. The cited chapter describes this context; it does not prove an absolute exclusion for every intragenic variant.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/books/NBK1441/ SUPPORT Other

"Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is characterized by this eyelid malformation present at birth in all individuals and age-related primary ovarian insufficiency (POI) in affected females"

Gives the two BPES-defining features that separate it from BRPF1 disease - obligate congenital eyelid malformation and female primary ovarian insufficiency, neither of which characterizes IDDDFP.

url:https://www.ncbi.nlm.nih.gov/books/NBK1441/ SUPPORT Other

"intellectual disability, microcephaly, speech delay, ventricular septum defect, cleft palate, and subtle skeletal features"

The GeneReviews chapter describes additional neurodevelopmental and congenital findings with contiguous deletions involving FOXL2 and neighboring genes.

📊

Related Datasets

brpf1 knockdown reduces inhibitory neurotransmission and regulates gene expression of GABAergic interneurons derived from MGE geo:GSE157903

Bulk RNA sequencing of primary mouse MGE-derived GABAergic interneurons after AAV-shBrpf1 or scramble treatment.

Mus musculus BULK RNA SEQ n=6 Illumina HiSeq 2500 (GPL17021)

Conditions: MGE interneuron culture, scramble control MGE interneuron culture, Brpf1 shRNA

PMID:33744924

GEO records three samples per condition. The paper reports three culture batches per condition. Transcript changes do not establish direct BRPF1 targets or mediation of electrophysiological changes.

Deficiency of intellectual disability-related gene Brpf1 attenuated hippocampal excitatory neurotransmission and impaired learning and memory behavior geo:GSE174600

Bulk RNA sequencing after Brpf1 knockdown in primary mouse hippocampal cultures and in stereotactically injected hippocampal CA1 tissue.

Mus musculus BULK RNA SEQ n=12 Illumina HiSeq 2500 (GPL17021)

Conditions: Hippocampal neuron culture, scramble control Hippocampal neuron culture, Brpf1 shRNA Hippocampal CA1 tissue, scramble control Hippocampal CA1 tissue, Brpf1 shRNA

PMID:34485298

GEO records three samples per condition. The paper describes three pairs of samples for each preparation. Culture and tissue contrasts must be analyzed separately; neither is a human heterozygous transcriptome.

Hippocampus-specific loss of intellectual disability-related gene Brpf1 impaired spatial and contextual learning geo:GSE212983

RNA-seq of hippocampal CA1 tissue from postnatal CaMKIIa-Cre Brpf1 conditional knockout and control mice.

Mus musculus BULK RNA SEQ n=8 Illumina NovaSeq 6000 (GPL24247)

Conditions: Control hippocampal CA1 tissue CaMKIIa-Cre Brpf1 conditional knockout hippocampal CA1 tissue

PMID:37862219

Four samples per group from two-month-old males. Bulk tissue and nominal DEG thresholds limit cell-specific and causal interpretation.

BRPF1 co-occupies with H3K4me3 and H3K23ac in human ESCs essential to pluripotency geo:GSE213695

SuperSeries containing transcriptomic, chromatin accessibility and occupancy profiling of engineered H1 embryonic stem cells.

Homo sapiens MULTI OMICS PERTURBATION n=18 Illumina NovaSeq 6000 (GPL24676; GEO record)

PMID:36711238

The total counts deposited samples across assays, not independent patients or eighteen biological donors. The study also deposits data under HRA001928. Complete engineered loss, differentiation state and assay-specific controls must be considered when using the data. GEO assigns platform GPL24676 (NovaSeq 6000), while the paper methods describe NextSeq 500 sequencing; this source discrepancy should be checked before platform-specific reanalysis. SubSeries are GSE213690, GSE213692 and GSE213694.

Microarray analysis of Wild-type vs. Brpf1-deficient E8.75 mouse embryo geo:GSE63908

Two-color microarray comparison of three pairs of control and Brpf1-deficient E8.75 mouse embryos.

Mus musculus MICROARRAY n=3 Agilent-028005 SurePrint G3 Mouse GE...

Conditions: Wild-type E8.75 mouse embryo Brpf1-deficient E8.75 mouse embryo

PMID:25773539

GEO lists three array samples, each hybridizing labeled material from a control-mutant pair: three samples represent six embryos, not three total embryos. Whole-embryo composition and global null genotype limit inference about human heterozygous neural cells.

🧫

Experimental Models

Brpf1-knockdown mouse MGE-derived interneuron cultures PRIMARY_CELL_CULTURE

AAV-shBrpf1 reduced Brpf1 transcript by approximately 40%. mIPSC amplitude and intrinsic excitability were affected, while mIPSC frequency, dendritic arbor measurements and SST differentiation were not significantly changed. Reduced PV differentiation was a nonsignificant trend.

Organism

Mus musculus NCBITaxon:10090

Cell source

E14.5 mouse medial ganglionic eminence

Culture

Primary neurons infected at DIV3; morphological and electrophysiological assessment at DIV14-15

Publication

PMID:33744924

Pathograph links

Reduced Inhibitory Neurotransmission in GABAergic Interneurons partially recapitulates fidelity: unknown observes: cellular Measures inhibitory postsynaptic currents after partial knockdown.

Limitations: Mouse primary culture after partial shRNA knockdown is not a patient-derived heterozygous neural model. The result does not establish the corresponding human mechanism.

Readouts

mIPSC amplitude

Reduced relative to scramble-treated neurons.

Direction: DECREASED

Show evidence (1 reference)

PMID:33744924 SUPPORT In Vitro

"The amplitude but not the frequency of mIPSCs decreased significantly"

DIV15 recordings found reduced amplitude without a significant frequency change.

mIPSC frequency

No statistically significant difference was detected.

Direction: UNCHANGED

Show evidence (1 reference)

PMID:33744924 SUPPORT In Vitro

"The amplitude but not the frequency of mIPSCs decreased significantly"

DIV15 recordings found reduced amplitude without a significant frequency change.

Show evidence (1 reference)

PMID:33744924 SUPPORT In Vitro

"The amplitude but not the frequency of mIPSCs decreased significantly"

DIV15 recordings found reduced amplitude without a significant frequency change.

Reduced Intrinsic Excitability of MGE-Derived GABAergic Interneurons partially recapitulates fidelity: unknown observes: cellular Current-clamp assays measure evoked firing.

Limitations: Mouse primary culture after partial shRNA knockdown is not a patient-derived heterozygous neural model. The result does not establish the corresponding human mechanism.

Readouts

Current threshold for evoked action potentials

More injected current was required to evoke firing.

Direction: INCREASED

Show evidence (1 reference)

PMID:33744924 SUPPORT In Vitro

"The AAV-shBrpf1 group required a larger incident current to induce the evoked APs, with a significant increase in the firing threshold"

Current-clamp recordings demonstrate increased threshold after partial knockdown, without a corresponding change in resting potential or maximum evoked frequency.

Maximum evoked firing frequency

No statistically significant change was detected.

Direction: UNCHANGED

Show evidence (1 reference)

PMID:33744924 SUPPORT In Vitro

"although the maximum frequency of evoked APs was not affected"

The firing threshold rose but maximum evoked frequency was preserved.

Show evidence (1 reference)

PMID:33744924 SUPPORT In Vitro

"The AAV-shBrpf1 group required a larger incident current to induce the evoked APs, with a significant increase in the firing threshold"

Current-clamp recordings demonstrate increased threshold after partial knockdown, without a corresponding change in resting potential or maximum evoked frequency.

The study also transplanted E13.5 MGE cells into P1 hosts; cortical laminar distribution after 35 days did not differ significantly. That in vivo migration assay is separate from the cultured-neuron electrophysiology. No behavioral or circuit E/I-ratio test was performed.

Show evidence (3 references)

PMID:33744924 SUPPORT In Vitro

"The amplitude but not the frequency of mIPSCs decreased significantly"

DIV15 recordings found reduced amplitude without a significant frequency change.

PMID:33744924 SUPPORT In Vitro

"The results showed that there was no significant difference in the number of intersections and total length of dendrites between the two groups"

No significant MAP2-positive arbor change was detected at DIV14-15 after approximately 40% transcript knockdown.

PMID:33744924 SUPPORT In Vitro

"although the maximum frequency of evoked APs was not affected"

The firing threshold rose but maximum evoked frequency was preserved.

Brpf1-knockdown mouse hippocampal neuron cultures PRIMARY_CELL_CULTURE

Approximately 50% transcript knockdown reduced mEPSC frequency while preserving amplitude and measured intrinsic membrane properties. Total dendritic length and Sholl intersections did not change significantly. Culture RNA sequencing and qPCR identified reduced C1ql1 and Gpr17; neither was tested by rescue as a mediator.

Organism

Mus musculus NCBITaxon:10090

Cell source

E17.5-E18.5 mouse hippocampi

Culture

AAV2-shBrpf1 at DIV3; assessment at DIV14-15

Publication

PMID:34485298

Pathograph links

Reduced Excitatory Synaptic Transmission in Forebrain Neurons partially recapitulates fidelity: unknown observes: cellular Measures synaptic currents after partial Brpf1 knockdown.

Limitations: Mouse primary culture after partial shRNA knockdown is not a patient-derived heterozygous neural model. The result does not establish the corresponding human mechanism.

Readouts

mEPSC frequency

Reduced frequency in knockdown cultures.

Direction: DECREASED

Show evidence (1 reference)

PMID:34485298 SUPPORT In Vitro

"The results showed that the mEPSC frequency but not amplitude significantly decreased upon Brpf1 knockdown"

The experiment distinguishes reduced event frequency from preserved amplitude in cultured hippocampal neurons.

mEPSC amplitude

No significant difference in amplitude.

Direction: UNCHANGED

Show evidence (1 reference)

PMID:34485298 SUPPORT In Vitro

"The results showed that the mEPSC frequency but not amplitude significantly decreased upon Brpf1 knockdown"

The experiment distinguishes reduced event frequency from preserved amplitude in cultured hippocampal neurons.

Show evidence (1 reference)

PMID:34485298 SUPPORT In Vitro

"The results showed that the mEPSC frequency but not amplitude significantly decreased upon Brpf1 knockdown"

The experiment distinguishes reduced event frequency from preserved amplitude in cultured hippocampal neurons.

Electrophysiology was performed in embryonic cultures. Adult hippocampal stereotactic knockdown and water-maze testing were separate experiments, not physiological and behavioral measurements from the same neurons or animals.

Show evidence (2 references)

PMID:34485298 SUPPORT In Vitro

"The results showed that the mEPSC frequency but not amplitude significantly decreased upon Brpf1 knockdown"

The experiment distinguishes reduced event frequency from preserved amplitude in cultured hippocampal neurons.

PMID:34485298 SUPPORT In Vitro

"The RMP, input resistance, firing threshold, and evoked APs did not show significant changes"

Membrane excitability measures remained unchanged under these conditions.

BRPF1 Pro370Ser patient-derived lymphoblastoid cells CELL_LINE

Patient-derived lymphoblastoid cells show reduced H3K23 propionylation and support biochemical intervention assays. Propionate increases propionylation; tested HDAC inhibitors other than beta-hydroxybutyrate increase acetylation and propionylation.

Organism

Homo sapiens NCBITaxon:9606

Cell source

Patient-derived lymphoblastoid cell line carrying Pro370Ser

Publication

PMID:32010779

Pathograph links

Deficient Histone H3K23 Propionylation partially recapitulates fidelity: unknown observes: cellular Measures the patient-cell propionylation deficit.

Limitations: A patient-derived non-neural transformed cell line does not establish effects in developing brain. No isogenic correction or clinical response was reported.

Readouts

Basal H3K23 propionylation

Reduced relative to control lymphoblastoid cells.

Direction: DECREASED

Show evidence (1 reference)

PMID:32010779 SUPPORT In Vitro

"this modification decreased in the lymphoblastoid cells (LCLs) prepared from the individual harboring the Pro370Ser variant"

H3K23 propionylation was reduced in this patient-derived cell line.

Show evidence (1 reference)

PMID:32010779 SUPPORT In Vitro

"this modification decreased in the lymphoblastoid cells (LCLs) prepared from the individual harboring the Pro370Ser variant"

H3K23 propionylation was reduced in this patient-derived cell line.

Deficient Histone H3K23 Propionylation rescues fidelity: unknown observes: cellular Tests biochemical response to sodium propionate.

Limitations: Biochemical rescue in one patient-derived cell line; neurological function and human efficacy were not tested.

Readouts

H3K23 propionylation after propionate

The mark increased after 24-hour sodium propionate exposure.

Direction: RESTORED

Show evidence (1 reference)

PMID:32010779 SUPPORT In Vitro

"The treatment also enhanced H3K23 propionylation in the patient-derived LCLs"

Propionate increased the mark in Pro370Ser cells.

Show evidence (1 reference)

PMID:32010779 SUPPORT In Vitro

"The treatment also enhanced H3K23 propionylation in the patient-derived LCLs"

Propionate increased the mark in Pro370Ser cells.

Deficient Histone H3K23 Acetylation rescues fidelity: unknown observes: cellular Tests biochemical response to HDAC inhibition.

Limitations: Drug-dependent biochemical response in lymphoblastoid cells does not demonstrate developmental or clinical rescue.

Readouts

H3K23 acetylation after HDAC inhibitor treatment

Increased with tested inhibitors except beta-hydroxybutyrate.

Direction: INCREASED

Show evidence (1 reference)

PMID:32010779 SUPPORT In Vitro

"We also tested LCLs from the individual harboring the Pro370Ser variant. As shown in Fig. 6C, all inhibitors except β-hydroxybutyrate enhanced H3K23 acetylation and propionylation."

Patient-derived lymphoblastoid cells show biochemical responses to the tested HDAC inhibitors; beta-hydroxybutyrate is an important negative comparison in this model.

Show evidence (1 reference)

PMID:32010779 SUPPORT In Vitro

"We also tested LCLs from the individual harboring the Pro370Ser variant. As shown in Fig. 6C, all inhibitors except β-hydroxybutyrate enhanced H3K23 acetylation and propionylation."

Patient-derived lymphoblastoid cells show biochemical responses to the tested HDAC inhibitors; beta-hydroxybutyrate is an important negative comparison in this model.

Show evidence (3 references)

PMID:32010779 SUPPORT In Vitro

"this modification decreased in the lymphoblastoid cells (LCLs) prepared from the individual harboring the Pro370Ser variant"

H3K23 propionylation was reduced in this patient-derived cell line.

PMID:32010779 SUPPORT In Vitro

"The treatment also enhanced H3K23 propionylation in the patient-derived LCLs"

Propionate increased the mark in Pro370Ser cells.

PMID:32010779 SUPPORT In Vitro

"We also tested LCLs from the individual harboring the Pro370Ser variant. As shown in Fig. 6C, all inhibitors except β-hydroxybutyrate enhanced H3K23 acetylation and propionylation."

Patient-derived lymphoblastoid cells show biochemical responses to the tested HDAC inhibitors; beta-hydroxybutyrate is an important negative comparison in this model.

Inducible Brpf1-null mouse embryonic fibroblasts PRIMARY_CELL_CULTURE

Complete Brpf1 deletion abolishes detectable H3K23 acetylation and propionylation. H3K9/H3K14 marks and total histone H3 acylation are not uniformly lost. Propionate fails to enhance H3K23 propionylation in null cells, whereas tested HDAC inhibitors increase both H3K23 marks. An earlier study of this inducible preparation found impaired proliferation and cell-cycle progression, reduced H3K9/H3K14 acetylation, unchanged Hbo1 protein and H4K16 acetylation, and increased p16 with decreased p27 transcription. Reduced embryonic Rpl10l expression was not reproduced in the fibroblasts.

Organism

Mus musculus NCBITaxon:10090

Cell source

Brpf1 floxed mouse embryonic fibroblasts carrying UBC-Cre/ERT2

Culture

Deletion induced with 4-hydroxytamoxifen in primary fibroblast culture

Publication

PMID:32010779

Pathograph links

Deficient Histone H3K23 Propionylation measures fidelity: unknown observes: cellular

Limitations: Complete loss in mouse fibroblasts differs from heterozygous human neural disease and from residual-function patient lymphoblastoid cells.

Readouts

H3K23 propionylation after Brpf1 deletion

Undetectable by the reported assays.

Direction: ABOLISHED

H3K23 propionylation response to propionate in null cells

Propionate failed to enhance the mark after complete Brpf1 loss.

Direction: UNCHANGED

Show evidence (2 references)

PMID:32010779 SUPPORT In Vitro

"H3K23 propionylation was undetectable in these mutant cells"

Brpf1-null mouse embryonic fibroblasts lacked detectable H3K23 propionylation.

+ 1 more reference

Deficient Histone H3K23 Acetylation rescues fidelity: unknown observes: cellular

Limitations: Biochemical drug response in complete-loss fibroblasts; no neurological or clinical rescue was tested.

Readouts

H3K23 acetylation after HDAC inhibitor exposure

Tested inhibitors corrected the measured biochemical deficit.

Direction: RESTORED

Show evidence (1 reference)

PMID:32010779 SUPPORT In Vitro

"all five HDAC inhibitors corrected the deficiency in H3K23 acetylation and propionylation"

HDAC inhibitors had a different response profile from propionate in Brpf1-null fibroblasts.

Altered Developmental Transcriptional Programs measures fidelity: unknown observes: cellular

Limitations: Induced biallelic loss in E15.5 mouse fibroblasts; changes in cell-cycle transcripts were not individually rescued and are not validated human diagnostic biomarkers.

Readouts

p16 and p27 transcription

p16 increased and p27 decreased in mutant fibroblasts; Rpl10l did not decrease as it did in E8.75 embryos.

Direction: ALTERED

Show evidence (1 reference)

PMID:25773539 SUPPORT In Vitro

"The transcript levels of p16 and p27 were affected in mutant MEFs"

The cellular preparation is distinct from the whole-embryo transcriptome.

Show evidence (4 references)

PMID:32010779 SUPPORT In Vitro

"H3K23 propionylation was undetectable in these mutant cells"

Brpf1-null mouse embryonic fibroblasts lacked detectable H3K23 propionylation.

PMID:32010779 SUPPORT In Vitro

"The enhancement of propionylation in response to propionate treatment was abolished in Brpf1−/− MEFs"

Propionate failed to enhance the mark after complete Brpf1 loss.

PMID:32010779 SUPPORT In Vitro

"all five HDAC inhibitors corrected the deficiency in H3K23 acetylation and propionylation"

HDAC inhibitors had a different response profile from propionate in Brpf1-null fibroblasts.

+ 1 more reference

Emx1-lineage Brpf1 conditional cortical neuron cultures PRIMARY_CELL_CULTURE

Genotype-dependent decreases in dendritic complexity and axonal length were measured in embryonic cortical cultures. These experiments are separate from acute CA1 slice electrophysiology and from Golgi spine analysis in adult brains.

Organism

Mus musculus NCBITaxon:10090

Cell source

E16.5 dorsal telencephalon from Brpf1 flox/flox controls, Emx1-Cre; Brpf1 flox/+ heterozygotes and Emx1-Cre; Brpf1 flox/flox conditional homozygotes

Culture

Dissociated cortical neurons; Tau staining at DIV5 and MAP2 staining at DIV14

Publication

PMID:31213987

Pathograph links

Impaired Dendritic Arborization partially recapitulates fidelity: unknown observes: cellular

Limitations: Conditional deletion in the mouse Emx1 lineage differs from constitutive heterozygous human BRPF1 disease; these measurements do not establish the corresponding patient mechanism.

Readouts

Total dendritic branch length at DIV14

Conditional heterozygotes showed a 17% reduction; homozygotes were more severely affected.

Direction: DECREASED

Show evidence (1 reference)

PMID:31213987 SUPPORT In Vitro

"Brpf1 HT neurons showed a 17% decrease in the total length of the dendritic branches compared with that of WT neurons."

E16.5 cortical cultures were examined at DIV14; conditional homozygous deletion caused a larger reduction.

Impaired Axonal Outgrowth partially recapitulates fidelity: unknown observes: cellular

Limitations: Conditional deletion in the mouse Emx1 lineage differs from constitutive heterozygous human BRPF1 disease; these measurements do not establish the corresponding patient mechanism.

Readouts

Tau-positive axon length at DIV5

Conditional heterozygotes showed a 20.3% reduction, with a larger homozygous effect.

Direction: DECREASED

Show evidence (1 reference)

PMID:31213987 SUPPORT In Vitro

"axonal elongation in HT cells was impaired, with a 20.3% decrease in length"

Tau-positive axons in E16.5 cortical cultures were measured at DIV5; conditional homozygous neurons had a more severe reduction.

Show evidence (2 references)

PMID:31213987 SUPPORT In Vitro

"Brpf1 HT neurons showed a 17% decrease in the total length of the dendritic branches compared with that of WT neurons."

E16.5 cortical cultures were examined at DIV14; conditional homozygous deletion caused a larger reduction.

PMID:31213987 SUPPORT In Vitro

"axonal elongation in HT cells was impaired, with a 20.3% decrease in length"

Tau-positive axons in E16.5 cortical cultures were measured at DIV5; conditional homozygous neurons had a more severe reduction.

BRPF1-null human H1 embryonic stem cells with inducible rescue OTHER

BRPF1 knockout progressively loses pluripotency, reduces H3K23ac and closes accessibility at stemness loci while opening lineage-associated regions. H3K4me3 remains substantially present. Wild-type BRPF1 rescues pluripotency and H3K23ac; N-terminal or PZP deletion fails to rescue effectively, whereas PWWP deletion largely retains rescue.

Organism

Homo sapiens NCBITaxon:9606

Cell source

H1/WA01 male human embryonic stem-cell line, with CRISPR-engineered BRPF1 knockout or FLAG knock-in

Culture

Matrigel-coated plates in mTeSR1 or ncTarget medium; inducible and lentiviral BRPF1 complementation

Publication

PMID:36711238

Pathograph links

Deficient Histone H3K23 Acetylation measures fidelity: unknown observes: cellular

Limitations: Complete engineered BRPF1 loss in an undifferentiated H1 embryonic stem-cell line is not a patient-specific heterozygous neural model. Rescue used ectopic BRPF1 expression; it does not demonstrate clinical or neuronal rescue.

Readouts

H3K23ac after endogenous BRPF1 deletion

H3K23ac was lost in knockout cells.

Direction: ABOLISHED

Show evidence (1 reference)

PMID:36711238 SUPPORT In Vitro

"BRPF1 deletion impairs H3K23ac in hESCs and leads to closed chromatin accessibility on stemness genes and hESC differentiation as well."

BRPF1-null H1 embryonic stem cells lose H3K23ac and accessibility at stemness loci. Other lineage-associated regions gain accessibility; this is not uniform genome-wide closure.

Deficient Histone H3K23 Acetylation rescues fidelity: unknown observes: cellular

Readouts

H3K23ac after induced BRPF1 expression

Doxycycline-dependent BRPF1 complementation restored the histone mark.

Direction: RESTORED

Show evidence (2 references)

PMID:36711238 SUPPORT In Vitro

"H3K14ac and H3K23ac were restored upon DOX treatment but lost"

Doxycycline-induced BRPF1 re-expression restored measured acetylation and pluripotency in the engineered endogenous-knockout line; withdrawal reversed the rescue.

+ 1 more reference

Altered Chromatin Accessibility measures fidelity: unknown observes: cellular

Readouts

Accessibility at stemness loci

ATAC-seq at days 12 and 30 identified reduced accessibility at stemness loci; lineage regions also showed gains.

Direction: DECREASED

Show evidence (1 reference)

PMID:36711238 SUPPORT In Vitro

"BRPF1 deletion impairs H3K23ac in hESCs and leads to closed chromatin accessibility on stemness genes and hESC differentiation as well."

BRPF1-null H1 embryonic stem cells lose H3K23ac and accessibility at stemness loci. Other lineage-associated regions gain accessibility; this is not uniform genome-wide closure.

Altered Developmental Transcriptional Programs measures fidelity: unknown observes: cellular

Readouts

Stemness and lineage gene expression

OCT4, NANOG and SOX2 expression declined while differentiation programs increased.

Direction: ALTERED

Show evidence (1 reference)

PMID:36711238 SUPPORT In Vitro

"BRPF1 deletion impairs H3K23ac in hESCs and leads to closed chromatin accessibility on stemness genes and hESC differentiation as well."

BRPF1-null H1 embryonic stem cells lose H3K23ac and accessibility at stemness loci. Other lineage-associated regions gain accessibility; this is not uniform genome-wide closure.

GSE213695 contains RNA-seq, ATAC-seq and ChIP-seq data. Direct BRPF1 recognition of H3K4me3 and the biochemical route from H3K23ac to accessibility were explicitly left unresolved. The OTHER model category denotes an embryonic stem-cell line, not an iPSC-derived or immortalized line.

Show evidence (3 references)

PMID:36711238 SUPPORT In Vitro

"BRPF1 deletion impairs H3K23ac in hESCs and leads to closed chromatin accessibility on stemness genes and hESC differentiation as well."

BRPF1-null H1 embryonic stem cells lose H3K23ac and accessibility at stemness loci. Other lineage-associated regions gain accessibility; this is not uniform genome-wide closure.

PMID:36711238 SUPPORT In Vitro

"H3K14ac and H3K23ac were restored upon DOX treatment but lost"

Doxycycline-induced BRPF1 re-expression restored measured acetylation and pluripotency in the engineered endogenous-knockout line; withdrawal reversed the rescue.

PMID:36711238 SUPPORT In Vitro

"N or PZP module deleted mut ant showed little effect on H3K23ac rescue"

N-terminal or PZP-deleted constructs failed to restore the mark effectively, whereas PWWP deletion largely retained rescue in this hESC assay. These engineered domains are not patient-variant classifications.

Brpf1-null fetal-liver and neonatal marrow colony cultures PRIMARY_CELL_CULTURE

Mutant progenitors formed fewer colonies, with smaller myeloid/erythroid colonies. These culture assays complement in vivo transplantation but do not distinguish reduced starting functional-cell numbers from every possible cell-intrinsic growth defect.

Organism

Mus musculus NCBITaxon:10090

Cell source

P6 bone marrow or E15.5 fetal liver from Brpf1 flox/flox; Vav1-iCre mice and controls

Culture

Methylcellulose myeloid/erythroid colony assays; neonatal marrow also tested in IL-7-containing pre-B colony medium

Publication

PMID:27500495

Pathograph links

Impaired Hematopoietic Stem and Progenitor Cell Maintenance measures fidelity: unknown observes: cellular

Limitations: Null mouse progenitors in cytokine-supported culture are not patient-derived heterozygous cells; results do not establish the mechanism of human cytopenias.

Readouts

Hematopoietic colony formation

Fewer myeloid/erythroid colonies from mutant fetal liver and marrow; fewer pre-B colonies from marrow.

Direction: DECREASED

Show evidence (1 reference)

PMID:27500495 SUPPORT In Vitro

"formed by mutant bone marrow cells was reduced compared to the control"

P6 marrow cells formed fewer and smaller myeloid/erythroid colonies; pre-B colonies and fetal-liver colony formation were also reduced.

Show evidence (1 reference)

PMID:27500495 SUPPORT In Vitro

"formed by mutant bone marrow cells was reduced compared to the control"

P6 marrow cells formed fewer and smaller myeloid/erythroid colonies; pre-B colonies and fetal-liver colony formation were also reduced.

🐁

Animal Models

Postnatal hippocampal Brpf1 shRNA knockdown mouse

Mice received hippocampal injections at four weeks of age and water-maze testing four weeks later. The authors reported a tendency toward reduced spatial performance, but acquisition latency and target-quadrant occupancy were unchanged. Culture electrophysiology in the same paper used separate embryonic neurons.

Species

Mus musculus

Genotype

Wild-type C57BL/6 mice receiving hippocampal AAV2-shBrpf1

Publication

PMID:34485298

Pathograph links

Impaired Learning and Memory measures fidelity: unknown observes: organism

Limitations: Five mice per group, regional postnatal knockdown and variable transcript reduction do not model lifelong heterozygous human loss. Negative principal maze readouts limit the claim of impaired spatial memory.

Readouts

Water-maze acquisition latency

Latency to reach the platform was almost the same between groups.

Direction: UNCHANGED

Probe-trial target-quadrant occupancy

No significant difference in the target quadrant was found.

Direction: UNCHANGED

Show evidence (2 references)

PMID:34485298 SUPPORT Model Organism

"Although the latency of mice to reach the platform was almost the same"

The acquisition-latency comparison did not demonstrate a learning deficit.

+ 1 more reference

Show evidence (2 references)

PMID:34485298 SUPPORT Model Organism

"Although the latency of mice to reach the platform was almost the same"

The acquisition-latency comparison did not demonstrate a learning deficit.

PMID:34485298 SUPPORT Model Organism

"although no significant difference in the target quadrant (SW) was found"

Target-quadrant occupancy was not significantly altered; reported behavioral effects were tendencies and differences in other quadrants.

Emx1-lineage conditional Brpf1 heterozygous mouse

Embryonic dorsal telencephalic deletion affects excitatory neurons and astroglial descendants while sparing ventrally derived interneurons. Behavioral experiments used 2-4-month-old C57BL/6 males; histological experiments used the ICR background. Acute CA1 slice electrophysiology, Golgi staining and electron microscopy are distinct measurements within this conditional model.

Species

Mus musculus

Genotype

Emx1-Cre; Brpf1 flox/+

Publication

PMID:31213987

Pathograph links

Impaired Dendritic Arborization partially recapitulates fidelity: unknown observes: cellular

Limitations: Conditional deletion in the mouse Emx1 lineage differs from constitutive heterozygous human BRPF1 disease; these measurements do not establish the corresponding patient mechanism.

Readouts

Dentate and cortical dendritic complexity

Golgi-stained dendrites had fewer Sholl intersections.

Direction: DECREASED

Show evidence (1 reference)

PMID:31213987 SUPPORT Model Organism

"Sholl analysis revealed a significant decrease in the number of intersections in Brpf1 HT and cKO neurons compared with that in WT neurons"

Golgi-stained dentate granule neurons had reduced dendritic complexity; similar changes were measured in layer V cortical neurons. The intervening transcriptional steps remain unresolved.

Reduced Dendritic Spine Density and Altered Spine Morphology partially recapitulates fidelity: unknown observes: cellular

Limitations: Conditional deletion in the mouse Emx1 lineage differs from constitutive heterozygous human BRPF1 disease; these measurements do not establish the corresponding patient mechanism.

Readouts

Cortical dendritic spine density

Fewer spines per unit dendrite length.

Direction: DECREASED

Cortical dendritic spine length

Remaining spines were longer.

Direction: INCREASED

Show evidence (2 references)

PMID:31213987 SUPPORT Model Organism

"Brpf1 HTs exhibited a significant reduction in the number of spines compared to that in WT mice."

Spines were counted along secondary apical dendritic branches of adult cortical pyramidal neurons.

+ 1 more reference

Reduced Excitatory Synaptic Transmission in Forebrain Neurons partially recapitulates fidelity: unknown observes: cellular

Limitations: Conditional deletion in the mouse Emx1 lineage differs from constitutive heterozygous human BRPF1 disease; these measurements do not establish the corresponding patient mechanism.

Readouts

CA1 miniature EPSC frequency and amplitude

Both measures decreased in acute slices from conditional heterozygotes.

Direction: DECREASED

Show evidence (1 reference)

PMID:31213987 SUPPORT Model Organism

"Collectively, these data show that Brpf1 haploinsufficiency causes reduced synaptic transmission and decreased cell excitability, which may contribute to abnormal behaviors."

Synaptic and behavioral deficits occur in the conditional heterozygous model, but their causal coupling was not tested by selective rescue.

Reduced Intrinsic Excitability of Hippocampal Pyramidal Neurons partially recapitulates fidelity: unknown observes: cellular

Limitations: Conditional deletion in the mouse Emx1 lineage differs from constitutive heterozygous human BRPF1 disease; these measurements do not establish the corresponding patient mechanism.

Readouts

Action-potential firing-current threshold

More injected current was required to evoke firing.

Direction: INCREASED

Resting membrane potential

No significant genotype difference was detected.

Direction: UNCHANGED

Show evidence (1 reference)

PMID:31213987 SUPPORT Model Organism

"The mean resting potential was comparable between HTs and WTs, while the mean action potential current threshold was significantly higher in the HTs than in the WTs"

Acute CA1 slice current-clamp recordings found increased firing-current threshold with preserved resting membrane potential.

Impaired Learning and Memory partially recapitulates fidelity: unknown observes: organism

Limitations: Conditional deletion in the mouse Emx1 lineage differs from constitutive heterozygous human BRPF1 disease; these measurements do not establish the corresponding patient mechanism.

Readouts

Water-maze target-quadrant occupancy

Reduced occupancy in the platform-free probe trial.

Direction: DECREASED

Show evidence (1 reference)

PMID:31213987 SUPPORT Model Organism

"Brpf1 HTs spent less time in the target quadrant where the platform was previously located"

Conditional heterozygous mice had reduced target-quadrant occupancy after water-maze training; contextual and cued fear-conditioning tests also showed reduced freezing.

Gross cortical layering, dentate granule-cell number and GFAP organization were preserved. Corpus callosum thickness was reduced by 17.7%. Synaptic vesicle number and density were unchanged in heterozygotes but reduced in conditional homozygotes. Histological and behavioral strain backgrounds differ, so the study does not establish a direct quantitative anatomy-behavior relationship.

Show evidence (3 references)

PMID:31213987 SUPPORT Model Organism

"Sholl analysis revealed a significant decrease in the number of intersections in Brpf1 HT and cKO neurons compared with that in WT neurons"

Golgi-stained dentate granule neurons had reduced dendritic complexity; similar changes were measured in layer V cortical neurons. The intervening transcriptional steps remain unresolved.

PMID:31213987 SUPPORT Model Organism

"Collectively, these data show that Brpf1 haploinsufficiency causes reduced synaptic transmission and decreased cell excitability, which may contribute to abnormal behaviors."

Synaptic and behavioral deficits occur in the conditional heterozygous model, but their causal coupling was not tested by selective rescue.

PMID:31213987 SUPPORT Model Organism

"Brpf1 HTs spent less time in the target quadrant where the platform was previously located"

Conditional heterozygous mice had reduced target-quadrant occupancy after water-maze training; contextual and cued fear-conditioning tests also showed reduced freezing.

Postnatal CaMKIIa-Cre conditional Brpf1 knockout mouse

C57BL/6J males with forebrain excitatory-neuron deletion beginning in the third to fourth postnatal week. Hippocampal Brpf1 RNA was reduced by approximately 60% at two months. The mice survived into adulthood, and gross cortical and hippocampal histology was preserved at six months.

Species

Mus musculus

Genotype

Brpf1 flox/flox; CaMKIIa-Cre

Publication

PMID:37862219

Pathograph links

Reduced Excitatory Synaptic Transmission in Forebrain Neurons measures fidelity: unknown observes: cellular

Limitations: Postnatal homozygous deletion in selected excitatory neurons differs from lifelong heterozygous human disease. Bulk CA1 RNA was measured at two months, electrophysiology at six months, and most behavior at two months; direct transcript-to-physiology-to-behavior mediation was not tested.

Readouts

CA1 mEPSC frequency at six months

Reduced frequency in acute slices.

Direction: DECREASED

CA1 mEPSC amplitude at six months

No significant amplitude change.

Direction: UNCHANGED

Show evidence (1 reference)

PMID:37862219 SUPPORT Model Organism

"We found that the frequency but not the amplitude of mEPSCs decreased significantly"

Acute CA1 slices from six-month-old CaMKIIa-Cre conditional homozygous mice showed reduced mEPSC frequency, with amplitude and measured membrane properties preserved.

Impaired Learning and Memory measures fidelity: unknown observes: organism

Readouts

Spatial-reference probe performance

Less time in the target quadrant at two months.

Direction: DECREASED

Contextual fear freezing

Reduced freezing at two months.

Direction: DECREASED

Cued fear freezing

No significant group difference at two months.

Direction: UNCHANGED

Water-maze acquisition latency

No significant group difference during training at two months.

Direction: UNCHANGED

Novel-object discrimination

Discrimination ratio was preserved at two months.

Direction: UNCHANGED

Show evidence (2 references)

PMID:37862219 SUPPORT Model Organism

"forebrain excitatory neuron-specific deletion ofBrpf1led to impaired contextual but not cued fear memory"

At two months, contextual freezing and spatial-reference probe performance were impaired, while cued freezing and acquisition latency were unchanged.

+ 1 more reference

Altered Developmental Transcriptional Programs measures fidelity: unknown observes: cellular

Readouts

Hippocampal CA1 gene expression

Both upregulated and downregulated genes; selected changes validated by qPCR.

Direction: ALTERED

Show evidence (1 reference)

PMID:37862219 SUPPORT Model Organism

"The results showed a dual role forBrpf1in regulating gene expression, that is, regulating both gene activation and suppression."

Notes

RNA sequencing is deposited as GSE212983. Small behavioral groups and a lack of significant social preference in control mice limit negative sociability conclusions. The paper names Rho as rhodopsin but then invokes Rho GTPase biology; that annotation inconsistency does not establish a Rho-GTPase mechanism. Visual acuity was not tested, and the authors identify it as a potential water-maze confound.

Show evidence (3 references)

PMID:37862219 SUPPORT Model Organism

"We found that the frequency but not the amplitude of mEPSCs decreased significantly"

Acute CA1 slices from six-month-old CaMKIIa-Cre conditional homozygous mice showed reduced mEPSC frequency, with amplitude and measured membrane properties preserved.

PMID:37862219 SUPPORT Model Organism

"forebrain excitatory neuron-specific deletion ofBrpf1led to impaired contextual but not cued fear memory"

At two months, contextual freezing and spatial-reference probe performance were impaired, while cued freezing and acquisition latency were unchanged.

PMID:37862219 SUPPORT Model Organism

"The results showed a dual role forBrpf1in regulating gene expression, that is, regulating both gene activation and suppression."

Hematopoietic Vav1-iCre Brpf1 conditional knockout mouse

C57BL/6J conditional homozygotes develop fetal stem/progenitor defects, progressive neonatal marrow aplasia and pancytopenia, with median death at P18 and no survival beyond P21 in the reported survival cohort. Competitive marrow and fetal-liver transplantation tests show severe loss of repopulating activity. Erythroid maturation is much less affected than the stem/progenitor compartment.

Species

Mus musculus

Genotype

Brpf1 flox/flox; Vav1-iCre, deleting exons 4-6 in hematopoietic lineages

Publication

PMID:27500495

Pathograph links

Impaired Hematopoietic Stem and Progenitor Cell Maintenance measures fidelity: unknown observes: cellular

Limitations: Complete blood-lineage loss in mice is more severe than heterozygous human BRPF1 disease. Slamf1/CD150 expression itself declines, so immunophenotypic counts should be interpreted alongside functional transplantation assays. Neither anemia nor thrombocytopenia in reported patients establishes this marrow-failure mechanism.

Readouts

Competitive marrow repopulating activity

Mutant donor cells failed to contribute detectably to recipient blood lineages over 4-16 weeks.

Direction: ABOLISHED

Marrow homing at 40 hours

Short-term donor-cell recovery was comparable to control.

Direction: UNCHANGED

Fetal LSK proliferation

Ki67 and cell-cycle analyses showed no clear fetal proliferation defect.

Direction: UNCHANGED

Neonatal marrow LSK proliferation

Fewer cycling LSK cells at P6.

Direction: DECREASED

Show evidence (3 references)

PMID:27500495 SUPPORT Model Organism

"the mutant bone marrow cells were unable to repopulate in the recipient peripheral blood"

Competitive transplantation found almost no mutant contribution at 4-16 weeks, supporting loss of functional repopulating activity.

+ 2 more references

Deficient Histone H3K23 Acetylation measures fidelity: unknown observes: cellular

Readouts

H3K23ac in sorted neonatal marrow LSK cells

Immunofluorescence was undetectable at P7.

Direction: ABOLISHED

Show evidence (1 reference)

PMID:27500495 SUPPORT Model Organism

"The fluorescence signal for lysine 23 acetylation was undetectable in sorted mutant LSK cells at P7"

Sorted-cell assays show loss of this histone mark; bulk marrow H3K9/H3K14 acetylation also declines.

Vav1-iCre does not complete deletion at E11.5; these experiments do not resolve BRPF1 function at the earliest emergence of hematopoietic stem cells. Postnatal maintenance independent of the fetal defect was not isolated.

Show evidence (2 references)

PMID:27500495 SUPPORT Model Organism

"the mutant bone marrow cells were unable to repopulate in the recipient peripheral blood"

Competitive transplantation found almost no mutant contribution at 4-16 weeks, supporting loss of functional repopulating activity.

PMID:27500495 SUPPORT Model Organism

"the mutant bone marrow cells are normal in homing"

Donor-cell recovery 40 hours after transplantation was preserved despite failed longer-term repopulation.

Hematopoietic Vav1-iCre Brpf1 conditional heterozygous mouse

The zygosity comparison reported survival indistinguishable from wild type and no significant change in neonatal LSK-cell numbers. This is a limited negative comparison, not a demonstration that every hematopoietic function is normal.

Species

Mus musculus

Genotype

Brpf1 flox/+; Vav1-iCre

Publication

PMID:27500495

Pathograph links

Impaired Hematopoietic Stem and Progenitor Cell Maintenance measures fidelity: unknown observes: cellular

Limitations: Heterozygosity is restricted to the targeted blood lineage. The report does not establish normal lifelong blood counts, stem-cell reserve or stress responses.

Readouts

Neonatal LSK-cell number

No significant difference from wild type in the reported comparison.

Direction: UNCHANGED

Show evidence (1 reference)

PMID:27500495 SUPPORT Model Organism

"No significant difference was observed between wild-type and heterozygous LSK cell numbers"

Conditional heterozygotes did not show the neonatal LSK depletion observed after homozygous deletion; this negative comparison limits direct extrapolation to human heterozygosity.

Show evidence (2 references)

PMID:27500495 SUPPORT Model Organism

"No significant difference was observed between wild-type and heterozygous LSK cell numbers"

Conditional heterozygotes did not show the neonatal LSK depletion observed after homozygous deletion; this negative comparison limits direct extrapolation to human heterozygosity.

PMID:27500495 SUPPORT Model Organism

"Brpf1fl/+ Vav1-iCre mice were indistinguishable from the wild-type"

The comparison concerns survival; it does not exclude subtle or age-dependent hematopoietic abnormalities.

Embryonic Emx1-Cre Brpf1 conditional homozygous mouse

Forebrain-specific deletion produces cortical abnormalities, partial callosal agenesis and predominantly early postnatal lethality. This is distinct from the conditional heterozygous and postnatal CaMKIIa-Cre models.

Species

Mus musculus

Genotype

Brpf1 flox/flox; Emx1-Cre

Publication

PMID:25568313

Pathograph links

Aberrant Cortical Neurogenesis measures fidelity: unknown observes: cellular

Limitations: Embryonic homozygous forebrain deletion is more severe than constitutive heterozygous human disease. Neural progenitor and callosal findings coexist but do not identify a unique causal mediator.

Readouts

Tbr2-positive intermediate neuronal progenitors

Fewer progenitors were observed in mutant forebrain.

Direction: DECREASED

Show evidence (1 reference)

PMID:25568313 SUPPORT Model Organism

"With respect to the control, the mutant forebrain contained fewer Tbr2-positive intermediate neuronal progenitors and displayed aberrant neurogenesis."

Identifies depletion of intermediate neuronal progenitors as the cellular basis of the cortical phenotype.

Abnormal Corpus Callosum Development measures fidelity: unknown observes: tissue

Readouts

Corpus callosum anatomy

Partial agenesis after conditional homozygous deletion.

Direction: ALTERED

Show evidence (1 reference)

PMID:25568313 SUPPORT Model Organism

"Here, we report that forebrain-specific inactivation of the mouse Brpf1 gene caused early postnatal lethality, neocortical abnormalities, and partial callosal agenesis."

The conditional homozygous model has a tissue-level callosal phenotype; it does not establish a universal callosal defect in heterozygous humans.

Show evidence (1 reference)

PMID:25568313 SUPPORT Model Organism

"Here, we report that forebrain-specific inactivation of the mouse Brpf1 gene caused early postnatal lethality, neocortical abnormalities, and partial callosal agenesis."

The conditional homozygous model has a tissue-level callosal phenotype; it does not establish a universal callosal defect in heterozygous humans.

Zebrafish brpf1 pharyngeal-patterning mutants

Three alleles and a splice-blocking morpholino produce anterior transformations of pharyngeal arches 2–6. Anterior Hox expression initiates normally but is not maintained; neural crest migration and more posterior Hox expression are preserved. The PWWP-lacking t25114 allele is not detectably milder than severe truncation alleles. Mouse Brpf1 mRNA partly rescues Hox expression. Trichostatin A rescues Hox expression and alleviates skeletal abnormalities; hoxb1a injection can normalize the arch marker pattern or overcorrect it to a bihyoid pattern.

Species

Danio rerio

Genotype

Homozygous brpf1 t20002, b943 or t25114

Publication

PMID:18469222

Pathograph links

Altered Developmental Transcriptional Programs partially recapitulates fidelity: unknown observes: cellular

Limitations: Homozygous zebrafish truncation or splice alleles cause homeotic pharyngeal transformations. Human BRPF1-associated facial dysmorphism has not been shown to be a homeotic transformation, and these rescue experiments do not establish clinical treatment benefit.

Readouts

Maintenance of anterior Hox expression in cranial neural crest

hoxa2b and hoxb2a are lost after initially normal expression; posterior Hox genes are relatively preserved.

Direction: DECREASED

Show evidence (1 reference)

PMID:18469222 SUPPORT Model Organism

"We conclude that Brpf1 is specifically required for the maintenance, but not for the initiation, of anterior Hox gene expression."

Zebrafish mutants lose maintenance of anterior Hox expression; initiation and neural crest migration were preserved. This is not a demonstrated human craniofacial pathway.

Altered Developmental Transcriptional Programs rescues fidelity: unknown observes: cellular

Readouts

Anterior Hox expression after mouse Brpf1 mRNA injection

Partial significant rescue at 33 hours post-fertilization.

Direction: INCREASED

hoxa2b expression after trichostatin A exposure

The reported 20–33-hour exposure restored the measured neural-crest transcriptional readout.

Direction: RESTORED

Show evidence (2 references)

PMID:18469222 SUPPORT Model Organism

"zebrafish brpf1 mutants injected with mouse Brpf1 mRNA displayed a partial, but significant rescue of anterior Hox gene expression at 33 hpf"

Cross-species mRNA rescue supports a conserved developmental function without reproducing the human heterozygous genotype.

+ 1 more reference

Show evidence (1 reference)

PMID:18469222 SUPPORT Model Organism

"We conclude that Brpf1 is specifically required for the maintenance, but not for the initiation, of anterior Hox gene expression."

Zebrafish mutants lose maintenance of anterior Hox expression; initiation and neural crest migration were preserved. This is not a demonstrated human craniofacial pathway.

Constitutive Brpf1-null mouse embryo

Global inactivation causes lethality around E9.5 with vascular disorganization in embryo, yolk sac and placenta, impaired placental labyrinth branching, and cranial neural tube closure defects. Reduced mitotic staining precedes conspicuous apoptosis, which appears at E10.5; gamma-H2AX staining is not detectably increased at E9.5. These severe complete-loss phenotypes should not be assigned to heterozygous human disease.

Species

Mus musculus

Genotype

Brpf1 homozygous inactive delta/delta or -/- alleles

Publication

PMID:25773539

Pathograph links

Altered Developmental Transcriptional Programs measures fidelity: unknown observes: cellular

Limitations: Whole-embryo expression after complete loss differs from heterozygous human neurons. Individual transcript changes were not rescued to establish mediation of vascular or neural tube defects.

Readouts

Rpl10l transcript in E8.75 embryos

Validated by RT-qPCR; the change is context-specific.

Direction: DECREASED

Scp3l transcript in E8.75 embryos

Validated by RT-qPCR; pathogenic mediation remains hypothetical.

Direction: INCREASED

Show evidence (1 reference)

PMID:25773539 SUPPORT Model Organism

"we confirmed that Rpl10l (ribosomal protein L10-like) mRNA decreased, whereas Scp3l (synaptonemal complex protein 3-like; or Gm773, for predicted gene 773) mRNA increased in Brpf1-null embryos"

Transcript changes were validated in E8.75 embryos; Rpl10l reduction was not reproduced in later embryonic fibroblasts.

Show evidence (2 references)

PMID:25773539 SUPPORT Model Organism

"the ablation leads to vascular defects in the placenta, yolk sac, and embryo proper, as well as abnormal neural tube closure."

Global null mouse embryos have severe developmental defects; these are not established clinical manifestations of heterozygous human BRPF1 disease.

PMID:25773539 SUPPORT Model Organism

"we confirmed that Rpl10l (ribosomal protein L10-like) mRNA decreased, whereas Scp3l (synaptonemal complex protein 3-like; or Gm773, for predicted gene 773) mRNA increased in Brpf1-null embryos"

Transcript changes were validated in E8.75 embryos; Rpl10l reduction was not reproduced in later embryonic fibroblasts.

{ }

Source YAML

click to show

name: BRPF1-Related Intellectual Disability
creation_date: "2026-07-31T00:00:00Z"
synonyms:
- Intellectual developmental disorder with dysmorphic facies and ptosis
- IDDDFP
- BRPF1-related disorder
- BRPF1-related neurodevelopmental disorder
- BRPF1-associated intellectual disability, ptosis, and facial dysmorphism
description: 'BRPF1-related intellectual disability (intellectual developmental disorder with dysmorphic facies and ptosis, IDDDFP; OMIM 617333) is an autosomal dominant neurodevelopmental disorder caused by heterozygous loss-of-function variants in BRPF1. BRPF1 is not itself an acetyltransferase: it is the multivalent chromatin-reader scaffold that assembles and activates the MYST lysine acetyltransferases KAT6A (MOZ) and KAT6B (MORF) together with ING4/ING5 and MEAF6. Its signature catalytic output is acetylation - and, as later shown, propionylation - of histone H3 at lysine 23 (H3K23), and tested patient variants can impair both acylations, with allele-specific effects. The clinical core is developmental delay with a strikingly consistent speech and language disorder, variable (usually mild-to-moderate, occasionally absent) intellectual disability, infantile hypotonia and feeding difficulty, and a recognizable periocular facial gestalt dominated by ptosis and blepharophimosis with downslanted palpebral fissures and a broad nasal bridge. Ocular involvement beyond the eyelids (strabismus, amblyopia, refractive error, coloboma, subclinical optic neuropathy) supports comprehensive ophthalmological
  assessment. Corpus callosum abnormalities have also been reported in a subset of imaged patients. Expressivity within families is wide, extending to carriers with normal intellect.'

category: Mendelian
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      A monogenic, autosomal dominant Mendelian disorder identified and
      diagnosed by exome sequencing.
    evidence:
    - reference: PMID:27939640
      reference_title: "Mutations in the Chromatin Regulator Gene BRPF1 Cause Syndromic Intellectual Disability and Deficient Histone Acetylation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Here, we describe an intellectual disability disorder in ten individuals
        with inherited or de novo monoallelic BRPF1 mutations.
      explanation: >-
        Establishes the entity as a monogenic, monoallelic (dominant) genetic
        disorder.
  - classification_value: NEUROLOGIC
    notes: >-
      The dominant clinical burden is neurodevelopmental: developmental delay,
      intellectual disability, speech and language disorder, and hypotonia.
    evidence:
    - reference: PMID:27939640
      reference_title: "Mutations in the Chromatin Regulator Gene BRPF1 Cause Syndromic Intellectual Disability and Deficient Histone Acetylation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Symptoms include infantile hypotonia, global developmental delay,
        intellectual disability, expressive language impairment, and facial
        dysmorphisms.
      explanation: >-
        The core symptom set is neurologic/neurodevelopmental.
disease_term:
  preferred_term: intellectual developmental disorder with dysmorphic facies and ptosis
  term:
    id: MONDO:0015022
    label: intellectual developmental disorder with dysmorphic facies and ptosis
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0015022
      label: intellectual developmental disorder with dysmorphic facies and ptosis
    mapping_predicate: skos:exactMatch
    mapping_source: Orphanet ORPHA:698090
    mapping_justification: >
      Orphanet's record for ORPHA:698090 (Ophthalmological abnormalities-facial
      dysmorphism-intellectual disability syndrome, synonym "BRPF1-related
      neurodevelopmental disorder") carries an Exact cross-reference to
      OMIM:617333, the OMIM phenotype MONDO:0015022 is built on. Orphanet lists
      BRPF1 (hgnc:14255) as the disease-causing gene, matching this entry.
parents:
- autosomal dominant syndromic intellectual disability

inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Heterozygous BRPF1 variants act in a dominant, haploinsufficiency mode.
    Unlike many de-novo-dominant chromatinopathies, a large fraction of reported
    BRPF1 variants are inherited from a mildly affected or apparently unaffected
    parent, and recurrence in one reported sibship suggested parental gonadal mosaicism.
    Expressivity is wide even within a single family.
  expressivity: VARIABLE
  evidence:
  - reference: PMID:27939640
    reference_title: "Mutations in the Chromatin Regulator Gene BRPF1 Cause Syndromic Intellectual Disability and Deficient Histone Acetylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we describe an intellectual disability disorder in ten individuals
      with inherited or de novo monoallelic BRPF1 mutations.
    explanation: >-
      Monoallelic (heterozygous) variants, both inherited and de novo, cause the
      disorder.
  - reference: PMID:37946714
    reference_title: "Mosaicism in BRPF1-Related Neurodevelopmental Disorder: Report of Two Sisters and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both de novo and inherited pathogenic variants have been previously
      reported in association with this disorder.
    explanation: >-
      Confirms the mixed de novo / inherited origin of pathogenic alleles.
  - reference: PMID:39837771
    reference_title: "The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Familial analysis revealed variability in clinical expression."
    explanation: >-
      The largest cohort documents variable expressivity within families.

references:
- reference: PMID:27939639
  title: Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual Disability with Associated Ptosis.
- reference: PMID:27939640
  title: Mutations in the Chromatin Regulator Gene BRPF1 Cause Syndromic Intellectual Disability and Deficient Histone Acetylation.
- reference: PMID:39837771
  title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
- reference: CGDS:HGNC_14255
  title: BRPF1 dosage sensitivity
- reference: ORPHA:698090
  title: Ophthalmological abnormalities-facial dysmorphism-intellectual disability syndrome
- reference: PMID:38346666
  title: 'Beyond ''speech delay'': Expanding the phenotype of BRPF1-related disorder.'
- reference: PMID:37946714
  title: 'Mosaicism in BRPF1-Related Neurodevelopmental Disorder: Report of Two Sisters and Literature Review.'
- reference: PMID:31020800
  title: BRPF1-associated intellectual disability, ptosis, and facial dysmorphism in a multiplex family.
- reference: PMID:32457794
  title: Novel Missense Variant in Heterozygous State in the BRPF1 Gene Leading to Intellectual Developmental Disorder With Dysmorphic Facies and Ptosis.
- reference: PMID:35243762
  title: 'BRPF1-associated syndrome: A patient with congenital ptosis, neurological findings, and normal intellectual development.'
- reference: PMID:31176769
  title: Novel BRPF1 mutation in a boy with intellectual disability, coloboma, facial nerve palsy and hypoplasia of the corpus callosum.
- reference: PMID:38590032
  title: 'Broadening the ocular phenotypic spectrum of ultra-rare BRPF1 variants: report of two cases.'
- reference: PMID:40752867
  title: 'Ocular findings of BRPF1 variants: a case report and literature review.'
- reference: PMID:37190896
  title: 'Anemia and thrombocytopenia due to a novel BRPF1 variant in a family from Çanakkale with intellectual disability and dysmorphic facies: Case report and review of the literature.'
- reference: PMID:32010779
  title: Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer.
- reference: PMID:36077605
  title: 'BRPF1-KAT6A/KAT6B Complex: Molecular Structure, Biological Function and Human Disease.'
- reference: PMID:36711238
  title: BRPF1 bridges H3K4me3 and H3K23ac in human embryonic stem cells and is essential to pluripotency.
- reference: PMID:31213987
  title: Brpf1 Haploinsufficiency Impairs Dendritic Arborization and Spine Formation, Leading to Cognitive Deficits.
- reference: PMID:34485298
  title: Deficiency of Intellectual Disability-Related Gene Brpf1 Attenuated Hippocampal Excitatory Synaptic Transmission and Impaired Spatial Learning and Memory Ability.
- reference: PMID:33744924
  title: Deficiency of intellectual disability-related gene Brpf1 reduced inhibitory neurotransmission in MGE-derived GABAergic interneurons.
- reference: PMID:37862219
  title: Forebrain excitatory neuron-specific loss of Brpf1 attenuates excitatory synaptic transmission and impairs spatial and fear memory.
- reference: PMID:25568313
  title: Deficiency of the chromatin regulator BRPF1 causes abnormal brain development.
- reference: PMID:24646517
  title: Expression atlas of the multivalent epigenetic regulator Brpf1 and its requirement for survival of mouse embryos.
- reference: PMID:27500495
  title: BRPF1 is essential for development of fetal hematopoietic stem cells.
- reference: PMID:41137536
  title: Non-RASopathy Genetic Syndromes Identified as the Molecular Cause of Disease in Patients Previously Diagnosed With Noonan Syndrome.
- reference: PMID:18469222
  title: The multidomain protein Brpf1 binds histones and is required for Hox gene expression and segmental identity.
- reference: PMID:25773539
  title: The chromatin regulator Brpf1 regulates embryo development and cell proliferation.
- reference: PMID:40593219
  title: 'Bromodomain and PHD Finger-Containing Protein 1: From Functions to a Developmental Disorder, Cancer, and Therapeutics.'
- reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1441/
  title: Blepharophimosis, Ptosis, and Epicanthus Inversus Syndrome - GeneReviews® - NCBI Bookshelf
  tags:
  - GeneReviews

mechanistic_hypotheses:
- hypothesis_group_id: h3k23_acetylation_loss
  hypothesis_label: H3K23 Acetylation Deficiency Branch
  status: CANONICAL
  description: >-
    The canonical molecular lesion is loss of BRPF1-dependent acetylation of
    histone H3 at lysine 23. Patient-derived BRPF1 variants impair H3K23
    acetylation in functional assays, and the same deficiency is reproduced in
    Brpf1-knockout mice, making this the best-supported route from gene to
    chromatin defect.
  evidence:
  - reference: PMID:27939640
    reference_title: "Mutations in the Chromatin Regulator Gene BRPF1 Cause Syndromic Intellectual Disability and Deficient Histone Acetylation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Functional assays showed that the resulting BRPF1 variants are pathogenic
      and impair acetylation of histone H3 at lysine 23, an abundant but poorly
      characterized epigenetic mark.
    explanation: >-
      Directly establishes impaired H3K23 acetylation as the molecular
      consequence of patient BRPF1 variants.
- hypothesis_group_id: h3k23_propionylation_loss
  hypothesis_label: H3K23 Propionylation Deficiency Branch
  status: EMERGING
  description: >-
    A later-recognized, non-redundant arm: the same BRPF1-KAT6 complexes also
    catalyze H3K23 propionylation, and patient BRPF1 variants impair this
    acylation as well. Whether the propionylation deficit contributes to the
    clinical phenotype independently of the acetylation deficit is not
    established; the two marks are currently inseparable in patient material.
    This branch nonetheless motivates the pharmacologic acylation-restoration
    strategy (propionate, butyrate, valproate, vorinostat) that has so far been
    demonstrated only in cell systems.
  evidence:
  - reference: PMID:32010779
    reference_title: "Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Moreover, we identify BRPF1 variants in 12 previously unidentified cases
      of syndromic intellectual disability and demonstrate that these cases and
      known BRPF1 variants impair H3K23 propionylation.
    explanation: >-
      Establishes propionylation loss as a distinct, patient-variant-associated
      acylation defect.

pathophysiology:
- name: Heterozygous BRPF1 Loss-of-Function Variation
  description: The initiating lesion is a heterozygous BRPF1 variant, either de novo or inherited. Reported alleles are predominantly protein-truncating (nonsense, frameshift) or whole-gene/partial deletions, with a smaller number of missense and stop-loss alleles; a single 3p25 contiguous deletion can remove BRPF1 together with SETD5.
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  genes:
  - preferred_term: BRPF1
    term:
      id: hgnc:14255
      label: BRPF1
  genetic_context:
    gene:
      preferred_term: BRPF1
      term:
        id: hgnc:14255
        label: BRPF1
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: Heterozygous BRPF1 truncating, splice, deletion and missense alleles. Recorded as LOSS_OF_FUNCTION (haploinsufficiency).
  evidence:
  - reference: PMID:27939639
    reference_title: Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual Disability with Associated Ptosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We performed exome sequencing in a large family affected by an autosomal-dominant form of mild syndromic ID with ptosis, growth retardation, and hypotonia, and we identified an inherited 2 bp deletion causing a frameshift in BRPF1 (c.1052_1053del) in five affected family members.
    explanation: The founding family establishes a heterozygous frameshift BRPF1 allele segregating with the phenotype.
  - reference: PMID:27939639
    reference_title: Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual Disability with Associated Ptosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We identified BRPF1 deletions or point mutations in six additional individuals with a similar phenotype.
    explanation: Documents the allelic spectrum as both deletions and point mutations.
  - reference: PMID:31020800
    reference_title: BRPF1-associated intellectual disability, ptosis, and facial dysmorphism in a multiplex family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: To conclude, BRPF1 haploinsufficiency is an underdiagnosed cause of intellectual disability of variable severity, ptosis and/or blepharophimosis and additional nonspecific features, and should be considered in relevant clinical circumstances.
    explanation: Multiplex-family study attributing the phenotype to BRPF1 haploinsufficiency.
  downstream:
  - target: BRPF1 Haploinsufficiency
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37946714
      reference_title: 'Mosaicism in BRPF1-Related Neurodevelopmental Disorder: Report of Two Sisters and Literature Review.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The frameshift pathogenic variant reported here lends further support to haploinsufficiency as the underlying mechanism of disease.
      explanation: Truncating alleles are interpreted as producing haploinsufficiency rather than a dominant-negative product.
- name: BRPF1 Haploinsufficiency
  description: Heterozygous loss-of-function variants reduce functional BRPF1 scaffold activity. Haploinsufficiency is supported by clinical genetics and dosage curation, but does not establish an exact halving of protein abundance. The c.1052_1053del transcript undergoes partial nonsense-mediated decay; its residual truncated product has allele-specific defects in stability, localization and partner recruitment in expression assays. Comparison of BRPF1 lesions, SETD5 lesions and deletions spanning both genes implicates BRPF1 dosage particularly in the periocular phenotype.
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:27939639
    reference_title: Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual Disability with Associated Ptosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We conclude that both genes contribute to the phenotypic severity of 3p25 deletion syndrome but that some specific features, such as ptosis and blepharophimosis, are mostly driven by BRPF1 haploinsufficiency.
    explanation: Attributes the discriminating periocular features specifically to BRPF1 dosage loss, separating it from the co-deleted SETD5.
  downstream:
  - target: Impaired BRPF1-KAT6 Acetyltransferase Complex Function
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27939640
      reference_title: Mutations in the Chromatin Regulator Gene BRPF1 Cause Syndromic Intellectual Disability and Deficient Histone Acetylation.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Bromodomain and PHD finger-containing protein 1 (BRPF1) is a multivalent chromatin regulator possessing three histone-binding domains, one non-specific DNA-binding module, and several motifs for interacting with and activating three lysine acetyltransferases.
      explanation: BRPF1's function is to interact with and activate the acetyltransferases, so reduced BRPF1 dose directly reduces complex activation.
  - target: Ptosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27939639
      reference_title: Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual Disability with Associated Ptosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: some specific features, such as ptosis and blepharophimosis, are mostly driven by BRPF1 haploinsufficiency
      explanation: The BRPF1-versus-SETD5 comparison attributes ptosis specifically to BRPF1 dosage; the developmental steps between chromatin and levator/eyelid development are unknown.
  - target: Blepharophimosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27939639
      reference_title: Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual Disability with Associated Ptosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: some specific features, such as ptosis and blepharophimosis, are mostly driven by BRPF1 haploinsufficiency
      explanation: Blepharophimosis is likewise assigned to BRPF1 dosage loss rather than to co-deleted genes.
- name: Impaired BRPF1-KAT6 Acetyltransferase Complex Function
  conforms_to: epigenetic_machinery_neurodevelopmental_dysregulation#Epigenetic Machinery Component Haploinsufficiency
  description: BRPF1 is the scaffold subunit of tetrameric MYST acetyltransferase complexes built around KAT6A (MOZ) or KAT6B (MORF) plus ING4/ING5 and MEAF6. Association with KAT7 (HBO1) has also been demonstrated in vitro, but its in-vivo relevance is less clear; KAT7 preferentially associates with BRD1 or BRPF3 in vivo. Patient variants can impair partner recruitment and catalytic stimulation, with effects that depend on the allele. For example, p.Val351GlyfsTer8 retains KAT6A binding but fails to recruit ING5 and MEAF6 in transfected cells. BRPF1-, KAT6A- and KAT6B-related disorders overlap clinically, but their differences do not by themselves establish which additional partners or independent activities account for that overlap.
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  molecular_functions:
  - preferred_term: histone acetyltransferase activity
    term:
      id: GO:0004402
      label: histone acetyltransferase activity
    modifier: DECREASED
  cellular_components:
  - preferred_term: MOZ/MORF histone acetyltransferase complex
    term:
      id: GO:0070776
      label: MOZ/MORF histone acetyltransferase complex
    modifier: ABNORMAL
  evidence:
  - reference: PMID:24646517
    reference_title: Expression atlas of the multivalent epigenetic regulator Brpf1 and its requirement for survival of mouse embryos.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Within these complexes, BRPF1 serves as a scaffold for bridging subunit interaction, stimulating acetyltransferase activity, governing substrate specificity and stimulating gene expression.
    explanation: Defines normal scaffold functions. The extent to which each function is disrupted requires allele-specific assays.
  - reference: PMID:36077605
    reference_title: 'BRPF1-KAT6A/KAT6B Complex: Molecular Structure, Biological Function and Human Disease.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: It functions in the form of a tetrameric complex with a monocytic leukemia zinc finger protein (MOZ or KAT6A), MOZ-related factor (MORF or KAT6B) or HAT bound to ORC1 (HBO1 or KAT7) and two small non-catalytic proteins, the inhibitor of growth 5 (ING5) or the paralog ING4 and MYST/Esa1-associated factor 6 (MEAF6).
    explanation: Defines the composition of the complexes that BRPF1 scaffolds.
  - reference: PMID:27939640
    reference_title: Mutations in the Chromatin Regulator Gene BRPF1 Cause Syndromic Intellectual Disability and Deficient Histone Acetylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: These clinical features overlap with but are not identical to those reported for persons with KAT6A or KAT6B mutations, suggesting that BRPF1 targets these two acetyltransferases and additional partners in humans.
    explanation: Documents clinical overlap and differences; the additional-partner explanation is the authors' interpretation.
  - reference: PMID:27939639
    reference_title: Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual Disability with Associated Ptosis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The protein variant shows an aberrant cellular location, loss of certain protein interactions, and decreased histone H3K23 acetylation.
    explanation: A patient allele changes localization and partner binding; the full text shows retained KAT6A binding alongside loss of ING5 and MEAF6 recruitment.
  - reference: PMID:27939639
    reference_title: Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual Disability with Associated Ptosis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Whereas the wild-type was able to bind ING5 and MEAF6, the p.Val351Glyfs∗8 variant failed to do so.
    explanation: Co-immunoprecipitation in transfected HEK293 cells identifies the affected partner interactions; the same experiment retained KAT6A binding.
  - reference: PMID:36077605
    reference_title: 'BRPF1-KAT6A/KAT6B Complex: Molecular Structure, Biological Function and Human Disease.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: the association of BRPF1 with KAT7 is not clear in vivo, although it was reported in vitro
    explanation: This review distinguishes demonstrated KAT6 complexes from the less certain in-vivo BRPF1-KAT7 association.
  downstream:
  - target: Deficient Histone H3K23 Acetylation
    causal_link_type: DIRECT
    hypothesis_groups:
    - h3k23_acetylation_loss
    evidence:
    - reference: PMID:32010779
      reference_title: Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Lysine acetyltransferase 6A (KAT6A) and its paralog KAT6B form stoichiometric complexes with bromodomain- and PHD finger-containing protein 1 (BRPF1) for acetylation of histone H3 at lysine 23 (H3K23).
      explanation: The complex's defining catalytic output is H3K23 acetylation, so impaired complex function directly reduces that mark.
  - target: Deficient Histone H3K23 Propionylation
    causal_link_type: DIRECT
    hypothesis_groups:
    - h3k23_propionylation_loss
    evidence:
    - reference: PMID:32010779
      reference_title: Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: We report that these complexes also catalyze H3K23 propionylation in vitro and in vivo.
      explanation: The same complexes carry out H3K23 propionylation, so complex impairment also reduces this acylation.
- name: Deficient Histone H3K23 Acetylation
  conforms_to: epigenetic_machinery_neurodevelopmental_dysregulation#Permissive-Repressive Chromatin State Imbalance
  description: 'Loss of BRPF1 scaffold activity can lower acetylation of histone H3 lysine 23; the effect depends on the allele and experimental context. In human embryonic stem cells, BRPF1, H3K4me3 and H3K23ac co-occupy open chromatin at stemness genes, linking BRPF1 occupancy with local histone modification. Co-occupancy does not itself establish direct recognition of H3K23ac by BRPF1. Assay context matters: the founding p.Val351GlyfsTer8 study found failure to stimulate H3K23 acetylation in transfected cells, while its patient-fibroblast decrease was not significant. Global H3, H3K9 and H3K14 acetylation were not detectably changed there. In the hESC knockout study, H3K4me3 persisted and H3K14ac was initially preserved before declining with differentiation; direct H3K4me3 recognition by BRPF1 was not biochemically resolved.'
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  molecular_functions:
  - preferred_term: histone H3K23 acetyltransferase activity
    term:
      id: GO:0043994
      label: histone H3K23 acetyltransferase activity
    modifier: DECREASED
  evidence:
  - reference: PMID:27939640
    reference_title: Mutations in the Chromatin Regulator Gene BRPF1 Cause Syndromic Intellectual Disability and Deficient Histone Acetylation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Functional assays showed that the resulting BRPF1 variants are pathogenic and impair acetylation of histone H3 at lysine 23, an abundant but poorly characterized epigenetic mark.
    explanation: Functional assays identify impaired H3K23 acetylation for patient-associated variants; the magnitude and detectability vary with allele and preparation.
  - reference: PMID:27939640
    reference_title: Mutations in the Chromatin Regulator Gene BRPF1 Cause Syndromic Intellectual Disability and Deficient Histone Acetylation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: We also found a similar deficiency in different lines of Brpf1-knockout mice.
    explanation: The acetylation deficit is reproduced in an independent in vivo system.
  - reference: PMID:27939639
    reference_title: Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual Disability with Associated Ptosis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: However, unlike wild-type BRPF1, the p.Val351Glyfs∗8 variant failed to stimulate K23 acetylation of histone H3
    explanation: The expression assay supports deficient stimulation of H3K23 acetylation. In patient fibroblasts from this study, the H3K23 decrease was slight and not statistically significant, so this is not evidence of a uniform measurable deficit in every patient sample.
  downstream:
  - target: Altered Chromatin Accessibility
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - h3k23_acetylation_loss
    evidence:
    - reference: PMID:36711238
      reference_title: BRPF1 bridges H3K4me3 and H3K23ac in human embryonic stem cells and is essential to pluripotency.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: BRPF1 deletion impairs H3K23ac in hESCs and leads to closed chromatin accessibility on stemness genes and hESC differentiation as well.
      explanation: BRPF1-null H1 embryonic stem cells lose H3K23ac and accessibility at stemness loci. Other lineage-associated regions gain accessibility; this is not uniform genome-wide closure. The paper explicitly identifies the biochemical link between H3K23ac loss and reduced accessibility as unresolved.
- name: Deficient Histone H3K23 Propionylation
  description: 'BRPF1-KAT6 complexes propionylate H3K23. Several patient variants impair this activity, and the mark is reduced in Pro370Ser lymphoblastoid cells and Arg455Ter lymphoblastoid cells and fibroblasts. Complete Brpf1 deletion abolishes detectable H3K23 propionylation in mouse embryos and cultured fibroblasts. Effects are allele- and assay-dependent: Pro76Leu retained stimulation in the biochemical assay, and some truncating products also retained activity. The independent contribution of propionylation loss to the human phenotype is unresolved.'
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  biological_processes:
  - preferred_term: peptidyl-lysine propionylation
    term:
      id: GO:0061921
      label: peptidyl-lysine propionylation
    modifier: DECREASED
  evidence:
  - reference: PMID:32010779
    reference_title: Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Moreover, we identify BRPF1 variants in 12 previously unidentified cases of syndromic intellectual disability and demonstrate that these cases and known BRPF1 variants impair H3K23 propionylation.
    explanation: Patient variants impair H3K23 propionylation.
  - reference: PMID:32010779
    reference_title: Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Brpf1 deletion obliterates the acylation in mouse embryos and fibroblasts.
    explanation: In vivo loss of Brpf1 abolishes the acylation, confirming BRPF1 dependence.
  - reference: PMID:32010779
    reference_title: Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The Pro76Leu variant was normally expressed and promoted the expression of ING5 and MEAF6 as wild-type BRPF1
    explanation: This variant retained stimulation of H3K23 acylation in the study; its disease relationship remained uncertain. A blanket loss-of-function assertion for every reported variant is inappropriate.
  downstream:
  - target: Altered Developmental Transcriptional Programs
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - h3k23_propionylation_loss
    evidence:
    - reference: PMID:32010779
      reference_title: Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Immunofluorescence microscopy and ATAC-See revealed the association of this modification with active chromatin.
      explanation: H3K23 propionylation associates with active chromatin. A contribution to altered transcription is hypothesized; selective loss or restoration of this mark was not shown to mediate the transcriptome or clinical phenotype.
- name: Altered Chromatin Accessibility
  description: Complete BRPF1 deletion in human H1 embryonic stem cells reduces ATAC-seq accessibility at stemness genes while increasing accessibility at lineage-associated genes. H3K4me3 remains substantially present despite loss of H3K23ac and pluripotency. Co-occupancy and rescue support BRPF1-dependent chromatin regulation, but the biochemical route from H3K23ac loss to accessibility change and its applicability to heterozygous patient neurons remain unresolved.
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  biological_processes:
  - preferred_term: chromatin organization
    term:
      id: GO:0006325
      label: chromatin organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:36711238
    reference_title: BRPF1 bridges H3K4me3 and H3K23ac in human embryonic stem cells and is essential to pluripotency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: BRPF1 deletion impairs H3K23ac in hESCs and leads to closed chromatin accessibility on stemness genes and hESC differentiation as well.
    explanation: BRPF1-null H1 embryonic stem cells lose H3K23ac and accessibility at stemness loci. Other lineage-associated regions gain accessibility; this is not uniform genome-wide closure.
  downstream:
  - target: Altered Developmental Transcriptional Programs
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36711238
      reference_title: BRPF1 bridges H3K4me3 and H3K23ac in human embryonic stem cells and is essential to pluripotency.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: BRPF1 deletion impairs H3K23ac in hESCs and leads to closed chromatin accessibility on stemness genes and hESC differentiation as well.
      explanation: Chromatin-accessibility changes accompany altered stemness and lineage expression after BRPF1 deletion. The study does not isolate accessibility as the sole mediator, and the inferred neural-disease connection is unproven.
- name: Altered Developmental Transcriptional Programs
  conforms_to: epigenetic_machinery_neurodevelopmental_dysregulation#Dysregulated Neurodevelopmental Transcriptional Program
  description: BRPF1 perturbation changes developmental gene expression in a context-dependent manner. Human embryonic stem-cell deletion suppresses stemness genes and activates lineage genes. In mouse hippocampal CA1 tissue, postnatal excitatory-neuron deletion both downregulates selected neural genes and derepresses normally suppressed transcription factors. These are distinct experimental systems; their transcriptomic changes do not identify a universal mediator of the human multisystem phenotype. In zebrafish mutants, anterior Hox expression is initiated normally but subsequently lost in cranial neural crest; this contrasts with elevated Hox expression after mouse forebrain deletion and illustrates tissue-dependent directionality.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  biological_processes:
  - preferred_term: regulation of transcription by RNA polymerase II
    term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
    modifier: ABNORMAL
  evidence:
  - reference: PMID:36711238
    reference_title: BRPF1 bridges H3K4me3 and H3K23ac in human embryonic stem cells and is essential to pluripotency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: BRPF1 deletion impairs H3K23ac in hESCs and leads to closed chromatin accessibility on stemness genes and hESC differentiation as well.
    explanation: BRPF1-null H1 embryonic stem cells lose H3K23ac and accessibility at stemness loci. Other lineage-associated regions gain accessibility; this is not uniform genome-wide closure.
  - reference: PMID:37862219
    reference_title: Forebrain excitatory neuron-specific loss of Brpf1 attenuates excitatory synaptic transmission and impairs spatial and fear memory.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: The results showed a dual role forBrpf1in regulating gene expression, that is, regulating both gene activation and suppression.
    explanation: RNA-seq and qPCR in hippocampal CA1 tissue show both directions of transcriptional change after postnatal conditional deletion. No individual transcript was rescued to prove mediation of physiology or behavior.
  - reference: PMID:18469222
    reference_title: The multidomain protein Brpf1 binds histones and is required for Hox gene expression and segmental identity.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: We conclude that Brpf1 is specifically required for the maintenance, but not for the initiation, of anterior Hox gene expression.
    explanation: Zebrafish mutants lose maintenance of anterior Hox expression; initiation and neural crest migration were preserved. This is not a demonstrated human craniofacial pathway.
  downstream:
  - target: Impaired Dendritic Arborization
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31213987
      reference_title: Brpf1 Haploinsufficiency Impairs Dendritic Arborization and Spine Formation, Leading to Cognitive Deficits.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Sholl analysis revealed a significant decrease in the number of intersections in Brpf1 HT and cKO neurons compared with that in WT neurons
      explanation: Golgi-stained dentate granule neurons had reduced dendritic complexity; similar changes were measured in layer V cortical neurons. The intervening transcriptional steps remain unresolved.
  - target: Reduced Inhibitory Neurotransmission in GABAergic Interneurons
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33744924
      reference_title: Deficiency of intellectual disability-related gene Brpf1 reduced inhibitory neurotransmission in MGE-derived GABAergic interneurons.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Our results demonstrated a key role of Brpf1 in inhibitory neurotransmission and related gene expression of GABAergic interneurons.
      explanation: Brpf1 knockdown changes cultured MGE-interneuron gene expression and synaptic physiology; transcriptional mediation is a hypothesis, not a rescue-demonstrated pathway.
  - target: Global Developmental Delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27939640
      reference_title: Mutations in the Chromatin Regulator Gene BRPF1 Cause Syndromic Intellectual Disability and Deficient Histone Acetylation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Symptoms include infantile hypotonia, global developmental delay, intellectual disability, expressive language impairment, and facial dysmorphisms.
      explanation: Global developmental delay is a core clinical endpoint of the chromatin defect.
  - target: Speech and Language Disorder
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38346666
      reference_title: 'Beyond ''speech delay'': Expanding the phenotype of BRPF1-related disorder.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: We have implicated BRPF1-related disorder as causative for speech and language disorder, including childhood apraxia of speech.
      explanation: Establishes speech and language disorder as a causally attributable endpoint of BRPF1 dysfunction.
  - target: Infantile Hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27939640
      reference_title: Mutations in the Chromatin Regulator Gene BRPF1 Cause Syndromic Intellectual Disability and Deficient Histone Acetylation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Symptoms include infantile hypotonia, global developmental delay, intellectual disability, expressive language impairment, and facial dysmorphisms.
      explanation: Infantile hypotonia is part of the core symptom set attributed to BRPF1 dysfunction.
  - target: Aberrant Cortical Neurogenesis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:25568313
      reference_title: Deficiency of the chromatin regulator BRPF1 causes abnormal brain development.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Molecularly, Brpf1 loss led to decreased transcription of multiple genes, such as Robo3 and Otx1, important for neocortical development.
      explanation: Developmental transcript changes accompany cortical abnormalities after conditional deletion; transcript-specific mediation or rescue was not established.
  - target: Impaired Hematopoietic Stem and Progenitor Cell Maintenance
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27500495
      reference_title: BRPF1 is essential for development of fetal hematopoietic stem cells.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: BRPF1 deficiency also reduced the expression of multipotency genes, including Slamf1, Mecom, Hoxa9, Hlf, Gfi1, Egr, and Gata3.
      explanation: The same transcriptional-program mechanism operates on hematopoietic multipotency genes.
  - target: Congenital Cardiac Anomalies
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32010779
      reference_title: Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Cardiac anomalies are present in a subset of the cases.
      explanation: Cardiac malformation occurs in a minority of BRPF1 cases described alongside the acylation defect.
  - target: Deregulated Ocular and Periocular Developmental Transcription Factor Programs
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39837771
      reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: has been shown to affect the transcriptional regulation of several key transcription factors, including Pitx2, Hmx1 and Pax6, which have been implicated in a wide range of ocular developmental abnormalities
      explanation: Identifies the ocular-developmental transcription factors whose regulation is lost downstream of the BRPF1 chromatin defect; the chromatin-to-transcription-factor steps are not individually mapped.
  - target: Reduced Intrinsic Excitability of MGE-Derived GABAergic Interneurons
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33744924
      reference_title: Deficiency of intellectual disability-related gene Brpf1 reduced inhibitory neurotransmission in MGE-derived GABAergic interneurons.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: For downregulated DEGs, We validated that Map2k7 was significantly decreased upon Brpf1 knockdown
      explanation: Map2k7 expression changes accompany intrinsic electrophysiological changes. No Map2k7 rescue establishes that it mediates the firing-threshold phenotype.
  - target: Reduced Dendritic Spine Density and Altered Spine Morphology
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31213987
      reference_title: Brpf1 Haploinsufficiency Impairs Dendritic Arborization and Spine Formation, Leading to Cognitive Deficits.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Statistical analysis revealed a significant increase in spine length in Brpf1 HT and cKO mice.
      explanation: Cortical spine length increased alongside a reduction in spine density; the measurements concern conditional mouse genotypes. Transcriptional mediation is inferred from BRPF1 function, not established by target-gene rescue.
  - target: Impaired Axonal Outgrowth
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31213987
      reference_title: Brpf1 Haploinsufficiency Impairs Dendritic Arborization and Spine Formation, Leading to Cognitive Deficits.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: axonal elongation in HT cells was impaired, with a 20.3% decrease in length
      explanation: Tau-positive axons in E16.5 cortical cultures were measured at DIV5; conditional homozygous neurons had a more severe reduction. Transcriptional mediation is inferred from BRPF1 function, not established by target-gene rescue.
  - target: Reduced Intrinsic Excitability of Hippocampal Pyramidal Neurons
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31213987
      reference_title: Brpf1 Haploinsufficiency Impairs Dendritic Arborization and Spine Formation, Leading to Cognitive Deficits.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: The mean resting potential was comparable between HTs and WTs, while the mean action potential current threshold was significantly higher in the HTs than in the WTs
      explanation: Acute CA1 slice current-clamp recordings found increased firing-current threshold with preserved resting membrane potential. Transcriptional mediation is inferred from BRPF1 function, not established by target-gene rescue.
  - target: Abnormal Corpus Callosum Development
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:25568313
      reference_title: Deficiency of the chromatin regulator BRPF1 causes abnormal brain development.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Here, we report that forebrain-specific inactivation of the mouse Brpf1 gene caused early postnatal lethality, neocortical abnormalities, and partial callosal agenesis.
      explanation: The conditional homozygous model has a tissue-level callosal phenotype; it does not establish a universal callosal defect in heterozygous humans. Transcriptional changes and callosal defects coexist, but individual gene mediation has not been established.
- name: Deregulated Ocular and Periocular Developmental Transcription Factor Programs
  description: BRPF1-dependent regulation of Pitx2, Hmx1 and Pax6 has been proposed as a route to the ocular and periocular phenotype. The cited clinical cohort extrapolates from developmental-model literature; it does not directly test these transcription factors in human periocular tissue. The connection to ptosis, blepharophimosis and ocular alignment remains hypothetical.
  biological_scale: CELLULAR
  mechanism_confidence: HYPOTHETICAL
  biological_processes:
  - preferred_term: regulation of transcription by RNA polymerase II
    term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
    modifier: ABNORMAL
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: has been shown to affect the transcriptional regulation of several key transcription factors, including Pitx2, Hmx1 and Pax6, which have been implicated in a wide range of ocular developmental abnormalities
    explanation: Names the three transcription factors that constitute this node and links them to ocular developmental abnormality.
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: This likely accounts for the significant frequency and variability of ocular defects observed in our cohort and reported in the literature.
    explanation: The authors present the mechanism as a likely explanation rather than a demonstrated one - the basis for the HYPOTHETICAL confidence level.
  - reference: PMID:27939639
    reference_title: Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual Disability with Associated Ptosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: some specific features, such as ptosis and blepharophimosis, are mostly driven by BRPF1 haploinsufficiency
    explanation: Establishes that the endpoints of this arm are attributable to BRPF1 dosage specifically, independent of the co-deleted SETD5.
  downstream:
  - target: Ptosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39837771
      reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: This likely accounts for the significant frequency and variability of ocular defects observed in our cohort and reported in the literature.
      explanation: The transcription-factor route is offered as the likely explanation for the ocular phenotype, of which ptosis is the most frequent component (20/29); the intervening morphogenetic steps are unknown.
  - target: Blepharophimosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39837771
      reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: This likely accounts for the significant frequency and variability of ocular defects observed in our cohort and reported in the literature.
      explanation: Blepharophimosis is part of the same periocular arm proposed to follow from deregulated ocular transcription factors.
  - target: Strabismus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39837771
      reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Ophthalmological abnormalities were found in 19 patients (66%), with strabismus present in 13 patients (48%).
      explanation: Strabismus is the commonest non-eyelid ocular defect in the cohort whose frequency and variability the transcription-factor route is proposed to explain.
- name: Aberrant Cortical Neurogenesis
  description: Early forebrain-specific Brpf1 homozygous deletion reduces Tbr2-positive intermediate neuronal progenitors and alters cortical neurogenesis in mice. Developmental transcript changes accompany these abnormalities, but specific transcriptional mediators have not been isolated by rescue. The severe conditional-null model is not equivalent to heterozygous human disease.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  biological_processes:
  - preferred_term: neurogenesis
    term:
      id: GO:0022008
      label: neurogenesis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:25568313
    reference_title: Deficiency of the chromatin regulator BRPF1 causes abnormal brain development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: With respect to the control, the mutant forebrain contained fewer Tbr2-positive intermediate neuronal progenitors and displayed aberrant neurogenesis.
    explanation: Identifies depletion of intermediate neuronal progenitors as the cellular basis of the cortical phenotype.
- name: Abnormal Corpus Callosum Development
  description: Conditional homozygous Brpf1 loss in the embryonic forebrain produces partial callosal agenesis in mice. Conditional heterozygotes in a separate study have a modest reduction in callosal thickness. These zygosity-dependent anatomical changes provide model evidence, while the route to rare human agenesis or hypoplasia remains unproven.
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:25568313
    reference_title: Deficiency of the chromatin regulator BRPF1 causes abnormal brain development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Here, we report that forebrain-specific inactivation of the mouse Brpf1 gene caused early postnatal lethality, neocortical abnormalities, and partial callosal agenesis.
    explanation: The conditional homozygous model has a tissue-level callosal phenotype; it does not establish a universal callosal defect in heterozygous humans.
  downstream:
  - target: Agenesis of the Corpus Callosum
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39837771
      reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Brain MRI was available for 17 patients, of whom two (12%) had agenesis of the corpus callosum and one had multifocal hyperintensities in the white matter.
      explanation: The clinical narrative specifies agenesis in two of the seventeen imaged patients; this is not the frequency of hypoplasia or of all brain abnormalities. This cross-species correspondence does not demonstrate the human causal pathway.
  - target: Hypoplasia of the Corpus Callosum
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31176769
      reference_title: Novel BRPF1 mutation in a boy with intellectual disability, coloboma, facial nerve palsy and hypoplasia of the corpus callosum.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: He presented with ID, bilateral iris colobomas, facial nerve palsy and severe hypoplasia of the corpus callosum.
      explanation: Directly identifies severe callosal hypoplasia in the reported patient. This cross-species correspondence does not demonstrate the human causal pathway.
- name: Impaired Hematopoietic Stem and Progenitor Cell Maintenance
  description: Hematopoietic Vav1-iCre Brpf1 homozygous deletion impairs fetal stem/progenitor function and causes progressive postnatal marrow failure in mice. The phenotype includes loss of repopulating capacity despite preserved marrow homing, reduced neonatal LSK proliferation, and increased apoptosis, oxidative stress and senescence. Fetal LSK proliferation is initially preserved. Conditional heterozygotes have unchanged survival and neonatal LSK-cell numbers in the reported tests. Human anemia and thrombocytopenia have been observed without establishing this severe stem-cell failure mechanism.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  cell_types:
  - preferred_term: fetal hematopoietic stem cell
    term:
      id: CL:0000037
      label: hematopoietic stem cell
  - preferred_term: hematopoietic multipotent progenitor cell
    term:
      id: CL:0000837
      label: hematopoietic multipotent progenitor cell
  biological_processes:
  - preferred_term: hemopoiesis
    term:
      id: GO:0030097
      label: hemopoiesis
    modifier: DECREASED
  evidence:
  - reference: PMID:27500495
    reference_title: BRPF1 is essential for development of fetal hematopoietic stem cells.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: The mutant bone marrow and fetal liver exhibited severe deficiency in HSCs and hematopoietic progenitors, along with elevated reactive oxygen species, senescence, and apoptosis.
    explanation: Defines the cellular hematopoietic deficit produced by Brpf1 loss.
  - reference: PMID:27500495
    reference_title: BRPF1 is essential for development of fetal hematopoietic stem cells.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Furthermore, BRPF1 was required for acetylation of histone H3 at lysine 23, a highly abundant but not well-characterized epigenetic mark.
    explanation: H3K23ac loss accompanies hematopoietic dysfunction. No mark-specific rescue establishes it as the sole mediator, and H3K9/H3K14 acetylation also decline in this null model.
  - reference: PMID:27500495
    reference_title: BRPF1 is essential for development of fetal hematopoietic stem cells.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: No significant difference was observed between wild-type and heterozygous LSK cell numbers
    explanation: Conditional heterozygotes did not show the neonatal LSK depletion observed after homozygous deletion; this negative comparison limits direct extrapolation to human heterozygosity.
  - reference: PMID:27500495
    reference_title: BRPF1 is essential for development of fetal hematopoietic stem cells.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: the mutant bone marrow cells were unable to repopulate in the recipient peripheral blood
    explanation: Competitive transplantation found almost no mutant contribution at 4-16 weeks, supporting loss of functional repopulating activity.
  - reference: PMID:27500495
    reference_title: BRPF1 is essential for development of fetal hematopoietic stem cells.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: the mutant bone marrow cells are normal in homing
    explanation: Donor-cell recovery 40 hours after transplantation was preserved despite failed longer-term repopulation.
  - reference: PMID:27500495
    reference_title: BRPF1 is essential for development of fetal hematopoietic stem cells.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: the proliferation index was normal in LSK cells from the mutant fetal liver
    explanation: Fetal LSK proliferation and cell-cycle profiles were preserved, unlike reduced neonatal marrow cycling.
  downstream:
  - target: Anemia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27500495
      reference_title: BRPF1 is essential for development of fetal hematopoietic stem cells.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Brpf1-deficient pups experienced early lethality due to acute bone marrow failure and aplastic anemia.
      explanation: Provides a candidate mechanism for reported human anemia, but in a homozygous conditional-null mouse far more severe than human disease.
  - target: Thrombocytopenia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27500495
      reference_title: BRPF1 is essential for development of fetal hematopoietic stem cells.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: The mutant bone marrow and fetal liver exhibited severe deficiency in HSCs and hematopoietic progenitors, along with elevated reactive oxygen species, senescence, and apoptosis.
      explanation: Multilineage progenitor loss offers a mechanism for the reported thrombocytopenia; this mechanism has not been demonstrated in the reported human cases.
- name: Impaired Dendritic Arborization
  conforms_to: epigenetic_machinery_neurodevelopmental_dysregulation#Impaired Neuronal Maturation, Plasticity, and Postnatal Neurogenesis
  description: Emx1-lineage conditional Brpf1 heterozygous mice have reduced dendritic branching in dentate granule cells and layer V cortical pyramidal neurons. E16.5 cortical cultures also show shorter and less complex dendrites at DIV14. Conditional homozygous loss produces more severe changes. These observations concern mouse neurons; they do not establish a human neuronal phenotype or a transcriptional mediator.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  cell_types:
  - preferred_term: hippocampal granule cell
    term:
      id: CL:0001033
      label: hippocampal granule cell
  - preferred_term: cortical pyramidal neuron
    term:
      id: CL:4023111
      label: cerebral cortex pyramidal neuron
  biological_processes:
  - preferred_term: dendrite morphogenesis
    term:
      id: GO:0048813
      label: dendrite morphogenesis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:31213987
    reference_title: Brpf1 Haploinsufficiency Impairs Dendritic Arborization and Spine Formation, Leading to Cognitive Deficits.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Sholl analysis revealed a significant decrease in the number of intersections in Brpf1 HT and cKO neurons compared with that in WT neurons
    explanation: Golgi-stained dentate granule neurons had reduced dendritic complexity; similar changes were measured in layer V cortical neurons. The intervening transcriptional steps remain unresolved.
- name: Reduced Dendritic Spine Density and Altered Spine Morphology
  description: Conditional Emx1-lineage Brpf1 heterozygous mice have fewer and longer spines on cortical pyramidal-neuron apical dendrites. Homozygous conditional loss has a more severe effect. Hippocampal CA3 electron microscopy separately shows lower synaptic density, smaller postsynaptic densities and narrower synaptic clefts. Spine and synaptic measurements accompany electrophysiological changes but were not selectively rescued to demonstrate mediation.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  cell_types:
  - preferred_term: cortical pyramidal neuron
    term:
      id: CL:4023111
      label: cerebral cortex pyramidal neuron
  biological_processes:
  - preferred_term: dendritic spine development
    term:
      id: GO:0060996
      label: dendritic spine development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:31213987
    reference_title: Brpf1 Haploinsufficiency Impairs Dendritic Arborization and Spine Formation, Leading to Cognitive Deficits.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Brpf1 HTs exhibited a significant reduction in the number of spines compared to that in WT mice.
    explanation: Spines were counted along secondary apical dendritic branches of adult cortical pyramidal neurons.
  - reference: PMID:31213987
    reference_title: Brpf1 Haploinsufficiency Impairs Dendritic Arborization and Spine Formation, Leading to Cognitive Deficits.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Statistical analysis revealed a significant increase in spine length in Brpf1 HT and cKO mice.
    explanation: Cortical spine length increased alongside a reduction in spine density; the measurements concern conditional mouse genotypes.
  downstream:
  - target: Reduced Excitatory Synaptic Transmission in Forebrain Neurons
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31213987
      reference_title: Brpf1 Haploinsufficiency Impairs Dendritic Arborization and Spine Formation, Leading to Cognitive Deficits.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Brpf1 haploinsufficiency results in the abnormal morphology of excitatory synapses, specifically reduced PSD length and cleft width, which may lead to reduced excitatory synaptic transmission.
      explanation: Structural and physiological abnormalities coexist in the conditional mouse model; a selective rescue establishing a causal sequence was not performed.
- name: Impaired Axonal Outgrowth
  description: Primary cortical neurons from E16.5 Emx1-lineage Brpf1 conditional heterozygotes have shorter Tau-positive axons at DIV5; conditional homozygous deletion produces a larger reduction. This culture phenotype does not by itself explain callosal anatomy or human cognitive impairment.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:31213987
    reference_title: Brpf1 Haploinsufficiency Impairs Dendritic Arborization and Spine Formation, Leading to Cognitive Deficits.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: axonal elongation in HT cells was impaired, with a 20.3% decrease in length
    explanation: Tau-positive axons in E16.5 cortical cultures were measured at DIV5; conditional homozygous neurons had a more severe reduction.
- name: Reduced Intrinsic Excitability of Hippocampal Pyramidal Neurons
  description: CA1 pyramidal neurons in acute slices from Emx1-lineage conditional Brpf1 heterozygotes have lower input resistance, a higher current threshold for firing and fewer spikes at selected current steps, while resting membrane potential is unchanged. These effects are distinct from mEPSC changes and were not observed in the separate mild hippocampal shRNA culture study.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  cell_types:
  - preferred_term: hippocampal pyramidal neuron
    term:
      id: CL:1001571
      label: hippocampal pyramidal neuron
  evidence:
  - reference: PMID:31213987
    reference_title: Brpf1 Haploinsufficiency Impairs Dendritic Arborization and Spine Formation, Leading to Cognitive Deficits.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: The mean resting potential was comparable between HTs and WTs, while the mean action potential current threshold was significantly higher in the HTs than in the WTs
    explanation: Acute CA1 slice current-clamp recordings found increased firing-current threshold with preserved resting membrane potential.
- name: Reduced Excitatory Synaptic Transmission in Forebrain Neurons
  description: Brpf1 perturbation reduces mEPSC frequency in several mouse neuronal preparations. Emx1-lineage conditional heterozygotes also have lower mEPSC amplitude in acute CA1 slices, whereas mild shRNA knockdown in hippocampal cultures preserves amplitude and measured arbor morphology. These preparation-specific results do not establish a universal temporal sequence from dendritic change to synaptic dysfunction.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  biological_processes:
  - preferred_term: excitatory postsynaptic potential
    term:
      id: GO:0060079
      label: excitatory postsynaptic potential
    modifier: DECREASED
  evidence:
  - reference: PMID:34485298
    reference_title: Deficiency of Intellectual Disability-Related Gene Brpf1 Attenuated Hippocampal Excitatory Synaptic Transmission and Impaired Spatial Learning and Memory Ability.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: We found that mild knockdown of Brpf1 reduced mEPSC frequency of cultured hippocampal neurons, before any significant changes of dendritic morphology showed.
    explanation: Cultured hippocampal neurons showed reduced mEPSC frequency without significant measured arbor changes at the assessed time point.
  - reference: PMID:31213987
    reference_title: Brpf1 Haploinsufficiency Impairs Dendritic Arborization and Spine Formation, Leading to Cognitive Deficits.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Collectively, these data show that Brpf1 haploinsufficiency causes reduced synaptic transmission and decreased cell excitability, which may contribute to abnormal behaviors.
    explanation: Synaptic and behavioral deficits occur in the conditional heterozygous model, but their causal coupling was not tested by selective rescue.
  - reference: PMID:37862219
    reference_title: Forebrain excitatory neuron-specific loss of Brpf1 attenuates excitatory synaptic transmission and impairs spatial and fear memory.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: We found that the frequency but not the amplitude of mEPSCs decreased significantly
    explanation: Acute CA1 slices from six-month-old CaMKIIa-Cre conditional homozygous mice showed reduced mEPSC frequency, with amplitude and measured membrane properties preserved.
  downstream:
  - target: Impaired Learning and Memory
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31213987
      reference_title: Brpf1 Haploinsufficiency Impairs Dendritic Arborization and Spine Formation, Leading to Cognitive Deficits.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Collectively, these data show that Brpf1 haploinsufficiency causes reduced synaptic transmission and decreased cell excitability, which may contribute to abnormal behaviors.
      explanation: Synaptic and behavioral deficits occur in the conditional heterozygous model, but their causal coupling was not tested by selective rescue.
    - reference: PMID:34485298
      reference_title: Deficiency of Intellectual Disability-Related Gene Brpf1 Attenuated Hippocampal Excitatory Synaptic Transmission and Impaired Spatial Learning and Memory Ability.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: although no significant difference in the target quadrant (SW) was found
      explanation: The adult hippocampal knockdown study reported a behavioral tendency, with unchanged acquisition latency and target-quadrant occupancy. Electrophysiology was measured in separate embryonic cultures, so it does not demonstrate synaptic mediation of behavior in the same animals.
- name: Reduced Inhibitory Neurotransmission in GABAergic Interneurons
  description: Partial Brpf1 knockdown in cultured mouse MGE-derived GABAergic interneurons reduced miniature inhibitory postsynaptic current amplitude without a significant change in frequency. This synaptic readout is distinct from the intrinsic excitability changes measured in the same cultures. Dendritic morphology and transplanted-cell cortical distribution were not significantly altered under the tested conditions. The findings do not establish a human circuit-level excitation/inhibition ratio or a causal route to seizures.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  cell_types:
  - preferred_term: MGE-derived GABAergic interneuron
    term:
      id: CL:0011005
      label: GABAergic interneuron
  biological_processes:
  - preferred_term: inhibitory postsynaptic potential
    term:
      id: GO:0060080
      label: inhibitory postsynaptic potential
    modifier: DECREASED
  evidence:
  - reference: PMID:33744924
    reference_title: Deficiency of intellectual disability-related gene Brpf1 reduced inhibitory neurotransmission in MGE-derived GABAergic interneurons.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The amplitude but not the frequency of mIPSCs decreased significantly
    explanation: Whole-cell recording at DIV15 after AAV-shBrpf1 infection at DIV3 found reduced mIPSC amplitude; frequency did not significantly differ.
- name: Reduced Intrinsic Excitability of MGE-Derived GABAergic Interneurons
  description: In cultured mouse MGE-derived interneurons, partial Brpf1 knockdown increased the injected-current threshold required to evoke action potentials and reduced spike counts at selected current steps. Resting membrane potential and maximum evoked firing frequency were unchanged. These cell-intrinsic responses are experimentally distinct from the reduced mIPSC amplitude and have not been tested as a cause of human cognitive or seizure phenotypes.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  cell_types:
  - preferred_term: MGE-derived GABAergic interneuron
    term:
      id: CL:0011005
      label: GABAergic interneuron
  evidence:
  - reference: PMID:33744924
    reference_title: Deficiency of intellectual disability-related gene Brpf1 reduced inhibitory neurotransmission in MGE-derived GABAergic interneurons.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The AAV-shBrpf1 group required a larger incident current to induce the evoked APs, with a significant increase in the firing threshold
    explanation: Current-clamp recordings demonstrate increased threshold after partial knockdown, without a corresponding change in resting potential or maximum evoked frequency.
- name: Impaired Learning and Memory
  description: Behavioral effects vary across mouse preparations and tasks. Embryonic Emx1-lineage heterozygotes show water-maze learning and memory deficits and reduced contextual and cued freezing. Postnatal CaMKIIa-Cre conditional homozygotes show impaired spatial reference and contextual fear memory, with acquisition, cued fear memory and object recognition preserved at two months. Regional shRNA knockdown yielded only a behavioral tendency. These tests are not equivalent to human intellectual disability, which has variable expressivity.
  biological_scale: ORGANISM
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:31213987
    reference_title: Brpf1 Haploinsufficiency Impairs Dendritic Arborization and Spine Formation, Leading to Cognitive Deficits.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Brpf1 HTs spent less time in the target quadrant where the platform was previously located
    explanation: Conditional heterozygous mice had reduced target-quadrant occupancy after water-maze training; contextual and cued fear-conditioning tests also showed reduced freezing.
  - reference: PMID:37862219
    reference_title: Forebrain excitatory neuron-specific loss of Brpf1 attenuates excitatory synaptic transmission and impairs spatial and fear memory.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: forebrain excitatory neuron-specific deletion ofBrpf1led to impaired contextual but not cued fear memory
    explanation: At two months, contextual freezing and spatial-reference probe performance were impaired, while cued freezing and acquisition latency were unchanged.
  - reference: PMID:37862219
    reference_title: Forebrain excitatory neuron-specific loss of Brpf1 attenuates excitatory synaptic transmission and impairs spatial and fear memory.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: The discrimination ratio of the cKO mice was similar to that of WT mice
    explanation: Novel-object recognition was unchanged at two months; the paper also reports preserved locomotion and no detected group difference in sociability or self-grooming.
  downstream:
  - target: Intellectual Disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31213987
      reference_title: Brpf1 Haploinsufficiency Impairs Dendritic Arborization and Spine Formation, Leading to Cognitive Deficits.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Our results demonstrate a critical role for Brpf1 dosage in neuron dendrite arborization, spine morphogenesis and behavior and provide insight into the pathogenesis of BRPF1-related ID.
      explanation: The mouse work is offered as insight into the pathogenesis of human BRPF1-related ID, but human neuronal confirmation is absent.

phenotypes:
- category: Neurodevelopmental
  name: Global Developmental Delay
  description: Global developmental delay affecting motor, language and adaptive domains is the presenting feature in most reported individuals, and was the reason for ascertainment in the founding series.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  frequency: FREQUENT
  notes: The two panels of Table 1 in Colson et al. 2025 record global developmental delay as present in 14 patients, absent in nine and unavailable in six. Among the 23 with recorded status, 14/23 is approximately 61%, supporting FREQUENT. This is a derived table count, distinct from the paper's 16/29 intellectual-disability count and its combined ID/DD wording.
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '| Global developmental delay | N | Y | Y | Y | Y | Y | Y | N | Y | Y | N | Y | Y | N |'
    explanation: Table 1, panel 1, provides individual global developmental delay status. Across both panels there are 14 Y, nine N and six N/A entries; only the 23 patients with known status form the frequency denominator.
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '| Global developmental delay | Y | N | N | Y | N | N | Y | Y | N/A | N | N/A | N/A | N/A | N/A | N/A |'
    explanation: Table 1, panel 2, provides individual global developmental delay status. Across both panels there are 14 Y, nine N and six N/A entries; only the 23 patients with known status form the frequency denominator.
  - reference: PMID:27939640
    reference_title: Mutations in the Chromatin Regulator Gene BRPF1 Cause Syndromic Intellectual Disability and Deficient Histone Acetylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Symptoms include infantile hypotonia, global developmental delay, intellectual disability, expressive language impairment, and facial dysmorphisms.
    explanation: Lists global developmental delay among the core symptoms of the founding ten-individual series.
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Our cohort presented with a wide range of clinical features including developmental delay, intellectual disability (ID) and characteristic dysmorphic facial features such as ptosis, blepharophimosis and a broad nasal bridge.
    explanation: The largest cohort (29 patients) confirms developmental delay as a core feature.
- category: Neurodevelopmental
  name: Intellectual Disability
  description: Intellectual disability is the defining feature of the OMIM entity but is not obligate. Where present it is predominantly mild to moderate, with variability between verbal and visual cognitive profiles. A speech-ascertained cohort found all four individuals formally tested had FSIQ at or above 70, and at least one reported individual with a pathogenic BRPF1 variant has normal intellectual development, so the band below describes a reported cohort frequency, not an obligate feature.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  frequency: FREQUENT
  notes: 'Frequency derivation: Colson et al. 2025 report ID in 16 of 29 patients with available data (55%), of whom six were mild and 10 moderate. 16/29 = 55%, which falls in the FREQUENT band (30-79%). The band is not OBLIGATE: a speech-ascertained cohort found FSIQ >= 70 in all four formally tested participants (PMID:38346666) and at least one carrier has normal intellect (PMID:35243762).'
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Of the 29 patients with available data, 16 (55%) presented with ID of varying severity: six patients had mild ID, while 10 patients had moderate ID.'
    explanation: 16/29 = 55%, which falls in the FREQUENT band (30-79%), and gives the mild/moderate severity split.
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Neuropsychological assessment reveals a predominance of mild to moderate ID, with cognitive profiles showing variability in verbal and visual processing.
    explanation: Establishes the mild-to-moderate severity distribution in the largest cohort.
  - reference: PMID:38346666
    reference_title: 'Beyond ''speech delay'': Expanding the phenotype of BRPF1-related disorder.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All those tested for cognitive abilities had a FSIQ ≥70 (4/4).
    explanation: 'Qualifies the claim: in a speech-ascertained cohort, formally tested individuals were not in the intellectual disability range.'
  - reference: PMID:35243762
    reference_title: 'BRPF1-associated syndrome: A patient with congenital ptosis, neurological findings, and normal intellectual development.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here, we describe a patient with normal intellectual development who had congenital ptosis, hypotonia, muscular weakness, atlanto-axial malformation, and pyramidal at the neurological examination.
    explanation: Documents a BRPF1 variant carrier with normal intellect, showing ID is not obligate.
- category: Neurodevelopmental
  name: Speech and Language Disorder
  description: Speech and language difficulties are prominent but variably recorded. The dedicated speech-language study found mostly mild-to-moderate deficits across receptive, expressive, written and social-pragmatic domains; phonological delay and disorder were common speech diagnoses. Formal assessment of language disorder and a history of delayed speech milestones are related but distinct endpoints.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  notes: 'A single frequency band is not assigned across different endpoints and assessment methods: language disorder was found in 11/12 formally assessed participants in the dedicated study, while delayed speech and language development was reported in 13/28 (46%) in Table 2 of the 2025 cohort. Neither figure establishes universal impairment across all BRPF1 carriers.'
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Delayed speech and language development were noted in 13 patients (46%).
    explanation: 'Table 2 specifies the denominator as 28: 13/28 is 46%. This concerns delayed speech-language milestones and cannot be equated directly with the formal language-disorder assessment in the separate study.'
  - reference: PMID:38346666
    reference_title: 'Beyond ''speech delay'': Expanding the phenotype of BRPF1-related disorder.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Language disorders were common (11/12), and most had mild to moderate deficits across receptive, expressive, written, and social-pragmatic domains.
    explanation: Language disorder occurred in 11/12 assessed participants in this study; the frequency is specific to this assessment and cohort.
  - reference: PMID:38346666
    reference_title: 'Beyond ''speech delay'': Expanding the phenotype of BRPF1-related disorder.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The universal involvement of speech and language impairment ... relative to the high degree of phenotypic variability in BRPF1-related disorder.
    explanation: The speech-ascertained study describes widespread involvement; its wording does not establish universal penetrance in an unselected population.
- category: Neurodevelopmental
  name: Childhood Apraxia of Speech
  description: A motor-planning speech disorder (childhood apraxia of speech) occurs in a substantial minority, alongside phonological delay and phonological disorder. The speech-phenotyping study distinguishes apraxia from other speech diagnoses but does not compare treatment regimens.
  phenotype_term:
    preferred_term: Speech apraxia
    term:
      id: HP:0011098
      label: Speech apraxia
  frequency: FREQUENT
  notes: 'Frequency derivation: childhood apraxia of speech in 3 of 9 formally assessed participants (PMID:38346666). 3/9 = 33%, which falls in the FREQUENT band (30-79%). The denominator is small and speech-ascertained, so the estimate is provisional.'
  evidence:
  - reference: PMID:38346666
    reference_title: 'Beyond ''speech delay'': Expanding the phenotype of BRPF1-related disorder.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Speech disorders were frequent (7/9), including phonological delay (6/9) and disorder (3/9), and childhood apraxia of speech (3/9).
    explanation: Childhood apraxia of speech in 3 of 9 assessed (33%) falls in the FREQUENT band.
- category: Neurologic
  name: Infantile Hypotonia
  description: Hypotonia with infantile onset is a core feature, contributing to early motor delay and to feeding difficulty. The cited cohort documents improvement in motor delay, but does not separately establish the course of hypotonia.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  frequency: FREQUENT
  notes: 'Frequency derivation: two independent cohorts agree on the band - infant hypotonia in 9/15 (60%) in the speech-phenotyping cohort (PMID:38346666) and hypotonia in 11/29 (approximately 38%; reported as 40%) in Colson et al. 2025. Both fall in the FREQUENT band (30-79%).'
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Hypotonia was observed in 11 patients (40%), including one with neonatal hypotonia.
    explanation: The paper reports 11/29 with hypotonia and rounds this to 40%. The calculated proportion is approximately 38%; both are FREQUENT.
  - reference: PMID:38346666
    reference_title: 'Beyond ''speech delay'': Expanding the phenotype of BRPF1-related disorder.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Participants had vision impairment (13/15), fine (8/15) and gross motor delay (10/15) which often resolved in later childhood, infant feeding impairment (8/15), and infant hypotonia (9/15).
    explanation: Infant hypotonia in 9 of 15 (60%) supports the FREQUENT band.
  - reference: PMID:27939640
    reference_title: Mutations in the Chromatin Regulator Gene BRPF1 Cause Syndromic Intellectual Disability and Deficient Histone Acetylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Symptoms include infantile hypotonia, global developmental delay, intellectual disability, expressive language impairment, and facial dysmorphisms.
    explanation: Independently lists infantile hypotonia as a core symptom.
- category: Neurologic
  name: Motor Delay
  description: Both fine and gross motor delay are common in early childhood and frequently resolve later, an important prognostic point for counselling.
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  frequency: FREQUENT
  notes: 'Frequency derivation: gross motor delay 10/15 (67%) and fine motor delay 8/15 (53%) in the speech-phenotyping cohort (PMID:38346666), and motor delay in 52% of Colson et al. 2025. All three figures fall in the FREQUENT band (30-79%).'
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Most patients had motor delay (52%).
    explanation: 52% in the largest cohort, which falls in the FREQUENT band (30-79%).
  - reference: PMID:38346666
    reference_title: 'Beyond ''speech delay'': Expanding the phenotype of BRPF1-related disorder.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Participants had vision impairment (13/15), fine (8/15) and gross motor delay (10/15) which often resolved in later childhood, infant feeding impairment (8/15), and infant hypotonia (9/15).
    explanation: Gross motor delay in 10 of 15 (67%) and fine motor delay in 8 of 15 (53%) both fall in the FREQUENT band.
- category: Gastrointestinal
  name: Feeding Difficulties
  description: 'Infant feeding impairment occurs and, with hypotonia and oromotor involvement, contributes to early failure to thrive in some individuals. No frequency band is assigned, and none of the evidence below is offered in support of one: the three published denominators straddle two bands - 3/26 (12%, OCCASIONAL) in the prospectively phenotyped 2025 cohort, 24/42 (57%, FREQUENT) in that paper''s literature comparison, and 8/15 (53%, FREQUENT) in the speech-ascertained cohort. Per docs/frequency-evidence-guidelines.md, omitting the band is preferred to picking between irreconcilable estimates.'
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  notes: Frequency deliberately omitted. Quotable denominators disagree across bands (12% versus 53-57%); the discrepancy most likely reflects ascertainment - earlier reports and the speech/feeding-focused cohort both enrich for oromotor involvement - but no source reconciles them, so no band is claimed.
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Feeding problems were observed in 12% of our series (3/26) compared with 57% of patients reported in the literature (24/42).
    explanation: Supports the disease-phenotype association and documents the cross-cohort disagreement (12% versus 57%) that is the stated reason no band is assigned.
  - reference: PMID:38346666
    reference_title: 'Beyond ''speech delay'': Expanding the phenotype of BRPF1-related disorder.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Participants had vision impairment (13/15), fine (8/15) and gross motor delay (10/15) which often resolved in later childhood, infant feeding impairment (8/15), and infant hypotonia (9/15).
    explanation: Supports the disease-phenotype association; infant feeding impairment in 8 of 15 (53%) is one of the two irreconcilable estimates and is not used to assign a band.
- category: Ophthalmologic
  name: Ptosis
  description: Ptosis, frequently congenital and sometimes unilateral, is the single most discriminating physical sign and gives the disorder its OMIM name. It may be the presenting complaint that leads to genetic diagnosis, and it is the feature specifically attributed to BRPF1 rather than SETD5 dosage in 3p25 deletions.
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  frequency: FREQUENT
  notes: 'Frequency derivation: Colson et al. 2025 report ptosis in 20 of 29 patients. 20/29 = 69%, which falls in the FREQUENT band (30-79%). This is the eponymous feature of IDDDFP and the highest-frequency craniofacial sign in the cohort, but it is not obligate.'
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Common features associated with IDDDFP included blepharophimosis (10/29; 34%), hypertelorism (14/29; 48%), ptosis (20/29; 69%), and a round face (17/27; 63%)
    explanation: Ptosis in 20/29 (69%) falls in the FREQUENT band (30-79%).
  - reference: PMID:37946714
    reference_title: 'Mosaicism in BRPF1-Related Neurodevelopmental Disorder: Report of Two Sisters and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Bromodomain and PHD finger containing 1 (BRPF1)-related neurodevelopmental disorder is characterized by intellectual disability, developmental delay, hypotonia, dysmorphic facial features, ptosis, and blepharophimosis.
    explanation: Ptosis is listed as a defining characteristic of the disorder.
  - reference: PMID:40752867
    reference_title: 'Ocular findings of BRPF1 variants: a case report and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We report the case of a 2-year-old girl who presented with drooping of the left upper lid since birth and who was ultimately diagnosed with IDDDFP.
    explanation: Illustrates congenital, unilateral ptosis as the presenting feature leading to diagnosis.
- category: Ophthalmologic
  name: Blepharophimosis
  description: Horizontally short palpebral fissures accompany ptosis in a large share of individuals and form the recognizable periocular gestalt together with downslanted palpebral fissures.
  phenotype_term:
    preferred_term: Blepharophimosis
    term:
      id: HP:0000581
      label: Blepharophimosis
  frequency: FREQUENT
  notes: 'Frequency derivation: blepharophimosis in 10 of 29 patients in Colson et al. 2025. 10/29 = 34%, which falls in the FREQUENT band (30-79%), at its lower edge.'
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Common features associated with IDDDFP included blepharophimosis (10/29; 34%), hypertelorism (14/29; 48%), ptosis (20/29; 69%), and a round face (17/27; 63%)
    explanation: Blepharophimosis in 10/29 (34%) falls in the FREQUENT band (30-79%).
  - reference: PMID:31176769
    reference_title: Novel BRPF1 mutation in a boy with intellectual disability, coloboma, facial nerve palsy and hypoplasia of the corpus callosum.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Besides intellectual disability (ID), ptosis and blepharophimosis are frequent findings, with refraction problems, amblyopia and strabism as other reported ophthalmological features.
    explanation: Describes blepharophimosis as a frequent finding across reported patients.
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: characteristic dysmorphic facial features such as ptosis, blepharophimosis and a broad nasal bridge
    explanation: The largest cohort lists blepharophimosis among the characteristic facial features.
- category: Craniofacial
  name: Downslanted Palpebral Fissures
  description: Downslanting palpebral fissures are part of the recurrent facial gestalt and were present in all affected members of a reported multiplex family.
  phenotype_term:
    preferred_term: Downslanted palpebral fissures
    term:
      id: HP:0000494
      label: Downslanted palpebral fissures
  notes: Frequency deliberately omitted. Colson et al. 2025 tabulate up-slanting (7/29) and narrow (10/29) palpebral fissures but do not report a downslanting count, and the only quotable source here is a four-member single family in which all four were affected - a denominator too small and too ascertainment-biased to support a population band.
  evidence:
  - reference: PMID:31020800
    reference_title: BRPF1-associated intellectual disability, ptosis, and facial dysmorphism in a multiplex family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The four affected individuals showed varying degrees of intellectual disability, distinct facial features including downslanted palpebral fissures, ptosis, and/or blepharophimosis.
    explanation: All four affected family members had downslanted palpebral fissures.
- category: Craniofacial
  name: Broad Nasal Bridge
  description: A broad nasal bridge is one of the characteristic facial features identified in the largest published cohort.
  phenotype_term:
    preferred_term: Wide nasal bridge
    term:
      id: HP:0000431
      label: Wide nasal bridge
  notes: Frequency deliberately omitted. The largest cohort names a broad nasal bridge among the characteristic features but reports a count only for bulbous nose (14/28), not for the nasal bridge itself, so no numerator and denominator exist to derive a band from.
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: characteristic dysmorphic facial features such as ptosis, blepharophimosis and a broad nasal bridge
    explanation: Names broad nasal bridge as a characteristic facial feature.
- category: Craniofacial
  name: Retrognathia
  description: Micrognathia and retrognathia are reported among the classical dysmorphic features.
  phenotype_term:
    preferred_term: Retrognathia
    term:
      id: HP:0000278
      label: Retrognathia
  frequency: FREQUENT
  notes: 'Frequency derivation: retrognathia in 12 of 29 patients in Colson et al. 2025. 12/29 = 41%, which falls in the FREQUENT band (30-79%).'
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Other notable features included up slanting palpebral fissures (7/29; 24%), epicanthus (12/29; 41%, with epicanthus inversus in 5/29), narrow palpebral fissures (10/29; 34%), palpebral oedema (8/29; 28%), low columella (9/29; 31%), bulbous nose (14/28; 50%), high palate (14/29; 48%), and retrognathia (12/29; 41%).
    explanation: Retrognathia in 12/29 (41%) falls in the FREQUENT band (30-79%).
  - reference: PMID:37190896
    reference_title: 'Anemia and thrombocytopenia due to a novel BRPF1 variant in a family from Çanakkale with intellectual disability and dysmorphic facies: Case report and review of the literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The patients demonstrated classical features of IDDDFP such as intellectual disability, developmental delay, ptosis, micro and retrognathia, and dysmorphic facial features, in addition to the anemia and thrombocytopenia.
    explanation: Lists retrognathia among the classical IDDDFP features.
- category: Craniofacial
  name: Palpebral Edema
  description: Palpebral oedema was newly recognized as a recurrent facial feature in the 2025 cohort of 29 patients, refining the recognizable periocular gestalt.
  phenotype_term:
    preferred_term: Palpebral edema
    term:
      id: HP:0100540
      label: Palpebral edema
  frequency: OCCASIONAL
  notes: 'Frequency derivation: palpebral oedema in 8 of 29 patients in Colson et al. 2025. 8/29 = 28%, which falls in the OCCASIONAL band (5-29%).'
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: palpebral oedema (8/29; 28%)
    explanation: Palpebral oedema in 8/29 (28%) falls in the OCCASIONAL band (5-29%).
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: New phenotypic features identified include palpebral oedema, laterally elongated eyebrows, low hanging columella and hypertrichosis.
    explanation: Identifies palpebral oedema as a newly described feature of the disorder.
- category: Craniofacial
  name: Hypertrichosis
  description: Hypertrichosis was among the newly identified phenotypic features in the 2025 cohort.
  phenotype_term:
    preferred_term: Hypertrichosis
    term:
      id: HP:0000998
      label: Hypertrichosis
  frequency: FREQUENT
  notes: 'Frequency derivation: hypertrichosis, mostly on the back and arms, in 9 of 29 patients in Colson et al. 2025. 9/29 = 31%, which falls in the FREQUENT band (30-79%), at its lower edge.'
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Cutaneous abnormalities were observed in approximately one third of the cohort, including laterally extended eyebrows (8/29, 28%), hypertrichosis, mostly on the back and arms (9/29; 31%), synophrys (10/28; 36%), and various hair abnormalities (12/29; 41%), such as fine hair, sparse hair, low posterior hairline, and high anterior hairline.
    explanation: Hypertrichosis in 9/29 (31%) falls in the FREQUENT band (30-79%).
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: New phenotypic features identified include palpebral oedema, laterally elongated eyebrows, low hanging columella and hypertrichosis.
    explanation: Names hypertrichosis as a newly recognized feature.
- category: Ophthalmologic
  name: Strabismus
  description: Strabismus is among the recurrent non-eyelid ocular findings and is one driver of the recommendation for systematic ophthalmological assessment.
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  frequency: FREQUENT
  notes: Colson et al. 2025 report strabismus in 13/27 assessed patients (48%) in the discussion and Table 2, supporting FREQUENT. The denominator is those with recorded strabismus status, not the full 29-patient cohort.
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Ophthalmological abnormalities were found in 19 patients (66%), with strabismus present in 13 patients (48%).
    explanation: Strabismus in 48% falls in the FREQUENT band (30-79%); ocular abnormalities overall reach 66%.
  - reference: PMID:38590032
    reference_title: 'Broadening the ocular phenotypic spectrum of ultra-rare BRPF1 variants: report of two cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The reported ocular involvement includes strabismus, amblyopia, and refraction errors.
    explanation: Lists strabismus among the established ocular manifestations.
- category: Ophthalmologic
  name: Amblyopia
  description: Amblyopia, often secondary to ptosis, strabismus or uncorrected refractive error, is a recognized and treatable complication - the main clinical reason early ophthalmological review matters.
  phenotype_term:
    preferred_term: Amblyopia
    term:
      id: HP:0000646
      label: Amblyopia
  frequency: OCCASIONAL
  notes: 'Frequency derivation: amblyopia in 3 of 29 patients in Colson et al. 2025. 3/29 = 10%, which falls in the OCCASIONAL band (5-29%). The same paper describes amblyopia as a sporadic finding in the wider literature.'
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Our cohort had similar findings: strabismus (13/27), myopia (5/29), hypermetropia (2/29), nystagmus (2/29), amblyopia (3/29) and cataract (1/29).'
    explanation: Amblyopia in 3/29 = 10%, which falls in the OCCASIONAL band (5-29%).
  - reference: PMID:38590032
    reference_title: 'Broadening the ocular phenotypic spectrum of ultra-rare BRPF1 variants: report of two cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The reported ocular involvement includes strabismus, amblyopia, and refraction errors.
    explanation: Amblyopia is an established component of the ocular phenotype.
  - reference: PMID:31176769
    reference_title: Novel BRPF1 mutation in a boy with intellectual disability, coloboma, facial nerve palsy and hypoplasia of the corpus callosum.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: with refraction problems, amblyopia and strabism as other reported ophthalmological features
    explanation: Independently confirms amblyopia among reported ophthalmological features.
- category: Ophthalmologic
  name: Iris Coloboma
  description: Bilateral iris coloboma has been reported in an individual with a de novo BRPF1 nonsense variant, proposed as an additional feature of the syndrome. This remains a single-case observation.
  phenotype_term:
    preferred_term: Iris coloboma
    term:
      id: HP:0000612
      label: Iris coloboma
  frequency: VERY_RARE
  notes: 'Frequency derivation: Colson et al. 2025 describe coloboma among the sporadic ocular findings of the literature and record none in their own 29-patient cohort (their ocular tally lists strabismus, myopia, hypermetropia, nystagmus, amblyopia and cataract, but no coloboma). The author wording "sporadic cases" maps to VERY_RARE (<5%) under the DisMech qualitative mapping.'
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In the literature, patients (41/53) are mainly reported to have visual impairments including strabismus, hypermetropia and myopia, with sporadic cases of coloboma, microphthalmia, nystagmus and amblyopia
    explanation: Author wording "sporadic cases" of coloboma maps to VERY_RARE (<5%) under the DisMech qualitative mapping.
  - reference: PMID:31176769
    reference_title: Novel BRPF1 mutation in a boy with intellectual disability, coloboma, facial nerve palsy and hypoplasia of the corpus callosum.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He presented with ID, bilateral iris colobomas, facial nerve palsy and severe hypoplasia of the corpus callosum.
    explanation: Reports bilateral iris coloboma in a BRPF1 nonsense-variant carrier.
  - reference: PMID:31176769
    reference_title: Novel BRPF1 mutation in a boy with intellectual disability, coloboma, facial nerve palsy and hypoplasia of the corpus callosum.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: indicates coloboma and facial nerve palsy as possible additional features of IDDDFP syndrome
    explanation: The authors frame coloboma as a possible, not established, feature.
- category: Ophthalmologic
  name: Subclinical Optic Neuropathy
  description: Bilateral subclinical optic neuropathy detected only by optical coherence tomography was found in two unrelated BRPF1 patients. Because it is asymptomatic it is easily missed on routine examination; the finding is the basis for recommending OCT-inclusive ophthalmological evaluation. Evidence rests on two cases.
  phenotype_term:
    preferred_term: Optic neuropathy
    term:
      id: HP:0001138
      label: Optic neuropathy
  notes: Frequency deliberately omitted. The only source is a two-patient OCT series with no cohort denominator, and because detection requires OCT the observed rate in any cohort not systematically imaged is uninformative. Colson et al. 2025 note only that two patients with frameshift variants have been described with optic neuropathy.
  evidence:
  - reference: PMID:38590032
    reference_title: 'Broadening the ocular phenotypic spectrum of ultra-rare BRPF1 variants: report of two cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Having detected a peculiar ocular phenotype in P1, we suggested optical coherence tomography (OCT) for P2; such an exam also detected bilateral subclinical optic neuropathy in this case.
    explanation: Documents subclinical optic neuropathy in both reported patients, detected by OCT.
  - reference: PMID:38590032
    reference_title: 'Broadening the ocular phenotypic spectrum of ultra-rare BRPF1 variants: report of two cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: To date, only a few patients with BRPF1 variants have been described, and none were reported to have optic neuropathy.
    explanation: Makes explicit that this is a novel observation in a very small number of patients.
- category: Neurologic
  name: Hypoplasia of the Corpus Callosum
  description: Severe corpus callosum hypoplasia was described in a boy with a de novo BRPF1 nonsense variant, intellectual disability, iris colobomas and facial nerve palsy. Hypoplasia is distinct from agenesis and is not assigned the agenesis frequency from the 2025 cohort.
  phenotype_term:
    preferred_term: Hypoplasia of the corpus callosum
    term:
      id: HP:0002079
      label: Hypoplasia of the corpus callosum
  notes: No subtype-specific denominator is available from the cited case report. The historical 5/22 figure concerns all structural brain abnormalities and is not a hypoplasia frequency or an imaging-only denominator.
  evidence:
  - reference: PMID:31176769
    reference_title: Novel BRPF1 mutation in a boy with intellectual disability, coloboma, facial nerve palsy and hypoplasia of the corpus callosum.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He presented with ID, bilateral iris colobomas, facial nerve palsy and severe hypoplasia of the corpus callosum.
    explanation: Directly identifies severe callosal hypoplasia in the reported patient.
- category: Neurologic
  name: Seizures
  description: Epilepsy was described among the clinical findings of the two founding 2017 series, but it is not a consistent feature and is absent in many reported individuals.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  frequency: OCCASIONAL
  notes: 'Frequency derivation: epilepsy documented in 4 of 29 patients in Colson et al. 2025. 4/29 = 14%, which falls in the OCCASIONAL band (5-29%).'
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Epilepsy was documented in 4 patients (14%) and 18 patients (62%) had behavioural disorders, including attention deficit/hyperactivity (33%), low frustration tolerance (29%), inappropriate laughter (14%), anxiety (21%), agitation (15%) and autistic behaviour (15%).
    explanation: Epilepsy in 4/29 (14%) falls in the OCCASIONAL band (5-29%).
  - reference: PMID:35243762
    reference_title: 'BRPF1-associated syndrome: A patient with congenital ptosis, neurological findings, and normal intellectual development.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In 2017, Mattiolli et al. and Yan et al. described a series of patients with clinical findings essentially characterized by intellectual disabilities, ptosis, hypotonia, epilepsy, and weakness.
    explanation: Epilepsy is listed among the findings of the two founding series.
- category: Neurologic
  name: Muscle Weakness
  description: Muscular weakness accompanies hypotonia in a subset of patients, including one with otherwise normal intellectual development.
  phenotype_term:
    preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  notes: Frequency deliberately omitted. Weakness is named in the founding series and in a single case report but is not tabulated separately from hypotonia in any cohort, so no numerator and denominator exist for it.
  evidence:
  - reference: PMID:35243762
    reference_title: 'BRPF1-associated syndrome: A patient with congenital ptosis, neurological findings, and normal intellectual development.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here, we describe a patient with normal intellectual development who had congenital ptosis, hypotonia, muscular weakness, atlanto-axial malformation, and pyramidal at the neurological examination.
    explanation: Documents muscular weakness in a BRPF1 variant carrier.
- category: Behavioral
  name: Attention Deficit Hyperactivity Disorder
  description: ADHD has been reported in BRPF1 variant carriers alongside mild intellectual disability and speech delay. Systematic behavioural phenotyping is lacking; one study noted adaptive behaviour was a relative strength compared with other chromatin-related neurodevelopmental disorders.
  phenotype_term:
    preferred_term: Attention deficit hyperactivity disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
  frequency: FREQUENT
  notes: 'Frequency derivation: attention deficit/hyperactivity in 33% of the 29-patient Colson et al. 2025 cohort, reported as a component of the 62% with any behavioural disorder. 33% falls in the FREQUENT band (30-79%).'
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 18 patients (62%) had behavioural disorders, including attention deficit/hyperactivity (33%), low frustration tolerance (29%), inappropriate laughter (14%), anxiety (21%), agitation (15%) and autistic behaviour (15%).
    explanation: Attention deficit/hyperactivity at 33% falls in the FREQUENT band (30-79%).
  - reference: PMID:37946714
    reference_title: 'Mosaicism in BRPF1-Related Neurodevelopmental Disorder: Report of Two Sisters and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Their history of mild intellectual disability, speech delay, attention deficient hyperactivity disorder (ADHD), and ptosis align with the features previously reported in the literature.
    explanation: Reports ADHD in two affected sisters and states it aligns with previously reported features.
- category: Cardiovascular
  name: Congenital Cardiac Anomalies
  description: Cardiac malformations occur in a minority of BRPF1 patients. Reported anomalies include patent ductus arteriosus and atrial or ventricular septal defects.
  phenotype_term:
    preferred_term: Abnormal heart morphology
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  frequency: VERY_RARE
  notes: The 2025 cohort reports one minor structural heart defect among 25 assessed patients (1/25, 4%). The literature aggregate of 9/49 includes atrioventricular nodal pauses and blocks as well as malformations, so it is not used as a frequency for abnormal heart morphology.
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Similarly, we observed one minor heart defect in our cohort (1/25).
    explanation: This is the structural finding in the new cohort, separate from the heterogeneous literature aggregate.
  - reference: PMID:32010779
    reference_title: Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Cardiac anomalies are present in a subset of the cases.
    explanation: Documents cardiac anomalies in a subset of the 12 newly identified BRPF1 cases.
- category: Hematologic
  name: Anemia
  description: Anemia was reported in a family with a BRPF1 nonsense variant and subsequently in one of 25 assessed patients in the 2025 cohort. The latter report found no evidence of bone marrow damage. Mouse hematopoietic-null models provide biological plausibility, but do not establish the cause of anemia in heterozygous humans.
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  frequency: VERY_RARE
  notes: 'Frequency derivation: 1 of 25 patients with haematological data in Colson et al. 2025 had anaemia. 1/25 = 4%, which falls in the VERY_RARE band (<5%). The founding observation was a single Turkish family in which the feature was newly described.'
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In our cohort, two different patients presented with haematopoietic abnormalities without evidence of bone marrow damage (7%, 1/25 with anaemia and 1/25 with thrombocytopenia).
    explanation: Anaemia in 1/25 = 4%, which falls in the VERY_RARE band (<5%).
  - reference: PMID:37190896
    reference_title: 'Anemia and thrombocytopenia due to a novel BRPF1 variant in a family from Çanakkale with intellectual disability and dysmorphic facies: Case report and review of the literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Additionally, the patients had hematopoietic disorders such as anemia and thrombocytopenia, which have not been previously described in IDDDFP patients.
    explanation: Single-family observation explicitly flagged by the authors as not previously described.
- category: Hematologic
  name: Thrombocytopenia
  description: Thrombocytopenia was reported in the same family as anemia and in a different individual in the 2025 cohort (1/25 assessed). These observations extend beyond the original family, but the causal relationship to BRPF1 haploinsufficiency remains uncertain.
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  frequency: VERY_RARE
  notes: 'Frequency derivation: 1 of 25 patients with haematological data in Colson et al. 2025 had thrombocytopenia. 1/25 = 4%, which falls in the VERY_RARE band (<5%).'
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In our cohort, two different patients presented with haematopoietic abnormalities without evidence of bone marrow damage (7%, 1/25 with anaemia and 1/25 with thrombocytopenia).
    explanation: Thrombocytopenia in 1/25 = 4%, which falls in the VERY_RARE band (<5%).
  - reference: PMID:37190896
    reference_title: 'Anemia and thrombocytopenia due to a novel BRPF1 variant in a family from Çanakkale with intellectual disability and dysmorphic facies: Case report and review of the literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Additionally, the patients had hematopoietic disorders such as anemia and thrombocytopenia, which have not been previously described in IDDDFP patients.
    explanation: Same single-family, previously undescribed hematological observation.
- category: Neurologic
  name: Facial Nerve Palsy
  description: Facial nerve palsy was reported in one patient with a de novo BRPF1 nonsense variant and proposed as a possible additional feature. Single-case evidence.
  phenotype_term:
    preferred_term: Facial palsy
    term:
      id: HP:0010628
      label: Facial palsy
  notes: Frequency deliberately omitted. Single-case evidence with no denominator; the feature is not tabulated in any BRPF1 cohort, including the 29-patient 2025 series.
  evidence:
  - reference: PMID:31176769
    reference_title: Novel BRPF1 mutation in a boy with intellectual disability, coloboma, facial nerve palsy and hypoplasia of the corpus callosum.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: indicates coloboma and facial nerve palsy as possible additional features of IDDDFP syndrome
    explanation: Proposed by the authors as a possible additional feature on single-case evidence.
- category: Craniofacial
  name: Round Face
  description: A round face is one of the two facial features Orphanet uses to define the syndrome and is among the most frequent craniofacial signs in the largest cohort.
  phenotype_term:
    preferred_term: Round face
    term:
      id: HP:0000311
      label: Round face
  frequency: FREQUENT
  notes: 'Frequency derivation: round face in 17 of 27 patients in Colson et al. 2025. 17/27 = 63%, which falls in the FREQUENT band (30-79%).'
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Common features associated with IDDDFP included blepharophimosis (10/29; 34%), hypertelorism (14/29; 48%), ptosis (20/29; 69%), and a round face (17/27; 63%)
    explanation: Round face in 17/27 (63%) falls in the FREQUENT band (30-79%).
  - reference: ORPHA:698090
    reference_title: Ophthalmological abnormalities-facial dysmorphism-intellectual disability syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: dysmorphic facial features such as ptosis and round face
    explanation: Orphanet's definition of the disorder names round face alongside ptosis as the defining dysmorphic features.
- category: Craniofacial
  name: Hypertelorism
  description: Increased interpupillary distance is part of the periocular gestalt and was documented in a multiplex family alongside ptosis and downslanted palpebral fissures.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  frequency: FREQUENT
  notes: 'Frequency derivation: hypertelorism in 14 of 29 patients in Colson et al. 2025. 14/29 = 48%, which falls in the FREQUENT band (30-79%).'
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Common features associated with IDDDFP included blepharophimosis (10/29; 34%), hypertelorism (14/29; 48%), ptosis (20/29; 69%), and a round face (17/27; 63%)
    explanation: Hypertelorism in 14/29 (48%) falls in the FREQUENT band (30-79%).
  - reference: PMID:31020800
    reference_title: BRPF1-associated intellectual disability, ptosis, and facial dysmorphism in a multiplex family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: he showed dysmorphic facial features, most notably bilateral ptosis, hypertelorism and downslanted palpebral fissures
    explanation: Independent documentation of hypertelorism in a BRPF1 multiplex family proband.
- category: Craniofacial
  name: Bulbous Nose
  description: A bulbous nasal tip accompanies the wide nasal bridge in the recognizable facial gestalt.
  phenotype_term:
    preferred_term: Bulbous nose
    term:
      id: HP:0000414
      label: Bulbous nose
  frequency: FREQUENT
  notes: 'Frequency derivation: bulbous nose in 14 of 28 patients in Colson et al. 2025. 14/28 = 50%, which falls in the FREQUENT band (30-79%).'
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: bulbous nose (14/28; 50%)
    explanation: Bulbous nose in 14/28 (50%) falls in the FREQUENT band (30-79%).
- category: Craniofacial
  name: High Palate
  description: A high-arched palate is a frequent oral finding and is relevant to early feeding and oromotor difficulty.
  phenotype_term:
    preferred_term: High palate
    term:
      id: HP:0000218
      label: High palate
  frequency: FREQUENT
  notes: 'Frequency derivation: high palate in 14 of 29 patients in Colson et al. 2025. 14/29 = 48%, which falls in the FREQUENT band (30-79%).'
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: high palate (14/29; 48%)
    explanation: High palate in 14/29 (48%) falls in the FREQUENT band (30-79%).
- category: Craniofacial
  name: Epicanthus
  description: Epicanthal folds complete the periocular gestalt; epicanthus inversus, the form characteristic of BPES, was present in a minority of those affected (5/29 of the largest cohort).
  phenotype_term:
    preferred_term: Epicanthus
    term:
      id: HP:0000286
      label: Epicanthus
  frequency: FREQUENT
  notes: 'Frequency derivation: epicanthus in 12 of 29 patients in Colson et al. 2025. 12/29 = 41%, which falls in the FREQUENT band (30-79%). Epicanthus inversus specifically was present in 5/29 (17%, OCCASIONAL).'
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: epicanthus (12/29; 41%, with epicanthus inversus in 5/29)
    explanation: Epicanthus in 12/29 (41%) falls in the FREQUENT band (30-79%); the inversus subtype is separately quantified at 5/29.
  - reference: PMID:32457794
    reference_title: Novel Missense Variant in Heterozygous State in the BRPF1 Gene Leading to Intellectual Developmental Disorder With Dysmorphic Facies and Ptosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: epicanthic folds and hypertelorism
    explanation: Independent documentation of epicanthal folds in a BRPF1 missense-variant carrier.
- category: Craniofacial
  name: Synophrys
  description: Synophrys was newly recognized as a recurrent feature in the 2025 cohort and is one of the signs that overlaps with Cornelia de Lange syndrome.
  phenotype_term:
    preferred_term: Synophrys
    term:
      id: HP:0000664
      label: Synophrys
  frequency: FREQUENT
  notes: 'Frequency derivation: synophrys in 10 of 28 patients in Colson et al. 2025. 10/28 = 36%, which falls in the FREQUENT band (30-79%).'
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: synophrys (10/28; 36%)
    explanation: Synophrys in 10/28 (36%) falls in the FREQUENT band (30-79%).
- category: Craniofacial
  name: Laterally Extended Eyebrows
  description: Laterally extended (elongated) eyebrows were among the newly identified facial features of the 2025 cohort.
  phenotype_term:
    preferred_term: Laterally extended eyebrow
    term:
      id: HP:0011230
      label: Laterally extended eyebrow
  frequency: OCCASIONAL
  notes: 'Frequency derivation: laterally extended eyebrows in 8 of 29 patients in Colson et al. 2025. 8/29 = 28%, which falls in the OCCASIONAL band (5-29%).'
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: laterally extended eyebrows (8/29, 28%)
    explanation: Laterally extended eyebrows in 8/29 (28%) fall in the OCCASIONAL band (5-29%).
- category: Craniofacial
  name: Low Hanging Columella
  description: A low-hanging columella was one of the newly described nasal features of the 2025 cohort.
  phenotype_term:
    preferred_term: Low hanging columella
    term:
      id: HP:0009765
      label: Low hanging columella
  frequency: FREQUENT
  notes: 'Frequency derivation: low columella in 9 of 29 patients in Colson et al. 2025. 9/29 = 31%, which falls in the FREQUENT band (30-79%), at its lower edge.'
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: low columella (9/29; 31%)
    explanation: Low columella in 9/29 (31%) falls in the FREQUENT band (30-79%).
- category: Integumentary
  name: Hair Abnormalities
  description: Fine hair, sparse hair, and low posterior or high anterior hairlines are recurrent and were highlighted in the 2025 cohort as newly described abnormalities of the phanera.
  phenotype_term:
    preferred_term: Abnormal hair morphology
    term:
      id: HP:0001595
      label: Abnormal hair morphology
  frequency: FREQUENT
  notes: 'Frequency derivation: various hair abnormalities in 12 of 29 patients in Colson et al. 2025. 12/29 = 41%, which falls in the FREQUENT band (30-79%).'
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: various hair abnormalities (12/29; 41%), such as fine hair, sparse hair, low posterior hairline, and high anterior hairline.
    explanation: Hair abnormalities in 12/29 (41%) fall in the FREQUENT band (30-79%).
- category: Behavioral
  name: Behavioural Disorder
  description: A behavioural phenotype is present in the majority of individuals and is a major contributor to caregiver burden. It is heterogeneous rather than stereotyped, spanning attention deficit/hyperactivity, low frustration tolerance, anxiety, agitation, inappropriate laughter and autistic behaviour.
  phenotype_term:
    preferred_term: Behavioural disorder
    term:
      id: HP:0000708
      label: Atypical behavior
  frequency: FREQUENT
  notes: 'Frequency derivation: 18 of 29 patients (62%) in Colson et al. 2025 had behavioural disorders. 62% falls in the FREQUENT band (30-79%). The HPO term label is "Atypical behavior"; the preferred_term keeps the clinical wording used by the source. The source also reports a combined aggressive/impulsive/violent category (6/27) and labels food-intake behavior as bulimia (4/29), without documenting diagnostic criteria or compensatory purging; these data do not establish bulimia nervosa.'
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 18 patients (62%) had behavioural disorders, including attention deficit/hyperactivity (33%), low frustration tolerance (29%), inappropriate laughter (14%), anxiety (21%), agitation (15%) and autistic behaviour (15%).
    explanation: Any behavioural disorder in 62% falls in the FREQUENT band (30-79%), with the component behaviours itemized.
- category: Behavioral
  name: Anxiety
  description: Anxiety is one of the component behaviours of the BRPF1 behavioural phenotype and is a treatable target for behavioural and, where indicated, pharmacological management.
  phenotype_term:
    preferred_term: Anxiety
    term:
      id: HP:0000739
      label: Anxiety
  frequency: OCCASIONAL
  notes: 'Frequency derivation: anxiety in 21% of the 29-patient Colson et al. 2025 cohort. 21% falls in the OCCASIONAL band (5-29%).'
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: anxiety (21%)
    explanation: Anxiety at 21% falls in the OCCASIONAL band (5-29%).
- category: Behavioral
  name: Autistic Behavior
  description: Autistic behaviour occurs in a minority. Separately, a BRPF1 variant was identified in an individual ascertained for autism, and the corresponding complex was shown to be functionally impaired, so a contribution of BRPF1 dysfunction to autism spectrum disorder is biochemically supported as well as clinically observed.
  phenotype_term:
    preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  frequency: OCCASIONAL
  notes: 'Frequency derivation: autistic behaviour in 15% of the 29-patient Colson et al. 2025 cohort. 15% falls in the OCCASIONAL band (5-29%).'
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: autistic behaviour (15%)
    explanation: Autistic behaviour at 15% falls in the OCCASIONAL band (5-29%).
  - reference: PMID:32010779
    reference_title: Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: These results indicate that BRPF1 dysfunction also contributes to autism spectrum disorder
    explanation: Functional support for a BRPF1 contribution to autism, based on a single variant found in an autistic individual; not a frequency claim.
- category: Neurologic
  name: Sleep Disturbance
  description: Sleep disturbance is a frequent and under-recognized component of the behavioural burden and a practical management target.
  phenotype_term:
    preferred_term: Sleep disturbance
    term:
      id: HP:0002360
      label: Sleep disturbance
  frequency: FREQUENT
  notes: 'Frequency derivation: sleep disturbance reported by nine of 29 patients in Colson et al. 2025. 9/29 = 31%, which falls in the FREQUENT band (30-79%), at its lower edge.'
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Sleep disturbance was reported by nine patients (31%).
    explanation: Sleep disturbance in 9/29 (31%) falls in the FREQUENT band (30-79%).
- category: Neurologic
  name: Microcephaly
  description: Microcephaly is part of the wider 3p25 deletion phenotype and was significantly enriched in individuals with BRPF1 disruption relative to SETD5-only deletions, but it is uncommon in BRPF1 point-variant cohorts.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  frequency: OCCASIONAL
  notes: 'Frequency derivation: two of 29 patients in Colson et al. 2025 had congenital microcephaly and none acquired it. 2/29 = 7%, which falls in the OCCASIONAL band (5-29%). Earlier reports give higher rates, which is consistent with the historical over-representation of contiguous 3p25 deletions.'
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: With the exception of two patients with congenital microcephaly, microcephaly was not observed in the cohort.
    explanation: 2/29 = 7%, which falls in the OCCASIONAL band (5-29%).
  - reference: PMID:31020800
    reference_title: BRPF1-associated intellectual disability, ptosis, and facial dysmorphism in a multiplex family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Their data demonstrated that microcephaly and ptosis (either unilateral or bilateral) and/or blepharophimosis were significantly more common in those with BRPF1 disruptions
    explanation: Attributes microcephaly within the 3p25 deletion region specifically to BRPF1 dosage rather than to SETD5.
- category: Neurologic
  name: Chiari Type I Malformation
  description: Chiari type I (Arnold-Chiari) malformation is one of the cerebral malformations reported in the BRPF1 literature and was found in one of two patients undergoing deep ocular and neurological phenotyping. It matters clinically because it can be symptomatic and surgically actionable.
  phenotype_term:
    preferred_term: Chiari type I malformation
    term:
      id: HP:0007099
      label: Chiari type I malformation
  notes: Frequency deliberately omitted. The largest cohort reports cerebral malformations collectively (13/26 in the literature, 3/17 in their own imaged patients) without breaking out a Chiari-specific count, and the only individually reported case has no denominator.
  evidence:
  - reference: PMID:38590032
    reference_title: 'Broadening the ocular phenotypic spectrum of ultra-rare BRPF1 variants: report of two cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: P1 had a Chiari Malformation type I and a subclinical optic neuropathy, which could not be explained by variations in other genes.
    explanation: Documents Chiari type I malformation in a BRPF1 variant carrier, with other genetic causes excluded.
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Cerebral malformations are commonly reported in the literature (13/26), including periventricular nodular heterotopia, Arnold-Chiari malformation and abnormalities of the corpus callosum
    explanation: Places Arnold-Chiari malformation within the reported spectrum of BRPF1 cerebral malformations, without a Chiari-specific denominator.
- category: Ophthalmologic
  name: Visual Impairment
  description: Vision impairment was reported in 13/15 participants in the dedicated speech-phenotyping study. The broader literature combines heterogeneous ocular abnormalities, including strabismus and refractive error; those findings should not automatically be equated with reduced visual acuity.
  phenotype_term:
    preferred_term: Visual impairment
    term:
      id: HP:0000505
      label: Visual impairment
  frequency: VERY_FREQUENT
  notes: The frequency describes the small speech-ascertained cohort (13/15), not an unbiased population estimate. The 41/53 literature aggregate is not used as an acuity-deficit denominator because it pools different ocular findings.
  evidence:
  - reference: PMID:38346666
    reference_title: 'Beyond ''speech delay'': Expanding the phenotype of BRPF1-related disorder.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Participants had vision impairment (13/15), fine (8/15) and gross motor delay (10/15) which often resolved in later childhood, infant feeding impairment (8/15), and infant hypotonia (9/15).
    explanation: The authors report vision impairment in 13/15 participants; ascertainment and endpoint definitions limit generalization.
- category: Ophthalmologic
  name: Refractive Error
  description: Refractive abnormalities were reported in 7/29 patients in the 2025 cohort, including myopia in 5/29 and hypermetropia in 2/29. These findings fall within the occasional frequency band and form part of the reported ocular spectrum.
  phenotype_term:
    preferred_term: Abnormality of refraction
    term:
      id: HP:0000539
      label: Abnormality of refraction
  frequency: OCCASIONAL
  notes: 'Frequency derivation: refractive disorders in seven of 29 patients in Colson et al. 2025. 7/29 = 24%, which falls in the OCCASIONAL band (5-29%), comprising myopia 5/29 and hypermetropia 2/29.'
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Refractive disorders were found in seven patients (24%)
    explanation: Refractive error in 7/29 (24%) falls in the OCCASIONAL band (5-29%).
  - reference: PMID:38590032
    reference_title: 'Broadening the ocular phenotypic spectrum of ultra-rare BRPF1 variants: report of two cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The reported ocular involvement includes strabismus, amblyopia, and refraction errors.
    explanation: Lists refraction errors among the established ocular manifestations.
- category: Gastrointestinal
  name: Gastroesophageal Reflux
  description: Gastro-oesophageal reflux is the commonest gastrointestinal problem and, with hypotonia and oromotor difficulty, is part of the infant feeding picture.
  phenotype_term:
    preferred_term: Gastroesophageal reflux
    term:
      id: HP:0002020
      label: Gastroesophageal reflux
  frequency: FREQUENT
  notes: 'Frequency derivation: reflux in 9 of 29 patients (31%) in Colson et al. 2025 and 4 of 15 (27%) in the independent Morison cohort. 31% falls in the FREQUENT band (30-79%) at its lower edge; the second estimate sits just below in OCCASIONAL, so the band should be read as borderline.'
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: oesophageal reflux was a common problem in our series, affecting 9 of 29 patients (31%), compared with 4 of 15 participants (27%) in the report by Morison and collaborators
    explanation: 9/29 = 31%, which falls in the FREQUENT band (30-79%); the independent 27% estimate is at the OCCASIONAL/FREQUENT boundary.
- category: Gastrointestinal
  name: Constipation
  description: Constipation occurs in a minority and is a routine but relevant supportive care target in a hypotonic neurodevelopmental population.
  phenotype_term:
    preferred_term: Constipation
    term:
      id: HP:0002019
      label: Constipation
  frequency: OCCASIONAL
  notes: 'Frequency derivation: constipation in 14% of the 29-patient Colson et al. 2025 cohort. 14% falls in the OCCASIONAL band (5-29%).'
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A few patients had constipation (14%) and bulimia (14%).
    explanation: Constipation at 14% falls in the OCCASIONAL band (5-29%).
- category: Growth
  name: Short Stature
  description: Height is usually normal in prospectively phenotyped patients but short stature is reported at a substantially higher rate in the earlier literature. Growth hormone secretion has not been tested in any reported series.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  notes: Frequency deliberately omitted. The two quotable denominators straddle bands - 6/29 (21%, OCCASIONAL) in the prospectively phenotyped 2025 cohort versus 17/42 (40%, FREQUENT) in that paper's literature comparison - and no source reconciles them, so no band is claimed.
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: short stature was noted in three patients (6/29, 21%), whereas short stature is relatively common in IDDDFP patients reported in the literature (17/42, 40%)
    explanation: Supports the disease-phenotype association and documents the 21% versus 40% discrepancy that is the stated reason no band is assigned.
  - reference: PMID:31020800
    reference_title: BRPF1-associated intellectual disability, ptosis, and facial dysmorphism in a multiplex family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: while strabismus and small stature were enriched in this group, however did not reach statistical significance
    explanation: Short stature trends with BRPF1 disruption within the 3p25 deletion region but the enrichment was not statistically significant.
- category: Growth
  name: Obesity
  description: A minority of patients are obese; body weight is otherwise typically normal for age and no reports of low weight were made in the largest cohort.
  phenotype_term:
    preferred_term: Obesity
    term:
      id: HP:0001513
      label: Obesity
  frequency: OCCASIONAL
  notes: 'Frequency derivation: four of 28 patients (14%) in Colson et al. 2025 were obese. 14% falls in the OCCASIONAL band (5-29%).'
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Weight changes were generally normal across age groups, with only four patients being obese (14%) and no reports of decreased body weight.
    explanation: Obesity at 14% falls in the OCCASIONAL band (5-29%).
- category: Genitourinary
  name: Cryptorchidism
  description: Cryptorchidism occurs in BRPF1-related disorder. The founding family already included a boy with unilateral cryptorchidism and surgery, and the 2025 cohort reported five affected patients. It was therefore not first described in 2025.
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  notes: The 2025 summary reports 5/27 across the cohort, not a male-only denominator, and reports a different percentage elsewhere. A male-specific frequency cannot be inferred from this aggregate. Its statement that cryptorchidism had not previously been reported conflicts with the founding 2017 report.
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: occurring in 5 of 27 patients (19%).
    explanation: Reports five affected patients; the aggregate denominator and inconsistent percentages do not establish a male-specific frequency.
  - reference: PMID:27939639
    reference_title: Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual Disability with Associated Ptosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He had surgery for his ptosis and for cryptorchidism.
    explanation: The founding family already included cryptorchidism requiring surgery, contradicting the later claim of novelty.
- category: Musculoskeletal
  name: Clinodactyly of the Fifth Finger
  description: Fifth-finger clinodactyly was reported in 8/27 patients in the 2025 cohort. Other limb findings include small hands, broad halluces and distal joint hypermobility.
  phenotype_term:
    preferred_term: Clinodactyly of the 5th finger
    term:
      id: HP:0004209
      label: Clinodactyly of the 5th finger
  frequency: FREQUENT
  notes: 'Frequency derivation: clinodactyly of the fifth digit in 8 of 27 patients in Colson et al. 2025. 8/27 = 30%, which falls in the FREQUENT band (30-79%), exactly at its lower boundary.'
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: No abnormalities were noted in the extremities, except for clinodactyly of the fifth digit in eight patients (8/27; 30%), prominent fingertip pads in six patients (6/27; 22%), and small hands with a wide hallux in four patients (4/23; 17%)
    explanation: Clinodactyly of the fifth digit in 8/27 (30%) falls in the FREQUENT band (30-79%) at its boundary.
- category: Musculoskeletal
  name: Prominent Fingertip Pads
  description: Prominent fingertip pads occur in a minority and are part of the minor acral findings described in the 2025 cohort.
  phenotype_term:
    preferred_term: Prominent fingertip pads
    term:
      id: HP:0001212
      label: Prominent fingertip pads
  frequency: OCCASIONAL
  notes: 'Frequency derivation: prominent fingertip pads in 6 of 27 patients in Colson et al. 2025. 6/27 = 22%, which falls in the OCCASIONAL band (5-29%).'
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: prominent fingertip pads in six patients (6/27; 22%)
    explanation: Prominent fingertip pads in 6/27 (22%) fall in the OCCASIONAL band (5-29%).
- name: Upslanted Palpebral Fissures
  category: Craniofacial
  description: Reported in 7/29 patients in the 2025 summary; downslanting is a separate, also reported configuration.
  phenotype_term:
    preferred_term: Upslanted palpebral fissure
    term:
      id: HP:0000582
      label: Upslanted palpebral fissure
  notes: Frequencies, where supplied, summarize reported 2025 cohort counts and are subject to ascertainment and incomplete assessment.
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '| Upslanted palpebral fissure | 7/29 (24%) | 4 (N/A) |'
    explanation: The source summary table explicitly records this finding; source inconsistencies are retained in the description.
  frequency: OCCASIONAL
- name: Small Hands
  category: Musculoskeletal
  description: Table 2 reports 4/27, whereas the discussion gives 6/29 for short hands. Both fall within the occasional band; the exact count is inconsistent.
  phenotype_term:
    preferred_term: Small hand
    term:
      id: HP:0200055
      label: Small hand
  notes: Frequencies, where supplied, summarize reported 2025 cohort counts and are subject to ascertainment and incomplete assessment.
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '| Small hand | 4/27 (15%) | 5/25 (20%) |'
    explanation: The source summary table explicitly records this finding; source inconsistencies are retained in the description.
  frequency: OCCASIONAL
- name: Broad Hallux
  category: Musculoskeletal
  description: The 2025 summary reports 4/27 patients.
  phenotype_term:
    preferred_term: Broad hallux
    term:
      id: HP:0010055
      label: Broad hallux
  notes: Frequencies, where supplied, summarize reported 2025 cohort counts and are subject to ascertainment and incomplete assessment.
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '| Broad hallux | 4/27 (15%) | N/A |'
    explanation: The source summary table explicitly records this finding; source inconsistencies are retained in the description.
  frequency: OCCASIONAL
- name: Distal Joint Hypermobility
  category: Musculoskeletal
  description: The 2025 summary reports distal joint laxity in 7/27; generalized hypermobility is not inferred.
  phenotype_term:
    preferred_term: Distal joint hypermobility
    term:
      id: HP:0020152
      label: Distal joint hypermobility
  notes: Frequencies, where supplied, summarize reported 2025 cohort counts and are subject to ascertainment and incomplete assessment.
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '| Distal joint laxity | 7/27 (26%) | 5 (N/A) |'
    explanation: The source summary table explicitly records this finding; source inconsistencies are retained in the description.
  frequency: OCCASIONAL
- name: Inappropriate Laughter
  category: Behavioral
  description: Reported as 4/25. This equals 16%, although the source prints 14%; either lies in the occasional band.
  phenotype_term:
    preferred_term: Inappropriate laughter
    term:
      id: HP:0000748
      label: Inappropriate laughter
  notes: Frequencies, where supplied, summarize reported 2025 cohort counts and are subject to ascertainment and incomplete assessment.
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '| Inappropriate laughter | 4/25 (14%) | N/A |'
    explanation: The source summary table explicitly records this finding; source inconsistencies are retained in the description.
  frequency: OCCASIONAL
- name: Low Frustration Tolerance
  category: Behavioral
  description: Table 2 gives 8/28, while the discussion uses 8/29. Both fall within the occasional band; this is not a separate psychiatric diagnosis.
  phenotype_term:
    preferred_term: Low frustration tolerance
    term:
      id: HP:0000744
      label: Low frustration tolerance
  notes: Frequencies, where supplied, summarize reported 2025 cohort counts and are subject to ascertainment and incomplete assessment.
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '| Low frustration tolerance | 8/28 (29%) | N/A |'
    explanation: The source summary table explicitly records this finding; source inconsistencies are retained in the description.
  frequency: OCCASIONAL
- name: Agitation
  category: Behavioral
  description: Reported in 4/27 patients; no specific cause of agitation is established.
  phenotype_term:
    preferred_term: Agitation
    term:
      id: HP:0000713
      label: Agitation
  notes: Frequencies, where supplied, summarize reported 2025 cohort counts and are subject to ascertainment and incomplete assessment.
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '| Agitation | 4/27 (15%) | N/A |'
    explanation: The source summary table explicitly records this finding; source inconsistencies are retained in the description.
  frequency: OCCASIONAL
- name: Recurrent Viral Infections
  category: Immunologic
  description: Reported in 4/28 patients. This observation does not establish immunodeficiency or the null-mouse marrow-failure mechanism.
  phenotype_term:
    preferred_term: Recurrent viral infections
    term:
      id: HP:0004429
      label: Recurrent viral infections
  notes: Frequencies, where supplied, summarize reported 2025 cohort counts and are subject to ascertainment and incomplete assessment.
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '| Recurrent viral infections | 4/28 (14%) | N/A |'
    explanation: The source summary table explicitly records this finding; source inconsistencies are retained in the description.
  frequency: OCCASIONAL
- name: Myopia
  category: Ophthalmologic
  description: Reported in 5/29 patients. Refractive error is recorded separately from measured visual acuity.
  phenotype_term:
    preferred_term: Myopia
    term:
      id: HP:0000545
      label: Myopia
  notes: Frequencies, where supplied, summarize reported 2025 cohort counts and are subject to ascertainment and incomplete assessment.
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '| Myopia | 5/29 (17%) | N/A |'
    explanation: The source summary table explicitly records this finding; source inconsistencies are retained in the description.
  frequency: OCCASIONAL
- name: Hypermetropia
  category: Ophthalmologic
  description: Reported in 2/29 patients.
  phenotype_term:
    preferred_term: Hypermetropia
    term:
      id: HP:0000540
      label: Hypermetropia
  notes: Frequencies, where supplied, summarize reported 2025 cohort counts and are subject to ascertainment and incomplete assessment.
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '| Hypermetropia | 2/29 (7%) | 6 (N/A) |'
    explanation: The source summary table explicitly records this finding; source inconsistencies are retained in the description.
  frequency: OCCASIONAL
- name: Horizontal Nystagmus
  category: Ophthalmologic
  description: Reported in 2/29 patients; the source specifies the direction of the eye movement.
  phenotype_term:
    preferred_term: Horizontal nystagmus
    term:
      id: HP:0000666
      label: Horizontal nystagmus
  notes: Frequencies, where supplied, summarize reported 2025 cohort counts and are subject to ascertainment and incomplete assessment.
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '| Horizontal nystagmus | 2/29 (7%) | 1 (N/A) |'
    explanation: The source summary table explicitly records this finding; source inconsistencies are retained in the description.
  frequency: OCCASIONAL
- name: Scoliosis
  category: Musculoskeletal
  description: Reported in 2/27 patients.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  notes: Frequencies, where supplied, summarize reported 2025 cohort counts and are subject to ascertainment and incomplete assessment.
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '| Scoliosis | 2/27 (7%) | N/A |'
    explanation: The source summary table explicitly records this finding; source inconsistencies are retained in the description.
  frequency: OCCASIONAL
- name: Plagiocephaly
  category: Craniofacial
  description: Reported in 2/28 patients; craniosynostosis is not established.
  phenotype_term:
    preferred_term: Plagiocephaly
    term:
      id: HP:0001357
      label: Plagiocephaly
  notes: Frequencies, where supplied, summarize reported 2025 cohort counts and are subject to ascertainment and incomplete assessment.
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '| Plagiocephaly | 2/28 (7%) | N/A |'
    explanation: The source summary table explicitly records this finding; source inconsistencies are retained in the description.
  frequency: OCCASIONAL
- name: Laryngomalacia
  category: Respiratory
  description: Table 2 and the results give two patients, while the discussion gives one and reverses the laryngomalacia/stridor counts. A frequency band is omitted because the discrepancy crosses the 5% boundary.
  phenotype_term:
    preferred_term: Laryngomalacia
    term:
      id: HP:0001601
      label: Laryngomalacia
  notes: Frequencies, where supplied, summarize reported 2025 cohort counts and are subject to ascertainment and incomplete assessment.
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '| Laryngomalacia | 2/28 (7%) | 5/15 (33%) |'
    explanation: The source summary table explicitly records this finding; source inconsistencies are retained in the description.
- name: Stridor
  category: Respiratory
  description: Table 2 and the results give one patient, whereas the discussion gives two. Stridor is recorded as a symptom without assuming it is always due to laryngomalacia; the inconsistent count precludes a single frequency band.
  phenotype_term:
    preferred_term: Stridor
    term:
      id: HP:0010307
      label: Stridor
  notes: Frequencies, where supplied, summarize reported 2025 cohort counts and are subject to ascertainment and incomplete assessment.
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '| Stridor | 1/28 (4%) | 2/15 (13%) |'
    explanation: The source summary table explicitly records this finding; source inconsistencies are retained in the description.
- name: Talipes Equinovarus
  category: Musculoskeletal
  description: Table 2 reports 1/28 in the new cohort; the founding family also included clubfeet. This band describes the 2025 cohort only, not cumulative penetrance.
  phenotype_term:
    preferred_term: Talipes equinovarus
    term:
      id: HP:0001762
      label: Talipes equinovarus
  notes: Frequencies, where supplied, summarize reported 2025 cohort counts and are subject to ascertainment and incomplete assessment.
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '| Talipes equinovarus | 1/28 (4%) | 3 (N/A) |'
    explanation: The source summary table explicitly records this finding; source inconsistencies are retained in the description.
  frequency: VERY_RARE
- name: Impulsivity
  category: Behavioral
  description: Impulsive behavior is recorded in individual patient entries. The combined 6/27 summary for aggressive, impulsive or violent behavior does not establish an individual frequency for each component.
  phenotype_term:
    preferred_term: Impulsivity
    term:
      id: HP:0100710
      label: Impulsivity
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Impulsive behavior, low frustration tolerance
    explanation: Individual patient entries in Table 1 explicitly identify impulsive behavior. The combined aggressive/impulsive/violent denominator in Table 2 is not a separate frequency estimate for each behavior.
- name: Agenesis of the Corpus Callosum
  category: Neurologic
  description: Callosal agenesis was reported in two patients among seventeen with available brain MRI in the 2025 cohort.
  phenotype_term:
    preferred_term: Agenesis of corpus callosum
    term:
      id: HP:0001274
      label: Agenesis of corpus callosum
  frequency: OCCASIONAL
  notes: The 2/17 estimate is restricted to imaged patients and may be influenced by clinical selection. It should not be generalized to all BRPF1 carriers.
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Brain MRI was available for 17 patients, of whom two (12%) had agenesis of the corpus callosum and one had multifocal hyperintensities in the white matter.
    explanation: The clinical narrative specifies agenesis in two of the seventeen imaged patients; this is not the frequency of hypoplasia or of all brain abnormalities.
- name: Facial Asymmetry
  category: Craniofacial
  description: Facial asymmetry was reported in 3/28 patients in the 2025 cohort.
  phenotype_term:
    preferred_term: Facial asymmetry
    term:
      id: HP:0000324
      label: Facial asymmetry
  frequency: OCCASIONAL
  notes: Frequency describes the reported cohort, with incomplete assessment and ascertainment limitations.
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '| Facial asymmetry | 3/28 (11%) | 3 (N/A) |'
    explanation: The summary table explicitly records this finding and denominator.
- name: Epicanthus Inversus
  category: Craniofacial
  description: Epicanthus inversus was reported in 5/29 patients in the 2025 cohort. It can overlap the eyelid findings of FOXL2-related BPES and is not by itself a discriminator.
  phenotype_term:
    preferred_term: Epicanthus inversus
    term:
      id: HP:0000537
      label: Epicanthus inversus
  frequency: OCCASIONAL
  notes: Frequency describes the reported cohort, with incomplete assessment and ascertainment limitations.
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: '| Epicanthus inversus | 5/29 (17%) | N/A |'
    explanation: The summary table explicitly records this finding and denominator.
- name: Atrioventricular Block
  category: Cardiovascular
  description: Atrioventricular nodal pauses and blocks are described in the clinical literature summarized by the 2025 cohort paper. They are recorded separately from structural cardiac anomalies; a block-specific denominator is not available.
  phenotype_term:
    preferred_term: Atrioventricular block
    term:
      id: HP:0001678
      label: Atrioventricular block
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: atrioventricular (AV) nodal pauses and blocks
    explanation: The clinical literature synthesis identifies conduction findings in addition to structural defects; it does not give a block-specific frequency or establish the cardiac mechanism.

prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  rate_high: 0.1
  notes: Orphanet records a validated worldwide point-prevalence class of <1 / 1 000 000 for ORPHA:698090, i.e. fewer than 0.1 cases per 100,000. Only the upper bound is recorded (rate_high) because the source gives an open-below class, not a point estimate.
  evidence:
  - reference: ORPHA:698090
    reference_title: Ophthalmological abnormalities-facial dysmorphism-intellectual disability syndrome
    supports: SUPPORT
    evidence_source: OTHER
    snippet: <1 / 1 000 000 | Worldwide | Point prevalence | ORPHANET
    explanation: Orphanet's epidemiology table gives a worldwide point-prevalence class of <1 / 1 000 000, which maps to PrevalenceClassEnum BELOW_1_IN_1000000.
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: These are dated literature counts, not a population prevalence or a deduplicated cumulative census. The 2020 study stated that BRPF1 variants had been reported in 40 cases of syndromic intellectual disability. The 2025 study described 29 new patients from 20 families and compared them with published cases. A total near 100 is not established by these citations. The cached Orphadata cases/families record provides no numerical count.
  evidence:
  - reference: PMID:32010779
    reference_title: Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: BRPF1 variants are present in 40 cases of syndromic intellectual disability
    explanation: Gives a cumulative published case count of 40 as of 2020.
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This study expands the clinical and molecular spectrum of IDDDFP by analysing 29 new patients from 20 families with confirmed BRPF1 variants.
    explanation: Describes 29 new patients from 20 families; it does not establish a deduplicated cumulative total near 100.

genetic:
- name: BRPF1 Pathogenic Variants
  gene_term:
    preferred_term: BRPF1
    term:
      id: hgnc:14255
      label: BRPF1
  association: Causative
  presence: Positive
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: 'BRPF1 lies at 3p25.3 (GRCh38 chr3:9731735-9748015, per the ClinGen dosage record cited below). Reported pathogenic alleles are heterozygous and predominantly loss-of-function - nonsense, frameshift, and whole- or partial-gene deletions - with a minority of missense and stop-loss variants whose pathogenicity requires variant-specific functional support. Both de novo and inherited alleles are common, and recurrence in one sibship suggests parental gonadal mosaicism despite negative parental buccal testing. Gonadal tissue and parent-of-origin were not established. A contiguous 3p25 deletion may remove BRPF1 with the neighbouring SETD5; in that setting both genes contribute to severity, but ptosis and blepharophimosis were particularly associated with BRPF1 disruption in the founding comparison. No robust genotype-phenotype correlation by variant position has been established. The authoritative dosage-mechanism assertion is ClinGen''s: haploinsufficiency score 3 (Sufficient Evidence), triplosensitivity score 0 (No Evidence), curated 2023-08-23 against MONDO:0015022. gnomAD constraint (pLI/LOEUF) is deliberately not asserted: no cached, quotable source for the exact values was available,
    and per the project evidence SOP an unsourceable number is dropped rather than approximated. The p.Val352Leu case report explicitly classifies that missense variant as uncertain significance in its methods, despite stronger causal wording elsewhere; structural modeling alone does not establish pathogenicity.'
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    description: Heterozygous BRPF1 variants segregate in an autosomal dominant pattern with variable expressivity; in one multiplex family the variant segregated fully with disease across two generations.
    evidence:
    - reference: PMID:31020800
      reference_title: BRPF1-associated intellectual disability, ptosis, and facial dysmorphism in a multiplex family.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: the mutation fully segregated with the disease in the family
      explanation: The familial p.Gln186Ter allele segregated with the BRPF1 phenotype. A sibling with Leber hereditary optic neuropathy instead carried an MT-ND1 variant and did not share the BRPF1 phenotype.
  evidence:
  - reference: CGDS:HGNC_14255
    reference_title: BRPF1 dosage sensitivity
    supports: SUPPORT
    evidence_source: OTHER
    snippet: BRPF1 | HGNC:14255 | 7862 | 3p25.3 | chr3:9731735-9748015 | 3 - Sufficient Evidence for Haploinsufficiency | 0 - No Evidence for Triplosensitivity | 2023-08-23
    explanation: ClinGen's dosage sensitivity curation scores BRPF1 haploinsufficiency at 3 (Sufficient Evidence) and triplosensitivity at 0 (No Evidence), fixing the disease mechanism as loss of one functional copy and locating the gene at 3p25.3.
  - reference: CGDS:HGNC_14255
    reference_title: BRPF1 dosage sensitivity
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Numerous loss-of-function mutations have been reported in intellectual developmental disorder with dysmorphic facies and ptosis (IDDDFP) patients, and functional analyses support a haploinsufficiency of the BRPF1 gene.
    explanation: ClinGen's evidence summary states the haploinsufficiency conclusion explicitly and grounds it in both variant spectrum and functional assays.
  - reference: PMID:27939640
    reference_title: Mutations in the Chromatin Regulator Gene BRPF1 Cause Syndromic Intellectual Disability and Deficient Histone Acetylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: These data indicate that aberrations in the chromatin regulator gene BRPF1 cause histone H3 acetylation deficiency and a previously unrecognized intellectual disability syndrome.
    explanation: Establishes BRPF1 as the causative gene for a distinct intellectual disability syndrome.
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Thirteen of the 17 unique variants were truncating variants leading to haploinsufficiency, including frameshift variants
    explanation: Quantifies the truncating predominance (13/17 unique alleles) that underpins the haploinsufficiency mechanism.
  - reference: PMID:32457794
    reference_title: Novel Missense Variant in Heterozygous State in the BRPF1 Gene Leading to Intellectual Developmental Disorder With Dysmorphic Facies and Ptosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Bioinformatics of WES data and candidate gene prioritization identified a novel variant in heterozygous state in the exon 3 of BRPF1 gene (ENST383829: c.1054G > C and p.Val352Leu).'
    explanation: Documents the reported p.Val352Leu missense allele, which the paper methods classify as uncertain significance. It is not confirmed functional loss of BRPF1.
  - reference: PMID:40752867
    reference_title: 'Ocular findings of BRPF1 variants: a case report and literature review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Genetic testing identified a maternally inherited stop-loss variant of the BRPF1 gene.
    explanation: Documents an inherited stop-loss allele, further widening the reported variant spectrum.
  - reference: PMID:37946714
    reference_title: 'Mosaicism in BRPF1-Related Neurodevelopmental Disorder: Report of Two Sisters and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The absence of the BRPF1 variant in parental buccal samples provides evidence of a de novo frameshift pathogenic variant, most likely as a result of parental gonadal mosaicism, which has not been previously reported.
    explanation: Recurrence in two sisters despite negative parental buccal samples suggests gonadal mosaicism; gonadal tissue was not tested and parent-of-origin was unresolved.
  - reference: PMID:32457794
    reference_title: Novel Missense Variant in Heterozygous State in the BRPF1 Gene Leading to Intellectual Developmental Disorder With Dysmorphic Facies and Ptosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The variant detected here was classified as variant with unclear significance according to the most recent ACMG guidelines.
    explanation: The methods explicitly give uncertain significance, despite stronger causal wording in the title and discussion. Structural effects were predicted, not experimentally measured.

diagnosis:
- name: Whole exome sequencing
  description: Exome sequencing can identify heterozygous BRPF1 sequence variants in patients with a suggestive neurodevelopmental phenotype. Testing has been performed in single individuals and trios, with segregation studies where available.
  diagnosis_term:
    preferred_term: Whole Exome Sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  results: A heterozygous pathogenic or likely pathogenic BRPF1 variant supports a molecular diagnosis in the appropriate clinical context. A variant of uncertain significance does not establish the diagnosis.
  evidence:
  - reference: PMID:31020800
    reference_title: BRPF1-associated intellectual disability, ptosis, and facial dysmorphism in a multiplex family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Molecular analysis of the family was pursued using whole exome sequencing (WES) and subsequent Sanger sequencing.
    explanation: Whole exome sequencing with Sanger confirmation is the route to diagnosis.
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In 17 patients, genotyping was conducted by exome sequencing (ES) or genome sequencing (GS) (single or trio) using routine techniques.
    explanation: The cohort documents both sequencing approaches; it does not separately report their diagnostic yields.
- name: Whole genome sequencing
  description: Genome sequencing is another documented route to identify BRPF1 variants. The 2025 cohort groups exome and genome sequencing together, without providing a genome-specific yield.
  diagnosis_term:
    preferred_term: Whole Genome Sequencing
    term:
      id: NCIT:C101294
      label: Whole Genome Sequencing
  results: A heterozygous pathogenic or likely pathogenic BRPF1 variant supports a molecular diagnosis in the appropriate clinical context. A variant of uncertain significance does not establish the diagnosis.
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In 17 patients, genotyping was conducted by exome sequencing (ES) or genome sequencing (GS) (single or trio) using routine techniques.
    explanation: The cohort documents both sequencing approaches; it does not separately report their diagnostic yields.
- name: BRPF1 copy-number analysis
  description: Whole-gene BRPF1 deletions and larger 3p25.3 deletions are documented disease-associated variants. Array comparative genomic hybridization detected deletions in the 2025 cohort, with segregation assessed by qPCR. A molecular workup needs to account for copy-number variation and the detection limits of the chosen assay; the source does not establish that every patient requires a separate microarray in addition to copy-number-sensitive sequencing.
  diagnosis_term:
    preferred_term: chromosomal microarray analysis
    term:
      id: NCIT:C18477
      label: Microarray Analysis
  results: A heterozygous whole-gene BRPF1 deletion, or a contiguous 3p25.3 deletion encompassing BRPF1 with or without SETD5, supports a molecular diagnosis. Deletions spanning SETD5 and other genes require interpretation as contiguous-gene disorders. Greater severity was observed in the small founding comparison, but it is not a deterministic individual prediction.
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Two variants were detected by array CGH, with segregation analysis performed by qPCR in 4 related patients.
    explanation: In the largest cohort, array CGH - not sequencing - was the modality that found two of the pathogenic alleles, with qPCR used for family segregation.
  - reference: PMID:27939639
    reference_title: Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual Disability with Associated Ptosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We identified BRPF1 deletions or point mutations in six additional individuals with a similar phenotype.
    explanation: The founding series already reported deletions alongside point mutations, establishing copy-number loss as part of the diagnostic yield.
  - reference: PMID:37190896
    reference_title: 'Anemia and thrombocytopenia due to a novel BRPF1 variant in a family from Çanakkale with intellectual disability and dysmorphic facies: Case report and review of the literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Apart from the variant in BRPF1, no additional genomic changes were detected by WES and chromosomal microarray analysis (CMA).
    explanation: Illustrates the paired sequencing-plus-CMA workup used to exclude additional or alternative copy-number causes.
- name: Comprehensive ophthalmological evaluation
  description: Detailed ophthalmological assessment can characterize ptosis, blepharophimosis, strabismus, amblyopia, refractive errors and coloboma. Optical coherence tomography identified subclinical optic nerve alterations in a two-case report. These sources support comprehensive assessment but do not establish a BRPF1-specific screening interval or routine OCT schedule.
  diagnosis_term:
    preferred_term: Eye Examination
    term:
      id: NCIT:C38060
      label: Eye Examination
  results: Identifies treatable amblyogenic factors (ptosis, strabismus, refractive error) and otherwise occult optic nerve involvement.
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Our findings highlight the diverse clinical manifestations of BRPF1-related disorders and suggest that comprehensive ophthalmological evaluation is essential for the management of these patients.
    explanation: The largest cohort explicitly recommends comprehensive ophthalmological evaluation.
  - reference: PMID:38590032
    reference_title: 'Broadening the ocular phenotypic spectrum of ultra-rare BRPF1 variants: report of two cases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Since subclinical optic nerve alterations can go easily undetected, our experience highlights the importance of a more detailed ophthalmologic evaluation in patients with BRPF1 variant.
    explanation: Supports adding OCT-level detail to the ophthalmological workup.

treatments:
- name: Multidisciplinary Supportive and Developmental Care
  description: Supportive care can be individualized to developmental, feeding, motor, educational and ocular needs. Coordinating these services is a care-planning inference from the clinical phenotype, not a tested BRPF1-specific program. The cited cohort specifically recommends comprehensive ophthalmological evaluation; other supportive interventions require assessment of the individual patient.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  therapeutic_modality: OTHER
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Our findings highlight the diverse clinical manifestations of BRPF1-related disorders and suggest that comprehensive ophthalmological evaluation is essential for the management of these patients.
    explanation: The cohort explicitly recommends comprehensive ophthalmological evaluation. This snippet does not evaluate multidisciplinary care or establish benefit from the broader supportive program.
  target_phenotypes:
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
- name: Speech and Language Therapy
  description: Speech and language therapy should address the individual speech and language profile, including childhood apraxia of speech where present. The dedicated speech-pathology study supports a formal differential diagnosis. It does not compare treatment effectiveness or establish this as the highest-yield intervention.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: speech therapy
    term:
      id: NCIT:C159273
      label: Speech Language Therapy
  therapeutic_modality: BEHAVIORAL
  evidence:
  - reference: PMID:38346666
    reference_title: 'Beyond ''speech delay'': Expanding the phenotype of BRPF1-related disorder.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We have implicated BRPF1-related disorder as causative for speech and language disorder, including childhood apraxia of speech.
    explanation: Establishes the specific speech diagnoses that therapy must target.
  - reference: PMID:37946714
    reference_title: 'Mosaicism in BRPF1-Related Neurodevelopmental Disorder: Report of Two Sisters and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Early developmental milestones were reported to be delayed primarily for speech and communication skills, for which she received speech therapy.
    explanation: Documents speech therapy use in an affected adult, without a controlled estimate of effectiveness.
  target_phenotypes:
  - preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  - preferred_term: Speech apraxia
    term:
      id: HP:0011098
      label: Speech apraxia
- name: Ptosis Repair Surgery
  description: Several affected individuals in the founding family underwent ptosis surgery. Two adults required repeat operations with limited results. These observations document treatment use and variable outcomes without establishing comparative efficacy, an optimal surgical approach or a syndrome-specific timing recommendation.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: ptosis repair surgery
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  therapeutic_modality: SURGERY
  evidence:
  - reference: PMID:27939639
    reference_title: Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual Disability with Associated Ptosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: who had surgery twice for her ptosis with limited results
    explanation: Describes repeat surgery in an affected adult from the founding family. The text also reports limited results after two operations in her sister; these observations do not establish a general success rate.
  target_phenotypes:
  - preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
- name: Physical Therapy
  description: Physical therapy is a supportive approach for motor delay and hypotonia, individualized to functional needs. The cited speech-phenotyping cohort documents motor impairment and improvement with age; it does not attribute that improvement to physical therapy or measure treatment efficacy.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  therapeutic_modality: BEHAVIORAL
  evidence:
  - reference: PMID:38346666
    reference_title: 'Beyond ''speech delay'': Expanding the phenotype of BRPF1-related disorder.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: fine (8/15) and gross motor delay (10/15) which often resolved in later childhood
    explanation: Documents motor impairment as a potential supportive-care target; the observed natural history is not evidence of physical-therapy efficacy.
  target_phenotypes:
  - preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  - preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
- name: Occupational Therapy
  description: Occupational therapy may address fine-motor and daily-living limitations when present. This is a supportive-care inference from the reported functional impairments; the cited cohort does not test occupational therapy outcomes.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: Occupational Therapy
    term:
      id: NCIT:C121351
      label: Occupational Therapy
  therapeutic_modality: BEHAVIORAL
  evidence:
  - reference: PMID:38346666
    reference_title: 'Beyond ''speech delay'': Expanding the phenotype of BRPF1-related disorder.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: fine (8/15) and gross motor delay (10/15) which often resolved in later childhood
    explanation: Fine-motor impairment provides a potential treatment target, without disorder-specific evidence of occupational-therapy benefit.
  target_phenotypes:
  - preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
- name: Genetic Counseling
  description: Counselling must cover the autosomal dominant 50% recurrence risk for an affected parent, the wide intrafamilial variability (including mildly affected or apparently unaffected carriers, so parental testing and careful parental phenotyping are essential), and the possibility of suspected gonadal mosaicism producing recurrence after an apparently de novo variant.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  therapeutic_modality: OTHER
  evidence:
  - reference: PMID:37946714
    reference_title: 'Mosaicism in BRPF1-Related Neurodevelopmental Disorder: Report of Two Sisters and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The absence of the BRPF1 variant in parental buccal samples provides evidence of a de novo frameshift pathogenic variant, most likely as a result of parental gonadal mosaicism, which has not been previously reported.
    explanation: Sibling recurrence despite negative parental buccal testing supports counselling about possible gonadal mosaicism; it was inferred rather than directly demonstrated.
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Familial analysis revealed variability in clinical expression.
    explanation: Intrafamilial variability is a key counselling point.
- name: Experimental HDAC Inhibition to Increase H3K23 Acylation
  description: Preclinical biochemical rescue only. Valproate, vorinostat, trichostatin A and butyrate increased H3K23 acetylation and propionylation in HEK293 cells and patient-derived Pro370Ser lymphoblastoid cells. Beta-hydroxybutyrate did not increase the marks in those systems, although it did in Brpf1-null mouse fibroblasts. These culture experiments establish model-dependent biochemical responses, not clinical efficacy or correction of neurodevelopment.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: butyrate
      term:
        id: CHEBI:17968
        label: butyrate
    - preferred_term: vorinostat
      term:
        id: CHEBI:45716
        label: vorinostat
    - preferred_term: valproic acid
      term:
        id: CHEBI:39867
        label: valproic acid
    - preferred_term: trichostatin A
      term:
        id: CHEBI:46024
        label: trichostatin A
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Deficient Histone H3K23 Acetylation
    treatment_effect: RESTORES
  - target: Deficient Histone H3K23 Propionylation
    treatment_effect: RESTORES
  evidence:
  - reference: PMID:32010779
    reference_title: Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: We also tested LCLs from the individual harboring the Pro370Ser variant. As shown in Fig. 6C, all inhibitors except β-hydroxybutyrate enhanced H3K23 acetylation and propionylation.
    explanation: Patient-derived lymphoblastoid cells show biochemical responses to the tested HDAC inhibitors; beta-hydroxybutyrate is an important negative comparison in this model.
  - reference: PMID:18469222
    reference_title: The multidomain protein Brpf1 binds histones and is required for Hox gene expression and segmental identity.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Treatment of mutants from 20–33 hpf rescued hoxa2b expression in CNC
    explanation: Trichostatin A restored the measured transcriptional readout in zebrafish; the experiment is preclinical. This separate model supports transcriptional rescue, not the H3K23-specific treatment targets above.
  notes: Investigational cell-culture findings. Neither neurological rescue nor clinical benefit was tested. Valproate is not proposed here as a clinical treatment for BRPF1-related disorder. A separate zebrafish experiment showed transcriptional and skeletal rescue after trichostatin A, without measuring H3K23-specific rescue or human neurodevelopmental outcomes.
- name: Experimental Propionate Supplementation to Increase H3K23 Propionylation
  description: In vitro sodium propionate treatment increased H3K23 propionylation in Pro370Ser patient-derived lymphoblastoid cells. It did not increase H3K23 acetylation. The propionylation response was absent in Brpf1-null mouse embryonic fibroblasts, making residual BRPF1 activity and model context relevant. The study does not establish dietary or drug efficacy in patients.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: propionate
      term:
        id: CHEBI:17272
        label: propionate
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Deficient Histone H3K23 Propionylation
    treatment_effect: RESTORES
  evidence:
  - reference: PMID:32010779
    reference_title: Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Propionate treatment stimulated H3K23 propionylation but not acetylation in MEFs
    explanation: Separates the propionylation response from acetylation; this source does not support targeting both defects with propionate.
  - reference: PMID:32010779
    reference_title: Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The treatment also enhanced H3K23 propionylation in the patient-derived LCLs
    explanation: The patient-derived response was demonstrated for the Pro370Ser lymphoblastoid line.
  - reference: PMID:32010779
    reference_title: Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The enhancement of propionylation in response to propionate treatment was abolished in Brpf1−/− MEFs
    explanation: Complete Brpf1 loss prevented this response, unlike the residual-function patient-cell setting.
  notes: Biochemical culture result only. The 10 mM sodium propionate exposure for 24 hours used in the experiment is not a patient dosing recommendation.
- name: Behavioural and ADHD Management
  description: Behavioral difficulties were reported in 18/29 patients in the 2025 cohort, including attention/hyperactivity, low frustration tolerance, anxiety and agitation; sleep disturbance was also reported. These findings identify potential targets for individualized behavioral assessment and support. The cited cohort does not measure caregiver burden, compare behavioral interventions or evaluate ADHD medications.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: behavioural counselling and ADHD management
    term:
      id: NCIT:C181743
      label: Behavioral Counseling
  therapeutic_modality: BEHAVIORAL
  target_phenotypes:
  - preferred_term: Behavioural disorder
    term:
      id: HP:0000708
      label: Atypical behavior
  - preferred_term: Attention deficit hyperactivity disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
  - preferred_term: Sleep disturbance
    term:
      id: HP:0002360
      label: Sleep disturbance
  evidence:
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 18 patients (62%) had behavioural disorders, including attention deficit/hyperactivity (33%), low frustration tolerance (29%), inappropriate laughter (14%), anxiety (21%), agitation (15%) and autistic behaviour (15%).
    explanation: Documents behavioral difficulties that may warrant individualized assessment and support; it does not test a counseling intervention or medication.
  - reference: PMID:39837771
    reference_title: 'The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Sleep disturbance was reported by nine patients (31%).
    explanation: Documents sleep disturbance as an additional care need; it does not test a sleep-management regimen.
  notes: The cited studies document behavioral and sleep difficulties, without testing a specific management regimen. A ClinicalTrials.gov API search on 2026-09-27 for BRPF1, IDDDFP and the full syndrome name returned no studies. This bounded search does not exclude enrollment in broader neurodevelopmental trials.

differential_diagnoses:
- name: Arboleda-Tham syndrome (KAT6A)
  description: KAT6A encodes an acetyltransferase scaffolded by BRPF1, creating mechanistic and phenotypic overlap. Both disorders can include developmental and speech impairment, hypotonia and congenital anomalies. BRPF1 families show wide variation in intellectual function and often prominent ptosis or blepharophimosis. Phenotype can guide testing, but the overlap requires gene-level molecular distinction; KAT6A clinical findings should not be assigned to BRPF1 solely because the proteins share a complex.
  disease_term:
    preferred_term: KAT6A syndrome
    term:
      id: MONDO:0014558
      label: autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome
  evidence:
  - reference: PMID:27939640
    reference_title: Mutations in the Chromatin Regulator Gene BRPF1 Cause Syndromic Intellectual Disability and Deficient Histone Acetylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: These clinical features overlap with but are not identical to those reported for persons with KAT6A or KAT6B mutations, suggesting that BRPF1 targets these two acetyltransferases and additional partners in humans.
    explanation: Explicitly separates the BRPF1 entity from KAT6A/KAT6B disorders despite the shared complex.
- name: Say-Barber-Biesecker-Young-Simpson syndrome (KAT6B)
  description: SBBYS is the other blepharophimosis-plus-intellectual-disability chromatinopathy in the same complex and is the most confusable clinical neighbour, since it too features blepharophimosis, ptosis and hypotonia. Discriminators favouring SBBYS are a mask-like immobile face, long thumbs and great toes, patellar hypoplasia or agenesis, dental anomalies, hypothyroidism and lacrimal duct anomalies, with generally more severe intellectual disability; SBBYS variants are almost always de novo truncating KAT6B alleles.
  disease_term:
    preferred_term: Say-Barber-Biesecker-Young-Simpson syndrome
    term:
      id: MONDO:0011365
      label: blepharophimosis - intellectual disability syndrome, SBBYS type
  evidence:
  - reference: PMID:27939640
    reference_title: Mutations in the Chromatin Regulator Gene BRPF1 Cause Syndromic Intellectual Disability and Deficient Histone Acetylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: These clinical features overlap with but are not identical to those reported for persons with KAT6A or KAT6B mutations, suggesting that BRPF1 targets these two acetyltransferases and additional partners in humans.
    explanation: The same source separates BRPF1 disease from the KAT6B disorders.
- name: Genitopatellar syndrome (KAT6B)
  description: An allelic KAT6B disorder with a characteristic combination of patellar agenesis or hypoplasia, contractures, genital abnormalities and other developmental findings. Genital abnormalities alone do not distinguish it from BRPF1-related disorder, because cryptorchidism is documented in BRPF1 cases. The combined phenotype and molecular diagnosis are more informative than an absolute absence claim.
  disease_term:
    preferred_term: genitopatellar syndrome
    term:
      id: MONDO:0011640
      label: genitopatellar syndrome
  evidence:
  - reference: PMID:36077605
    reference_title: 'BRPF1-KAT6A/KAT6B Complex: Molecular Structure, Biological Function and Human Disease.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: BRPF1, KAT6A and KAT6B mutations were identified as the cause of neurodevelopmental disorders, leukemia, medulloblastoma and other types of cancer, with germline mutations associated with neurodevelopmental disorders displaying intellectual disability, and somatic variants associated with leukemia, medulloblastoma and other cancers.
    explanation: Establishes KAT6B as a separate cause of intellectual-disability syndromes within the same complex, making its phenotypes differentials rather than the same entity.
  - reference: PMID:27939639
    reference_title: Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual Disability with Associated Ptosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He had surgery for his ptosis and for cryptorchidism.
    explanation: The founding family already included cryptorchidism requiring surgery, contradicting the later claim of novelty.
- name: SETD5 haploinsufficiency intellectual disability
  description: The critical co-located confounder. SETD5 is immediately adjacent to BRPF1 at 3p25, and before BRPF1 was characterized most of the 3p25 deletion phenotype was attributed to SETD5. Isolated SETD5 haploinsufficiency causes intellectual disability with facial dysmorphism but does not preferentially produce ptosis and blepharophimosis; those features track with BRPF1 loss.
  disease_term:
    preferred_term: SETD5 haploinsufficiency
    term:
      id: MONDO:0014336
      label: intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency
  evidence:
  - reference: PMID:27939639
    reference_title: Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual Disability with Associated Ptosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Deletions of the 3p25 region, containing BRPF1 and SETD5, cause a defined ID syndrome where most of the clinical features are attributed to SETD5 deficiency.
    explanation: States the historical attribution of the 3p25 phenotype to SETD5, the reason BRPF1 was recognized late.
  - reference: PMID:27939639
    reference_title: Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual Disability with Associated Ptosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We compared the clinical symptoms of individuals carrying mutations or small deletions of BRPF1 alone or SETD5 alone with those of individuals with deletions encompassing both BRPF1 and SETD5.
    explanation: The direct comparison that separates the two adjacent genes' contributions.
- name: 3p25.3 microdeletion syndrome
  description: A contiguous gene deletion that can encompass both BRPF1 and SETD5. It should be considered whenever the phenotype is more severe than expected for an isolated BRPF1 variant; chromosomal microarray distinguishes it from a single-nucleotide BRPF1 variant.
  disease_term:
    preferred_term: 3p25.3 microdeletion syndrome
    term:
      id: MONDO:0018564
      label: 3p25.3 microdeletion syndrome
  evidence:
  - reference: PMID:27939639
    reference_title: Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual Disability with Associated Ptosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We conclude that both genes contribute to the phenotypic severity of 3p25 deletion syndrome
    explanation: Establishes the two-gene contiguous-deletion entity as distinct from single-gene BRPF1 disease.
- name: Noonan syndrome and other RASopathies
  description: Facial dysmorphism, short stature and developmental delay can prompt a clinical Noonan diagnosis. In a series of clinically diagnosed patients with negative RASopathy panels, exome sequencing established BRPF1 among the alternative diagnoses. The overlap supports molecular evaluation; the cited report does not establish absolute absence of individual RASopathy-associated features in BRPF1-related disease.
  disease_term:
    preferred_term: Noonan syndrome
    term:
      id: MONDO:0018997
      label: Noonan syndrome
  evidence:
  - reference: PMID:41137536
    reference_title: Non-RASopathy Genetic Syndromes Identified as the Molecular Cause of Disease in Patients Previously Diagnosed With Noonan Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In six cases, alternative genetic diagnoses were established due to variants in SETD5, BRPF1, DPH1, ACTB, CREBBP, and GATA4, genes associated with syndromes presenting overlapping phenotypes with NS.
    explanation: Documents BRPF1 being found in patients carrying a clinical Noonan diagnosis, making Noonan a real differential.
- name: Blepharophimosis, ptosis, and epicanthus inversus syndrome
  description: FOXL2-related BPES overlaps the eyelid phenotype of BRPF1-related disorder, including epicanthus inversus. Congenital eyelid malformation and age-related primary ovarian insufficiency characterize BPES, while the broader neurodevelopmental phenotype can favor BRPF1 or a contiguous-gene deletion. Molecular testing distinguishes these causes.
  disease_term:
    preferred_term: blepharophimosis, ptosis, and epicanthus inversus syndrome
    term:
      id: MONDO:0007201
      label: blepharophimosis, ptosis, and epicanthus inversus syndrome
  distinguishing_features:
  - The eyelid malformation is present at birth in every affected individual in BPES, whereas ptosis is present in 20/29 (69%) of BRPF1 patients.
  - Age-related primary ovarian insufficiency in affected females is a defining BPES feature in the cited GeneReviews chapter; the BRPF1 cohorts cited here do not establish a comparable association.
  - Additional neurodevelopmental findings in BPES warrant consideration of a contiguous deletion involving FOXL2 and neighboring genes. The cited chapter describes this context; it does not prove an absolute exclusion for every intragenic variant.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1441/
    reference_title: Blepharophimosis, Ptosis, and Epicanthus Inversus Syndrome - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is characterized by this eyelid malformation present at birth in all individuals and age-related primary ovarian insufficiency (POI) in affected females
    explanation: Gives the two BPES-defining features that separate it from BRPF1 disease - obligate congenital eyelid malformation and female primary ovarian insufficiency, neither of which characterizes IDDDFP.
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1441/
    reference_title: Blepharophimosis, Ptosis, and Epicanthus Inversus Syndrome - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: intellectual disability, microcephaly, speech delay, ventricular septum defect, cleft palate, and subtle skeletal features
    explanation: The GeneReviews chapter describes additional neurodevelopmental and congenital findings with contiguous deletions involving FOXL2 and neighboring genes.

discussions:
- discussion_id: brpf1_zygosity_and_species_model_mismatch
  prompt: How do zygosity, affected cell lineage and deletion timing influence the relevance of mouse and stem-cell BRPF1 models to variable human heterozygous disease?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Aberrant Cortical Neurogenesis
  - pathophysiology#Abnormal Corpus Callosum Development
  - pathophysiology#Impaired Hematopoietic Stem and Progenitor Cell Maintenance
  - pathophysiology#Impaired Learning and Memory
  rationale: Complete global, early forebrain and hematopoietic loss can cause lethal mouse phenotypes, whereas postnatal CaMKIIa-Cre conditional mice survive and have selective physiological and behavioral effects. Emx1-lineage conditional heterozygotes match human zygosity only within the targeted lineage, not throughout the organism. Human expressivity varies, including a reported individual with normal intellectual development; these observations do not establish normal life expectancy. Human callosal abnormalities are uncommon. Anemia and thrombocytopenia have been reported in a family and in additional individuals in the 2025 cohort, without demonstrating the severe stem-cell failure mechanism of the homozygous hematopoietic mouse model. Global null embryos also have placental and vascular defects with cranial neural tube failure. Zebrafish pharyngeal homeotic transformations establish a developmental role, but have no demonstrated equivalent in human heterozygous craniofacial dysmorphism.
  proposed_experiments:
  - experiment_id: exp_brpf1_human_allelic_series_organoid
    name: BRPF1 zygosity-matched allelic series in human iPSC-derived cortical neurons and organoids
    description: In an isogenic human iPSC background, build a BRPF1 allelic series (heterozygous null, heterozygous patient truncating and missense alleles, homozygous null) and differentiate to cortical neurons and forebrain organoids. Read out H3K23 acetylation and propionylation, chromatin accessibility, intermediate-progenitor (TBR2) abundance, dendritic arborization, and excitatory and inhibitory synaptic physiology. This directly tests whether the heterozygous human state reproduces the null-allele mouse phenotypes and, if so, at what magnitude.
    experiment_type:
      preferred_term: isogenic allelic-series loss-of-function experiment
  - experiment_id: exp_brpf1_episignature
    name: Test for a BRPF1 DNA methylation episignature in patient blood
    description: Profile genome-wide DNA methylation in blood from variant-confirmed BRPF1 cases, matched controls and KAT6A/KAT6B cases. A reproducible signature could complement existing patient-cell histone-acylation assays and could be evaluated for variant interpretation. Its diagnostic performance, specificity and sensitivity would require validation; a positive cohort-level result alone would not resolve every variant of uncertain significance.
    experiment_type:
      preferred_term: DNA methylation episignature study
  evidence:
  - reference: PMID:25568313
    reference_title: Deficiency of the chromatin regulator BRPF1 causes abnormal brain development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Here, we report that forebrain-specific inactivation of the mouse Brpf1 gene caused early postnatal lethality, neocortical abnormalities, and partial callosal agenesis.
    explanation: The forebrain model is a conditional null with a lethal phenotype that has no human counterpart.
  - reference: PMID:24646517
    reference_title: Expression atlas of the multivalent epigenetic regulator Brpf1 and its requirement for survival of mouse embryos.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: In support of this, inactivation of the mouse Brpf1 gene causes lethality around embryonic day 9.5.
    explanation: Complete Brpf1 loss is embryonic-lethal in mouse, unlike human heterozygous disease.
  - reference: PMID:35243762
    reference_title: 'BRPF1-associated syndrome: A patient with congenital ptosis, neurological findings, and normal intellectual development.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here, we describe a patient with normal intellectual development who had congenital ptosis, hypotonia, muscular weakness, atlanto-axial malformation, and pyramidal at the neurological examination.
    explanation: Documents variable human cognitive expressivity. Mouse behavioral tasks are not equivalent to human intellectual assessment.
  - reference: PMID:25773539
    reference_title: The chromatin regulator Brpf1 regulates embryo development and cell proliferation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: the ablation leads to vascular defects in the placenta, yolk sac, and embryo proper, as well as abnormal neural tube closure.
    explanation: Global null mouse embryos have severe developmental defects; these are not established clinical manifestations of heterozygous human BRPF1 disease.
  - reference: PMID:18469222
    reference_title: The multidomain protein Brpf1 binds histones and is required for Hox gene expression and segmental identity.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: We conclude that Brpf1 is specifically required for the maintenance, but not for the initiation, of anterior Hox gene expression.
    explanation: Zebrafish mutants lose maintenance of anterior Hox expression; initiation and neural crest migration were preserved. This is not a demonstrated human craniofacial pathway.

notes: Clinical expression varies widely, including within families, and a reliable genotype-phenotype correlation is not established. Cohort frequencies depend on ascertainment, assessment and missing data; speech-ascertained samples and imaging-only denominators should not be treated as population penetrance. Larger deletions require interpretation of additional genes, including SETD5. Cellular and animal studies identify plausible pathways but differ in zygosity, cell type and developmental timing from heterozygous human disease. Ocular transcription-factor and neuronal mechanism links remain model-based where direct human evidence is absent. The cited GeneReviews chapter NBK1441 concerns FOXL2-related BPES in the differential diagnosis; it is not a BRPF1 clinical baseline.

experimental_models:
- name: Brpf1-knockdown mouse MGE-derived interneuron cultures
  experimental_model_type: PRIMARY_CELL_CULTURE
  organism:
    preferred_term: Mus musculus
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  cell_source: E14.5 mouse medial ganglionic eminence
  culture_system: Primary neurons infected at DIV3; morphological and electrophysiological assessment at DIV14-15
  publication: PMID:33744924
  description: AAV-shBrpf1 reduced Brpf1 transcript by approximately 40%. mIPSC amplitude and intrinsic excitability were affected, while mIPSC frequency, dendritic arbor measurements and SST differentiation were not significantly changed. Reduced PV differentiation was a nonsignificant trend.
  modeled_mechanisms:
  - target: Reduced Inhibitory Neurotransmission in GABAergic Interneurons
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    fidelity: UNKNOWN
    description: Measures inhibitory postsynaptic currents after partial knockdown.
    limitations: Mouse primary culture after partial shRNA knockdown is not a patient-derived heterozygous neural model. The result does not establish the corresponding human mechanism.
    readouts:
    - name: mIPSC amplitude
      target: Reduced Inhibitory Neurotransmission in GABAergic Interneurons
      direction: DECREASED
      description: Reduced relative to scramble-treated neurons.
      evidence:
      - reference: PMID:33744924
        reference_title: Deficiency of intellectual disability-related gene Brpf1 reduced inhibitory neurotransmission in MGE-derived GABAergic interneurons.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: The amplitude but not the frequency of mIPSCs decreased significantly
        explanation: DIV15 recordings found reduced amplitude without a significant frequency change.
    - name: mIPSC frequency
      target: Reduced Inhibitory Neurotransmission in GABAergic Interneurons
      direction: UNCHANGED
      description: No statistically significant difference was detected.
      evidence:
      - reference: PMID:33744924
        reference_title: Deficiency of intellectual disability-related gene Brpf1 reduced inhibitory neurotransmission in MGE-derived GABAergic interneurons.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: The amplitude but not the frequency of mIPSCs decreased significantly
        explanation: DIV15 recordings found reduced amplitude without a significant frequency change.
    evidence:
    - reference: PMID:33744924
      reference_title: Deficiency of intellectual disability-related gene Brpf1 reduced inhibitory neurotransmission in MGE-derived GABAergic interneurons.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: The amplitude but not the frequency of mIPSCs decreased significantly
      explanation: DIV15 recordings found reduced amplitude without a significant frequency change.
  - target: Reduced Intrinsic Excitability of MGE-Derived GABAergic Interneurons
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    fidelity: UNKNOWN
    description: Current-clamp assays measure evoked firing.
    limitations: Mouse primary culture after partial shRNA knockdown is not a patient-derived heterozygous neural model. The result does not establish the corresponding human mechanism.
    readouts:
    - name: Current threshold for evoked action potentials
      target: Reduced Intrinsic Excitability of MGE-Derived GABAergic Interneurons
      direction: INCREASED
      description: More injected current was required to evoke firing.
      evidence:
      - reference: PMID:33744924
        reference_title: Deficiency of intellectual disability-related gene Brpf1 reduced inhibitory neurotransmission in MGE-derived GABAergic interneurons.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: The AAV-shBrpf1 group required a larger incident current to induce the evoked APs, with a significant increase in the firing threshold
        explanation: Current-clamp recordings demonstrate increased threshold after partial knockdown, without a corresponding change in resting potential or maximum evoked frequency.
    - name: Maximum evoked firing frequency
      target: Reduced Intrinsic Excitability of MGE-Derived GABAergic Interneurons
      direction: UNCHANGED
      description: No statistically significant change was detected.
      evidence:
      - reference: PMID:33744924
        reference_title: Deficiency of intellectual disability-related gene Brpf1 reduced inhibitory neurotransmission in MGE-derived GABAergic interneurons.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: although the maximum frequency of evoked APs was not affected
        explanation: The firing threshold rose but maximum evoked frequency was preserved.
    evidence:
    - reference: PMID:33744924
      reference_title: Deficiency of intellectual disability-related gene Brpf1 reduced inhibitory neurotransmission in MGE-derived GABAergic interneurons.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: The AAV-shBrpf1 group required a larger incident current to induce the evoked APs, with a significant increase in the firing threshold
      explanation: Current-clamp recordings demonstrate increased threshold after partial knockdown, without a corresponding change in resting potential or maximum evoked frequency.
  evidence:
  - reference: PMID:33744924
    reference_title: Deficiency of intellectual disability-related gene Brpf1 reduced inhibitory neurotransmission in MGE-derived GABAergic interneurons.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The amplitude but not the frequency of mIPSCs decreased significantly
    explanation: DIV15 recordings found reduced amplitude without a significant frequency change.
  - reference: PMID:33744924
    reference_title: Deficiency of intellectual disability-related gene Brpf1 reduced inhibitory neurotransmission in MGE-derived GABAergic interneurons.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The results showed that there was no significant difference in the number of intersections and total length of dendrites between the two groups
    explanation: No significant MAP2-positive arbor change was detected at DIV14-15 after approximately 40% transcript knockdown.
  - reference: PMID:33744924
    reference_title: Deficiency of intellectual disability-related gene Brpf1 reduced inhibitory neurotransmission in MGE-derived GABAergic interneurons.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: although the maximum frequency of evoked APs was not affected
    explanation: The firing threshold rose but maximum evoked frequency was preserved.
  notes: The study also transplanted E13.5 MGE cells into P1 hosts; cortical laminar distribution after 35 days did not differ significantly. That in vivo migration assay is separate from the cultured-neuron electrophysiology. No behavioral or circuit E/I-ratio test was performed.
- name: Brpf1-knockdown mouse hippocampal neuron cultures
  experimental_model_type: PRIMARY_CELL_CULTURE
  organism:
    preferred_term: Mus musculus
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  cell_source: E17.5-E18.5 mouse hippocampi
  culture_system: AAV2-shBrpf1 at DIV3; assessment at DIV14-15
  publication: PMID:34485298
  description: Approximately 50% transcript knockdown reduced mEPSC frequency while preserving amplitude and measured intrinsic membrane properties. Total dendritic length and Sholl intersections did not change significantly. Culture RNA sequencing and qPCR identified reduced C1ql1 and Gpr17; neither was tested by rescue as a mediator.
  modeled_mechanisms:
  - target: Reduced Excitatory Synaptic Transmission in Forebrain Neurons
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    fidelity: UNKNOWN
    description: Measures synaptic currents after partial Brpf1 knockdown.
    limitations: Mouse primary culture after partial shRNA knockdown is not a patient-derived heterozygous neural model. The result does not establish the corresponding human mechanism.
    readouts:
    - name: mEPSC frequency
      target: Reduced Excitatory Synaptic Transmission in Forebrain Neurons
      direction: DECREASED
      description: Reduced frequency in knockdown cultures.
      evidence:
      - reference: PMID:34485298
        reference_title: Deficiency of Intellectual Disability-Related Gene Brpf1 Attenuated Hippocampal Excitatory Synaptic Transmission and Impaired Spatial Learning and Memory Ability.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: The results showed that the mEPSC frequency but not amplitude significantly decreased upon Brpf1 knockdown
        explanation: The experiment distinguishes reduced event frequency from preserved amplitude in cultured hippocampal neurons.
    - name: mEPSC amplitude
      target: Reduced Excitatory Synaptic Transmission in Forebrain Neurons
      direction: UNCHANGED
      description: No significant difference in amplitude.
      evidence:
      - reference: PMID:34485298
        reference_title: Deficiency of Intellectual Disability-Related Gene Brpf1 Attenuated Hippocampal Excitatory Synaptic Transmission and Impaired Spatial Learning and Memory Ability.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: The results showed that the mEPSC frequency but not amplitude significantly decreased upon Brpf1 knockdown
        explanation: The experiment distinguishes reduced event frequency from preserved amplitude in cultured hippocampal neurons.
    evidence:
    - reference: PMID:34485298
      reference_title: Deficiency of Intellectual Disability-Related Gene Brpf1 Attenuated Hippocampal Excitatory Synaptic Transmission and Impaired Spatial Learning and Memory Ability.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: The results showed that the mEPSC frequency but not amplitude significantly decreased upon Brpf1 knockdown
      explanation: The experiment distinguishes reduced event frequency from preserved amplitude in cultured hippocampal neurons.
  evidence:
  - reference: PMID:34485298
    reference_title: Deficiency of Intellectual Disability-Related Gene Brpf1 Attenuated Hippocampal Excitatory Synaptic Transmission and Impaired Spatial Learning and Memory Ability.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The results showed that the mEPSC frequency but not amplitude significantly decreased upon Brpf1 knockdown
    explanation: The experiment distinguishes reduced event frequency from preserved amplitude in cultured hippocampal neurons.
  - reference: PMID:34485298
    reference_title: Deficiency of Intellectual Disability-Related Gene Brpf1 Attenuated Hippocampal Excitatory Synaptic Transmission and Impaired Spatial Learning and Memory Ability.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The RMP, input resistance, firing threshold, and evoked APs did not show significant changes
    explanation: Membrane excitability measures remained unchanged under these conditions.
  notes: Electrophysiology was performed in embryonic cultures. Adult hippocampal stereotactic knockdown and water-maze testing were separate experiments, not physiological and behavioral measurements from the same neurons or animals.
- name: BRPF1 Pro370Ser patient-derived lymphoblastoid cells
  experimental_model_type: CELL_LINE
  organism:
    preferred_term: Homo sapiens
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: Patient-derived lymphoblastoid cell line carrying Pro370Ser
  publication: PMID:32010779
  description: Patient-derived lymphoblastoid cells show reduced H3K23 propionylation and support biochemical intervention assays. Propionate increases propionylation; tested HDAC inhibitors other than beta-hydroxybutyrate increase acetylation and propionylation.
  modeled_mechanisms:
  - target: Deficient Histone H3K23 Propionylation
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    fidelity: UNKNOWN
    description: Measures the patient-cell propionylation deficit.
    limitations: A patient-derived non-neural transformed cell line does not establish effects in developing brain. No isogenic correction or clinical response was reported.
    readouts:
    - name: Basal H3K23 propionylation
      target: Deficient Histone H3K23 Propionylation
      direction: DECREASED
      description: Reduced relative to control lymphoblastoid cells.
      evidence:
      - reference: PMID:32010779
        reference_title: Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: this modification decreased in the lymphoblastoid cells (LCLs) prepared from the individual harboring the Pro370Ser variant
        explanation: H3K23 propionylation was reduced in this patient-derived cell line.
    evidence:
    - reference: PMID:32010779
      reference_title: Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: this modification decreased in the lymphoblastoid cells (LCLs) prepared from the individual harboring the Pro370Ser variant
      explanation: H3K23 propionylation was reduced in this patient-derived cell line.
  - target: Deficient Histone H3K23 Propionylation
    relationship: RESCUES
    model_scale: CELLULAR
    fidelity: UNKNOWN
    description: Tests biochemical response to sodium propionate.
    limitations: Biochemical rescue in one patient-derived cell line; neurological function and human efficacy were not tested.
    readouts:
    - name: H3K23 propionylation after propionate
      target: Deficient Histone H3K23 Propionylation
      direction: RESTORED
      description: The mark increased after 24-hour sodium propionate exposure.
      evidence:
      - reference: PMID:32010779
        reference_title: Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: The treatment also enhanced H3K23 propionylation in the patient-derived LCLs
        explanation: Propionate increased the mark in Pro370Ser cells.
    evidence:
    - reference: PMID:32010779
      reference_title: Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: The treatment also enhanced H3K23 propionylation in the patient-derived LCLs
      explanation: Propionate increased the mark in Pro370Ser cells.
  - target: Deficient Histone H3K23 Acetylation
    relationship: RESCUES
    model_scale: CELLULAR
    fidelity: UNKNOWN
    description: Tests biochemical response to HDAC inhibition.
    limitations: Drug-dependent biochemical response in lymphoblastoid cells does not demonstrate developmental or clinical rescue.
    readouts:
    - name: H3K23 acetylation after HDAC inhibitor treatment
      target: Deficient Histone H3K23 Acetylation
      direction: INCREASED
      description: Increased with tested inhibitors except beta-hydroxybutyrate.
      evidence:
      - reference: PMID:32010779
        reference_title: Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: We also tested LCLs from the individual harboring the Pro370Ser variant. As shown in Fig. 6C, all inhibitors except β-hydroxybutyrate enhanced H3K23 acetylation and propionylation.
        explanation: Patient-derived lymphoblastoid cells show biochemical responses to the tested HDAC inhibitors; beta-hydroxybutyrate is an important negative comparison in this model.
    evidence:
    - reference: PMID:32010779
      reference_title: Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: We also tested LCLs from the individual harboring the Pro370Ser variant. As shown in Fig. 6C, all inhibitors except β-hydroxybutyrate enhanced H3K23 acetylation and propionylation.
      explanation: Patient-derived lymphoblastoid cells show biochemical responses to the tested HDAC inhibitors; beta-hydroxybutyrate is an important negative comparison in this model.
  evidence:
  - reference: PMID:32010779
    reference_title: Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: this modification decreased in the lymphoblastoid cells (LCLs) prepared from the individual harboring the Pro370Ser variant
    explanation: H3K23 propionylation was reduced in this patient-derived cell line.
  - reference: PMID:32010779
    reference_title: Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The treatment also enhanced H3K23 propionylation in the patient-derived LCLs
    explanation: Propionate increased the mark in Pro370Ser cells.
  - reference: PMID:32010779
    reference_title: Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: We also tested LCLs from the individual harboring the Pro370Ser variant. As shown in Fig. 6C, all inhibitors except β-hydroxybutyrate enhanced H3K23 acetylation and propionylation.
    explanation: Patient-derived lymphoblastoid cells show biochemical responses to the tested HDAC inhibitors; beta-hydroxybutyrate is an important negative comparison in this model.
- name: Inducible Brpf1-null mouse embryonic fibroblasts
  experimental_model_type: PRIMARY_CELL_CULTURE
  organism:
    preferred_term: Mus musculus
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  cell_source: Brpf1 floxed mouse embryonic fibroblasts carrying UBC-Cre/ERT2
  culture_system: Deletion induced with 4-hydroxytamoxifen in primary fibroblast culture
  publication: PMID:32010779
  description: Complete Brpf1 deletion abolishes detectable H3K23 acetylation and propionylation. H3K9/H3K14 marks and total histone H3 acylation are not uniformly lost. Propionate fails to enhance H3K23 propionylation in null cells, whereas tested HDAC inhibitors increase both H3K23 marks. An earlier study of this inducible preparation found impaired proliferation and cell-cycle progression, reduced H3K9/H3K14 acetylation, unchanged Hbo1 protein and H4K16 acetylation, and increased p16 with decreased p27 transcription. Reduced embryonic Rpl10l expression was not reproduced in the fibroblasts.
  modeled_mechanisms:
  - target: Deficient Histone H3K23 Propionylation
    relationship: MEASURES
    model_scale: CELLULAR
    fidelity: UNKNOWN
    limitations: Complete loss in mouse fibroblasts differs from heterozygous human neural disease and from residual-function patient lymphoblastoid cells.
    readouts:
    - name: H3K23 propionylation after Brpf1 deletion
      target: Deficient Histone H3K23 Propionylation
      direction: ABOLISHED
      description: Undetectable by the reported assays.
    - name: H3K23 propionylation response to propionate in null cells
      target: Deficient Histone H3K23 Propionylation
      direction: UNCHANGED
      description: Propionate failed to enhance the mark after complete Brpf1 loss.
    evidence:
    - reference: PMID:32010779
      reference_title: Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: H3K23 propionylation was undetectable in these mutant cells
      explanation: Brpf1-null mouse embryonic fibroblasts lacked detectable H3K23 propionylation.
    - reference: PMID:32010779
      reference_title: Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: The enhancement of propionylation in response to propionate treatment was abolished in Brpf1−/− MEFs
      explanation: Propionate failed to enhance the mark after complete Brpf1 loss.
  - target: Deficient Histone H3K23 Acetylation
    relationship: RESCUES
    model_scale: CELLULAR
    fidelity: UNKNOWN
    limitations: Biochemical drug response in complete-loss fibroblasts; no neurological or clinical rescue was tested.
    readouts:
    - name: H3K23 acetylation after HDAC inhibitor exposure
      target: Deficient Histone H3K23 Acetylation
      direction: RESTORED
      description: Tested inhibitors corrected the measured biochemical deficit.
    evidence:
    - reference: PMID:32010779
      reference_title: Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: all five HDAC inhibitors corrected the deficiency in H3K23 acetylation and propionylation
      explanation: HDAC inhibitors had a different response profile from propionate in Brpf1-null fibroblasts.
  - target: Altered Developmental Transcriptional Programs
    relationship: MEASURES
    model_scale: CELLULAR
    fidelity: UNKNOWN
    limitations: Induced biallelic loss in E15.5 mouse fibroblasts; changes in cell-cycle transcripts were not individually rescued and are not validated human diagnostic biomarkers.
    readouts:
    - name: p16 and p27 transcription
      target: Altered Developmental Transcriptional Programs
      direction: ALTERED
      description: p16 increased and p27 decreased in mutant fibroblasts; Rpl10l did not decrease as it did in E8.75 embryos.
    evidence:
    - reference: PMID:25773539
      reference_title: The chromatin regulator Brpf1 regulates embryo development and cell proliferation.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: The transcript levels of p16 and p27 were affected in mutant MEFs
      explanation: The cellular preparation is distinct from the whole-embryo transcriptome.
  evidence:
  - reference: PMID:32010779
    reference_title: Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: H3K23 propionylation was undetectable in these mutant cells
    explanation: Brpf1-null mouse embryonic fibroblasts lacked detectable H3K23 propionylation.
  - reference: PMID:32010779
    reference_title: Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The enhancement of propionylation in response to propionate treatment was abolished in Brpf1−/− MEFs
    explanation: Propionate failed to enhance the mark after complete Brpf1 loss.
  - reference: PMID:32010779
    reference_title: Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: all five HDAC inhibitors corrected the deficiency in H3K23 acetylation and propionylation
    explanation: HDAC inhibitors had a different response profile from propionate in Brpf1-null fibroblasts.
  - reference: PMID:25773539
    reference_title: The chromatin regulator Brpf1 regulates embryo development and cell proliferation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: the induced inactivation inhibited growth (Fig. 8A) and cell cycle progression (Fig. 8, B and C) of embryonic fibroblasts.
    explanation: Inducible complete loss impairs growth in primary fibroblasts; this does not establish a comparable proliferative defect in heterozygous patient cells.
- name: Emx1-lineage Brpf1 conditional cortical neuron cultures
  experimental_model_type: PRIMARY_CELL_CULTURE
  organism:
    preferred_term: Mus musculus
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  cell_source: E16.5 dorsal telencephalon from Brpf1 flox/flox controls, Emx1-Cre; Brpf1 flox/+ heterozygotes and Emx1-Cre; Brpf1 flox/flox conditional homozygotes
  culture_system: Dissociated cortical neurons; Tau staining at DIV5 and MAP2 staining at DIV14
  publication: PMID:31213987
  description: Genotype-dependent decreases in dendritic complexity and axonal length were measured in embryonic cortical cultures. These experiments are separate from acute CA1 slice electrophysiology and from Golgi spine analysis in adult brains.
  modeled_mechanisms:
  - target: Impaired Dendritic Arborization
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    fidelity: UNKNOWN
    limitations: Conditional deletion in the mouse Emx1 lineage differs from constitutive heterozygous human BRPF1 disease; these measurements do not establish the corresponding patient mechanism.
    readouts:
    - name: Total dendritic branch length at DIV14
      target: Impaired Dendritic Arborization
      direction: DECREASED
      description: Conditional heterozygotes showed a 17% reduction; homozygotes were more severely affected.
    evidence:
    - reference: PMID:31213987
      reference_title: Brpf1 Haploinsufficiency Impairs Dendritic Arborization and Spine Formation, Leading to Cognitive Deficits.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Brpf1 HT neurons showed a 17% decrease in the total length of the dendritic branches compared with that of WT neurons.
      explanation: E16.5 cortical cultures were examined at DIV14; conditional homozygous deletion caused a larger reduction.
  - target: Impaired Axonal Outgrowth
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    fidelity: UNKNOWN
    limitations: Conditional deletion in the mouse Emx1 lineage differs from constitutive heterozygous human BRPF1 disease; these measurements do not establish the corresponding patient mechanism.
    readouts:
    - name: Tau-positive axon length at DIV5
      target: Impaired Axonal Outgrowth
      direction: DECREASED
      description: Conditional heterozygotes showed a 20.3% reduction, with a larger homozygous effect.
    evidence:
    - reference: PMID:31213987
      reference_title: Brpf1 Haploinsufficiency Impairs Dendritic Arborization and Spine Formation, Leading to Cognitive Deficits.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: axonal elongation in HT cells was impaired, with a 20.3% decrease in length
      explanation: Tau-positive axons in E16.5 cortical cultures were measured at DIV5; conditional homozygous neurons had a more severe reduction.
  evidence:
  - reference: PMID:31213987
    reference_title: Brpf1 Haploinsufficiency Impairs Dendritic Arborization and Spine Formation, Leading to Cognitive Deficits.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Brpf1 HT neurons showed a 17% decrease in the total length of the dendritic branches compared with that of WT neurons.
    explanation: E16.5 cortical cultures were examined at DIV14; conditional homozygous deletion caused a larger reduction.
  - reference: PMID:31213987
    reference_title: Brpf1 Haploinsufficiency Impairs Dendritic Arborization and Spine Formation, Leading to Cognitive Deficits.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: axonal elongation in HT cells was impaired, with a 20.3% decrease in length
    explanation: Tau-positive axons in E16.5 cortical cultures were measured at DIV5; conditional homozygous neurons had a more severe reduction.
- name: BRPF1-null human H1 embryonic stem cells with inducible rescue
  experimental_model_type: OTHER
  organism:
    preferred_term: Homo sapiens
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: H1/WA01 male human embryonic stem-cell line, with CRISPR-engineered BRPF1 knockout or FLAG knock-in
  culture_system: Matrigel-coated plates in mTeSR1 or ncTarget medium; inducible and lentiviral BRPF1 complementation
  publication: PMID:36711238
  description: BRPF1 knockout progressively loses pluripotency, reduces H3K23ac and closes accessibility at stemness loci while opening lineage-associated regions. H3K4me3 remains substantially present. Wild-type BRPF1 rescues pluripotency and H3K23ac; N-terminal or PZP deletion fails to rescue effectively, whereas PWWP deletion largely retains rescue.
  modeled_mechanisms:
  - target: Deficient Histone H3K23 Acetylation
    relationship: MEASURES
    model_scale: CELLULAR
    fidelity: UNKNOWN
    limitations: Complete engineered BRPF1 loss in an undifferentiated H1 embryonic stem-cell line is not a patient-specific heterozygous neural model. Rescue used ectopic BRPF1 expression; it does not demonstrate clinical or neuronal rescue.
    readouts:
    - name: H3K23ac after endogenous BRPF1 deletion
      target: Deficient Histone H3K23 Acetylation
      direction: ABOLISHED
      description: H3K23ac was lost in knockout cells.
    evidence:
    - reference: PMID:36711238
      reference_title: BRPF1 bridges H3K4me3 and H3K23ac in human embryonic stem cells and is essential to pluripotency.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: BRPF1 deletion impairs H3K23ac in hESCs and leads to closed chromatin accessibility on stemness genes and hESC differentiation as well.
      explanation: BRPF1-null H1 embryonic stem cells lose H3K23ac and accessibility at stemness loci. Other lineage-associated regions gain accessibility; this is not uniform genome-wide closure.
  - target: Deficient Histone H3K23 Acetylation
    relationship: RESCUES
    model_scale: CELLULAR
    fidelity: UNKNOWN
    limitations: Complete engineered BRPF1 loss in an undifferentiated H1 embryonic stem-cell line is not a patient-specific heterozygous neural model. Rescue used ectopic BRPF1 expression; it does not demonstrate clinical or neuronal rescue.
    readouts:
    - name: H3K23ac after induced BRPF1 expression
      target: Deficient Histone H3K23 Acetylation
      direction: RESTORED
      description: Doxycycline-dependent BRPF1 complementation restored the histone mark.
    evidence:
    - reference: PMID:36711238
      reference_title: BRPF1 bridges H3K4me3 and H3K23ac in human embryonic stem cells and is essential to pluripotency.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: H3K14ac and H3K23ac were restored upon DOX treatment but lost
      explanation: Doxycycline-induced BRPF1 re-expression restored measured acetylation and pluripotency in the engineered endogenous-knockout line; withdrawal reversed the rescue.
    - reference: PMID:36711238
      reference_title: BRPF1 bridges H3K4me3 and H3K23ac in human embryonic stem cells and is essential to pluripotency.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: N or PZP module deleted mut ant showed little effect on H3K23ac rescue
      explanation: N-terminal or PZP-deleted constructs failed to restore the mark effectively, whereas PWWP deletion largely retained rescue in this hESC assay. These engineered domains are not patient-variant classifications.
  - target: Altered Chromatin Accessibility
    relationship: MEASURES
    model_scale: CELLULAR
    fidelity: UNKNOWN
    limitations: Complete engineered BRPF1 loss in an undifferentiated H1 embryonic stem-cell line is not a patient-specific heterozygous neural model. Rescue used ectopic BRPF1 expression; it does not demonstrate clinical or neuronal rescue.
    readouts:
    - name: Accessibility at stemness loci
      target: Altered Chromatin Accessibility
      direction: DECREASED
      description: ATAC-seq at days 12 and 30 identified reduced accessibility at stemness loci; lineage regions also showed gains.
    evidence:
    - reference: PMID:36711238
      reference_title: BRPF1 bridges H3K4me3 and H3K23ac in human embryonic stem cells and is essential to pluripotency.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: BRPF1 deletion impairs H3K23ac in hESCs and leads to closed chromatin accessibility on stemness genes and hESC differentiation as well.
      explanation: BRPF1-null H1 embryonic stem cells lose H3K23ac and accessibility at stemness loci. Other lineage-associated regions gain accessibility; this is not uniform genome-wide closure.
  - target: Altered Developmental Transcriptional Programs
    relationship: MEASURES
    model_scale: CELLULAR
    fidelity: UNKNOWN
    limitations: Complete engineered BRPF1 loss in an undifferentiated H1 embryonic stem-cell line is not a patient-specific heterozygous neural model. Rescue used ectopic BRPF1 expression; it does not demonstrate clinical or neuronal rescue.
    readouts:
    - name: Stemness and lineage gene expression
      target: Altered Developmental Transcriptional Programs
      direction: ALTERED
      description: OCT4, NANOG and SOX2 expression declined while differentiation programs increased.
    evidence:
    - reference: PMID:36711238
      reference_title: BRPF1 bridges H3K4me3 and H3K23ac in human embryonic stem cells and is essential to pluripotency.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: BRPF1 deletion impairs H3K23ac in hESCs and leads to closed chromatin accessibility on stemness genes and hESC differentiation as well.
      explanation: BRPF1-null H1 embryonic stem cells lose H3K23ac and accessibility at stemness loci. Other lineage-associated regions gain accessibility; this is not uniform genome-wide closure.
  evidence:
  - reference: PMID:36711238
    reference_title: BRPF1 bridges H3K4me3 and H3K23ac in human embryonic stem cells and is essential to pluripotency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: BRPF1 deletion impairs H3K23ac in hESCs and leads to closed chromatin accessibility on stemness genes and hESC differentiation as well.
    explanation: BRPF1-null H1 embryonic stem cells lose H3K23ac and accessibility at stemness loci. Other lineage-associated regions gain accessibility; this is not uniform genome-wide closure.
  - reference: PMID:36711238
    reference_title: BRPF1 bridges H3K4me3 and H3K23ac in human embryonic stem cells and is essential to pluripotency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: H3K14ac and H3K23ac were restored upon DOX treatment but lost
    explanation: Doxycycline-induced BRPF1 re-expression restored measured acetylation and pluripotency in the engineered endogenous-knockout line; withdrawal reversed the rescue.
  - reference: PMID:36711238
    reference_title: BRPF1 bridges H3K4me3 and H3K23ac in human embryonic stem cells and is essential to pluripotency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: N or PZP module deleted mut ant showed little effect on H3K23ac rescue
    explanation: N-terminal or PZP-deleted constructs failed to restore the mark effectively, whereas PWWP deletion largely retained rescue in this hESC assay. These engineered domains are not patient-variant classifications.
  notes: GSE213695 contains RNA-seq, ATAC-seq and ChIP-seq data. Direct BRPF1 recognition of H3K4me3 and the biochemical route from H3K23ac to accessibility were explicitly left unresolved. The OTHER model category denotes an embryonic stem-cell line, not an iPSC-derived or immortalized line.
- name: Brpf1-null fetal-liver and neonatal marrow colony cultures
  experimental_model_type: PRIMARY_CELL_CULTURE
  organism:
    preferred_term: Mus musculus
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  cell_source: P6 bone marrow or E15.5 fetal liver from Brpf1 flox/flox; Vav1-iCre mice and controls
  culture_system: Methylcellulose myeloid/erythroid colony assays; neonatal marrow also tested in IL-7-containing pre-B colony medium
  publication: PMID:27500495
  description: Mutant progenitors formed fewer colonies, with smaller myeloid/erythroid colonies. These culture assays complement in vivo transplantation but do not distinguish reduced starting functional-cell numbers from every possible cell-intrinsic growth defect.
  modeled_mechanisms:
  - target: Impaired Hematopoietic Stem and Progenitor Cell Maintenance
    relationship: MEASURES
    model_scale: CELLULAR
    fidelity: UNKNOWN
    limitations: Null mouse progenitors in cytokine-supported culture are not patient-derived heterozygous cells; results do not establish the mechanism of human cytopenias.
    readouts:
    - name: Hematopoietic colony formation
      target: Impaired Hematopoietic Stem and Progenitor Cell Maintenance
      direction: DECREASED
      description: Fewer myeloid/erythroid colonies from mutant fetal liver and marrow; fewer pre-B colonies from marrow.
    evidence:
    - reference: PMID:27500495
      reference_title: BRPF1 is essential for development of fetal hematopoietic stem cells.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: formed by mutant bone marrow cells was reduced compared to the control
      explanation: P6 marrow cells formed fewer and smaller myeloid/erythroid colonies; pre-B colonies and fetal-liver colony formation were also reduced.
  evidence:
  - reference: PMID:27500495
    reference_title: BRPF1 is essential for development of fetal hematopoietic stem cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: formed by mutant bone marrow cells was reduced compared to the control
    explanation: P6 marrow cells formed fewer and smaller myeloid/erythroid colonies; pre-B colonies and fetal-liver colony formation were also reduced.

animal_models:
- name: Postnatal hippocampal Brpf1 shRNA knockdown mouse
  species: Mus musculus
  genotype: Wild-type C57BL/6 mice receiving hippocampal AAV2-shBrpf1
  description: Mice received hippocampal injections at four weeks of age and water-maze testing four weeks later. The authors reported a tendency toward reduced spatial performance, but acquisition latency and target-quadrant occupancy were unchanged. Culture electrophysiology in the same paper used separate embryonic neurons.
  publication: PMID:34485298
  modeled_mechanisms:
  - target: Impaired Learning and Memory
    relationship: MEASURES
    model_scale: ORGANISM
    fidelity: UNKNOWN
    limitations: Five mice per group, regional postnatal knockdown and variable transcript reduction do not model lifelong heterozygous human loss. Negative principal maze readouts limit the claim of impaired spatial memory.
    readouts:
    - name: Water-maze acquisition latency
      target: Impaired Learning and Memory
      direction: UNCHANGED
      description: Latency to reach the platform was almost the same between groups.
    - name: Probe-trial target-quadrant occupancy
      target: Impaired Learning and Memory
      direction: UNCHANGED
      description: No significant difference in the target quadrant was found.
    evidence:
    - reference: PMID:34485298
      reference_title: Deficiency of Intellectual Disability-Related Gene Brpf1 Attenuated Hippocampal Excitatory Synaptic Transmission and Impaired Spatial Learning and Memory Ability.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Although the latency of mice to reach the platform was almost the same
      explanation: The acquisition-latency comparison did not demonstrate a learning deficit.
    - reference: PMID:34485298
      reference_title: Deficiency of Intellectual Disability-Related Gene Brpf1 Attenuated Hippocampal Excitatory Synaptic Transmission and Impaired Spatial Learning and Memory Ability.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: although no significant difference in the target quadrant (SW) was found
      explanation: Target-quadrant occupancy was not significantly altered; reported behavioral effects were tendencies and differences in other quadrants.
  evidence:
  - reference: PMID:34485298
    reference_title: Deficiency of Intellectual Disability-Related Gene Brpf1 Attenuated Hippocampal Excitatory Synaptic Transmission and Impaired Spatial Learning and Memory Ability.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Although the latency of mice to reach the platform was almost the same
    explanation: The acquisition-latency comparison did not demonstrate a learning deficit.
  - reference: PMID:34485298
    reference_title: Deficiency of Intellectual Disability-Related Gene Brpf1 Attenuated Hippocampal Excitatory Synaptic Transmission and Impaired Spatial Learning and Memory Ability.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: although no significant difference in the target quadrant (SW) was found
    explanation: Target-quadrant occupancy was not significantly altered; reported behavioral effects were tendencies and differences in other quadrants.
- name: Emx1-lineage conditional Brpf1 heterozygous mouse
  species: Mus musculus
  genotype: Emx1-Cre; Brpf1 flox/+
  description: Embryonic dorsal telencephalic deletion affects excitatory neurons and astroglial descendants while sparing ventrally derived interneurons. Behavioral experiments used 2-4-month-old C57BL/6 males; histological experiments used the ICR background. Acute CA1 slice electrophysiology, Golgi staining and electron microscopy are distinct measurements within this conditional model.
  publication: PMID:31213987
  modeled_mechanisms:
  - target: Impaired Dendritic Arborization
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    fidelity: UNKNOWN
    limitations: Conditional deletion in the mouse Emx1 lineage differs from constitutive heterozygous human BRPF1 disease; these measurements do not establish the corresponding patient mechanism.
    readouts:
    - name: Dentate and cortical dendritic complexity
      target: Impaired Dendritic Arborization
      direction: DECREASED
      description: Golgi-stained dendrites had fewer Sholl intersections.
    evidence:
    - reference: PMID:31213987
      reference_title: Brpf1 Haploinsufficiency Impairs Dendritic Arborization and Spine Formation, Leading to Cognitive Deficits.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Sholl analysis revealed a significant decrease in the number of intersections in Brpf1 HT and cKO neurons compared with that in WT neurons
      explanation: Golgi-stained dentate granule neurons had reduced dendritic complexity; similar changes were measured in layer V cortical neurons. The intervening transcriptional steps remain unresolved.
  - target: Reduced Dendritic Spine Density and Altered Spine Morphology
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    fidelity: UNKNOWN
    limitations: Conditional deletion in the mouse Emx1 lineage differs from constitutive heterozygous human BRPF1 disease; these measurements do not establish the corresponding patient mechanism.
    readouts:
    - name: Cortical dendritic spine density
      target: Reduced Dendritic Spine Density and Altered Spine Morphology
      direction: DECREASED
      description: Fewer spines per unit dendrite length.
    - name: Cortical dendritic spine length
      target: Reduced Dendritic Spine Density and Altered Spine Morphology
      direction: INCREASED
      description: Remaining spines were longer.
    evidence:
    - reference: PMID:31213987
      reference_title: Brpf1 Haploinsufficiency Impairs Dendritic Arborization and Spine Formation, Leading to Cognitive Deficits.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Brpf1 HTs exhibited a significant reduction in the number of spines compared to that in WT mice.
      explanation: Spines were counted along secondary apical dendritic branches of adult cortical pyramidal neurons.
    - reference: PMID:31213987
      reference_title: Brpf1 Haploinsufficiency Impairs Dendritic Arborization and Spine Formation, Leading to Cognitive Deficits.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Statistical analysis revealed a significant increase in spine length in Brpf1 HT and cKO mice.
      explanation: Cortical spine length increased alongside a reduction in spine density; the measurements concern conditional mouse genotypes.
  - target: Reduced Excitatory Synaptic Transmission in Forebrain Neurons
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    fidelity: UNKNOWN
    limitations: Conditional deletion in the mouse Emx1 lineage differs from constitutive heterozygous human BRPF1 disease; these measurements do not establish the corresponding patient mechanism.
    readouts:
    - name: CA1 miniature EPSC frequency and amplitude
      target: Reduced Excitatory Synaptic Transmission in Forebrain Neurons
      direction: DECREASED
      description: Both measures decreased in acute slices from conditional heterozygotes.
    evidence:
    - reference: PMID:31213987
      reference_title: Brpf1 Haploinsufficiency Impairs Dendritic Arborization and Spine Formation, Leading to Cognitive Deficits.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Collectively, these data show that Brpf1 haploinsufficiency causes reduced synaptic transmission and decreased cell excitability, which may contribute to abnormal behaviors.
      explanation: Synaptic and behavioral deficits occur in the conditional heterozygous model, but their causal coupling was not tested by selective rescue.
  - target: Reduced Intrinsic Excitability of Hippocampal Pyramidal Neurons
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    fidelity: UNKNOWN
    limitations: Conditional deletion in the mouse Emx1 lineage differs from constitutive heterozygous human BRPF1 disease; these measurements do not establish the corresponding patient mechanism.
    readouts:
    - name: Action-potential firing-current threshold
      target: Reduced Intrinsic Excitability of Hippocampal Pyramidal Neurons
      direction: INCREASED
      description: More injected current was required to evoke firing.
    - name: Resting membrane potential
      target: Reduced Intrinsic Excitability of Hippocampal Pyramidal Neurons
      direction: UNCHANGED
      description: No significant genotype difference was detected.
    evidence:
    - reference: PMID:31213987
      reference_title: Brpf1 Haploinsufficiency Impairs Dendritic Arborization and Spine Formation, Leading to Cognitive Deficits.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: The mean resting potential was comparable between HTs and WTs, while the mean action potential current threshold was significantly higher in the HTs than in the WTs
      explanation: Acute CA1 slice current-clamp recordings found increased firing-current threshold with preserved resting membrane potential.
  - target: Impaired Learning and Memory
    relationship: PARTIALLY_RECAPITULATES
    model_scale: ORGANISM
    fidelity: UNKNOWN
    limitations: Conditional deletion in the mouse Emx1 lineage differs from constitutive heterozygous human BRPF1 disease; these measurements do not establish the corresponding patient mechanism.
    readouts:
    - name: Water-maze target-quadrant occupancy
      target: Impaired Learning and Memory
      direction: DECREASED
      description: Reduced occupancy in the platform-free probe trial.
    evidence:
    - reference: PMID:31213987
      reference_title: Brpf1 Haploinsufficiency Impairs Dendritic Arborization and Spine Formation, Leading to Cognitive Deficits.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Brpf1 HTs spent less time in the target quadrant where the platform was previously located
      explanation: Conditional heterozygous mice had reduced target-quadrant occupancy after water-maze training; contextual and cued fear-conditioning tests also showed reduced freezing.
  evidence:
  - reference: PMID:31213987
    reference_title: Brpf1 Haploinsufficiency Impairs Dendritic Arborization and Spine Formation, Leading to Cognitive Deficits.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Sholl analysis revealed a significant decrease in the number of intersections in Brpf1 HT and cKO neurons compared with that in WT neurons
    explanation: Golgi-stained dentate granule neurons had reduced dendritic complexity; similar changes were measured in layer V cortical neurons. The intervening transcriptional steps remain unresolved.
  - reference: PMID:31213987
    reference_title: Brpf1 Haploinsufficiency Impairs Dendritic Arborization and Spine Formation, Leading to Cognitive Deficits.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Collectively, these data show that Brpf1 haploinsufficiency causes reduced synaptic transmission and decreased cell excitability, which may contribute to abnormal behaviors.
    explanation: Synaptic and behavioral deficits occur in the conditional heterozygous model, but their causal coupling was not tested by selective rescue.
  - reference: PMID:31213987
    reference_title: Brpf1 Haploinsufficiency Impairs Dendritic Arborization and Spine Formation, Leading to Cognitive Deficits.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Brpf1 HTs spent less time in the target quadrant where the platform was previously located
    explanation: Conditional heterozygous mice had reduced target-quadrant occupancy after water-maze training; contextual and cued fear-conditioning tests also showed reduced freezing.
  notes: Gross cortical layering, dentate granule-cell number and GFAP organization were preserved. Corpus callosum thickness was reduced by 17.7%. Synaptic vesicle number and density were unchanged in heterozygotes but reduced in conditional homozygotes. Histological and behavioral strain backgrounds differ, so the study does not establish a direct quantitative anatomy-behavior relationship.
- name: Postnatal CaMKIIa-Cre conditional Brpf1 knockout mouse
  species: Mus musculus
  genotype: Brpf1 flox/flox; CaMKIIa-Cre
  description: C57BL/6J males with forebrain excitatory-neuron deletion beginning in the third to fourth postnatal week. Hippocampal Brpf1 RNA was reduced by approximately 60% at two months. The mice survived into adulthood, and gross cortical and hippocampal histology was preserved at six months.
  publication: PMID:37862219
  modeled_mechanisms:
  - target: Reduced Excitatory Synaptic Transmission in Forebrain Neurons
    relationship: MEASURES
    model_scale: CELLULAR
    fidelity: UNKNOWN
    limitations: Postnatal homozygous deletion in selected excitatory neurons differs from lifelong heterozygous human disease. Bulk CA1 RNA was measured at two months, electrophysiology at six months, and most behavior at two months; direct transcript-to-physiology-to-behavior mediation was not tested.
    readouts:
    - name: CA1 mEPSC frequency at six months
      target: Reduced Excitatory Synaptic Transmission in Forebrain Neurons
      direction: DECREASED
      description: Reduced frequency in acute slices.
    - name: CA1 mEPSC amplitude at six months
      target: Reduced Excitatory Synaptic Transmission in Forebrain Neurons
      direction: UNCHANGED
      description: No significant amplitude change.
    evidence:
    - reference: PMID:37862219
      reference_title: Forebrain excitatory neuron-specific loss of Brpf1 attenuates excitatory synaptic transmission and impairs spatial and fear memory.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: We found that the frequency but not the amplitude of mEPSCs decreased significantly
      explanation: Acute CA1 slices from six-month-old CaMKIIa-Cre conditional homozygous mice showed reduced mEPSC frequency, with amplitude and measured membrane properties preserved.
  - target: Impaired Learning and Memory
    relationship: MEASURES
    model_scale: ORGANISM
    fidelity: UNKNOWN
    limitations: Postnatal homozygous deletion in selected excitatory neurons differs from lifelong heterozygous human disease. Bulk CA1 RNA was measured at two months, electrophysiology at six months, and most behavior at two months; direct transcript-to-physiology-to-behavior mediation was not tested.
    readouts:
    - name: Spatial-reference probe performance
      target: Impaired Learning and Memory
      direction: DECREASED
      description: Less time in the target quadrant at two months.
    - name: Contextual fear freezing
      target: Impaired Learning and Memory
      direction: DECREASED
      description: Reduced freezing at two months.
    - name: Cued fear freezing
      target: Impaired Learning and Memory
      direction: UNCHANGED
      description: No significant group difference at two months.
    - name: Water-maze acquisition latency
      target: Impaired Learning and Memory
      direction: UNCHANGED
      description: No significant group difference during training at two months.
    - name: Novel-object discrimination
      target: Impaired Learning and Memory
      direction: UNCHANGED
      description: Discrimination ratio was preserved at two months.
    evidence:
    - reference: PMID:37862219
      reference_title: Forebrain excitatory neuron-specific loss of Brpf1 attenuates excitatory synaptic transmission and impairs spatial and fear memory.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: forebrain excitatory neuron-specific deletion ofBrpf1led to impaired contextual but not cued fear memory
      explanation: At two months, contextual freezing and spatial-reference probe performance were impaired, while cued freezing and acquisition latency were unchanged.
    - reference: PMID:37862219
      reference_title: Forebrain excitatory neuron-specific loss of Brpf1 attenuates excitatory synaptic transmission and impairs spatial and fear memory.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: The discrimination ratio of the cKO mice was similar to that of WT mice
      explanation: Novel-object recognition was unchanged at two months; the paper also reports preserved locomotion and no detected group difference in sociability or self-grooming.
  - target: Altered Developmental Transcriptional Programs
    relationship: MEASURES
    model_scale: CELLULAR
    fidelity: UNKNOWN
    limitations: Postnatal homozygous deletion in selected excitatory neurons differs from lifelong heterozygous human disease. Bulk CA1 RNA was measured at two months, electrophysiology at six months, and most behavior at two months; direct transcript-to-physiology-to-behavior mediation was not tested.
    readouts:
    - name: Hippocampal CA1 gene expression
      target: Altered Developmental Transcriptional Programs
      direction: ALTERED
      description: Both upregulated and downregulated genes; selected changes validated by qPCR.
    evidence:
    - reference: PMID:37862219
      reference_title: Forebrain excitatory neuron-specific loss of Brpf1 attenuates excitatory synaptic transmission and impairs spatial and fear memory.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: The results showed a dual role forBrpf1in regulating gene expression, that is, regulating both gene activation and suppression.
      explanation: RNA-seq and qPCR in hippocampal CA1 tissue show both directions of transcriptional change after postnatal conditional deletion. No individual transcript was rescued to prove mediation of physiology or behavior.
  evidence:
  - reference: PMID:37862219
    reference_title: Forebrain excitatory neuron-specific loss of Brpf1 attenuates excitatory synaptic transmission and impairs spatial and fear memory.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: We found that the frequency but not the amplitude of mEPSCs decreased significantly
    explanation: Acute CA1 slices from six-month-old CaMKIIa-Cre conditional homozygous mice showed reduced mEPSC frequency, with amplitude and measured membrane properties preserved.
  - reference: PMID:37862219
    reference_title: Forebrain excitatory neuron-specific loss of Brpf1 attenuates excitatory synaptic transmission and impairs spatial and fear memory.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: forebrain excitatory neuron-specific deletion ofBrpf1led to impaired contextual but not cued fear memory
    explanation: At two months, contextual freezing and spatial-reference probe performance were impaired, while cued freezing and acquisition latency were unchanged.
  - reference: PMID:37862219
    reference_title: Forebrain excitatory neuron-specific loss of Brpf1 attenuates excitatory synaptic transmission and impairs spatial and fear memory.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: The results showed a dual role forBrpf1in regulating gene expression, that is, regulating both gene activation and suppression.
    explanation: RNA-seq and qPCR in hippocampal CA1 tissue show both directions of transcriptional change after postnatal conditional deletion. No individual transcript was rescued to prove mediation of physiology or behavior.
  notes: RNA sequencing is deposited as GSE212983. Small behavioral groups and a lack of significant social preference in control mice limit negative sociability conclusions. The paper names Rho as rhodopsin but then invokes Rho GTPase biology; that annotation inconsistency does not establish a Rho-GTPase mechanism. Visual acuity was not tested, and the authors identify it as a potential water-maze confound.
- name: Hematopoietic Vav1-iCre Brpf1 conditional knockout mouse
  species: Mus musculus
  genotype: Brpf1 flox/flox; Vav1-iCre, deleting exons 4-6 in hematopoietic lineages
  publication: PMID:27500495
  description: C57BL/6J conditional homozygotes develop fetal stem/progenitor defects, progressive neonatal marrow aplasia and pancytopenia, with median death at P18 and no survival beyond P21 in the reported survival cohort. Competitive marrow and fetal-liver transplantation tests show severe loss of repopulating activity. Erythroid maturation is much less affected than the stem/progenitor compartment.
  modeled_mechanisms:
  - target: Impaired Hematopoietic Stem and Progenitor Cell Maintenance
    relationship: MEASURES
    model_scale: CELLULAR
    fidelity: UNKNOWN
    limitations: Complete blood-lineage loss in mice is more severe than heterozygous human BRPF1 disease. Slamf1/CD150 expression itself declines, so immunophenotypic counts should be interpreted alongside functional transplantation assays. Neither anemia nor thrombocytopenia in reported patients establishes this marrow-failure mechanism.
    readouts:
    - name: Competitive marrow repopulating activity
      target: Impaired Hematopoietic Stem and Progenitor Cell Maintenance
      direction: ABOLISHED
      description: Mutant donor cells failed to contribute detectably to recipient blood lineages over 4-16 weeks.
    - name: Marrow homing at 40 hours
      target: Impaired Hematopoietic Stem and Progenitor Cell Maintenance
      direction: UNCHANGED
      description: Short-term donor-cell recovery was comparable to control.
    - name: Fetal LSK proliferation
      target: Impaired Hematopoietic Stem and Progenitor Cell Maintenance
      direction: UNCHANGED
      description: Ki67 and cell-cycle analyses showed no clear fetal proliferation defect.
    - name: Neonatal marrow LSK proliferation
      target: Impaired Hematopoietic Stem and Progenitor Cell Maintenance
      direction: DECREASED
      description: Fewer cycling LSK cells at P6.
    evidence:
    - reference: PMID:27500495
      reference_title: BRPF1 is essential for development of fetal hematopoietic stem cells.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: the mutant bone marrow cells were unable to repopulate in the recipient peripheral blood
      explanation: Competitive transplantation found almost no mutant contribution at 4-16 weeks, supporting loss of functional repopulating activity.
    - reference: PMID:27500495
      reference_title: BRPF1 is essential for development of fetal hematopoietic stem cells.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: the mutant bone marrow cells are normal in homing
      explanation: Donor-cell recovery 40 hours after transplantation was preserved despite failed longer-term repopulation.
    - reference: PMID:27500495
      reference_title: BRPF1 is essential for development of fetal hematopoietic stem cells.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: the proliferation index was normal in LSK cells from the mutant fetal liver
      explanation: Fetal LSK proliferation and cell-cycle profiles were preserved, unlike reduced neonatal marrow cycling.
  - target: Deficient Histone H3K23 Acetylation
    relationship: MEASURES
    model_scale: CELLULAR
    fidelity: UNKNOWN
    limitations: Complete blood-lineage loss in mice is more severe than heterozygous human BRPF1 disease. Slamf1/CD150 expression itself declines, so immunophenotypic counts should be interpreted alongside functional transplantation assays. Neither anemia nor thrombocytopenia in reported patients establishes this marrow-failure mechanism.
    readouts:
    - name: H3K23ac in sorted neonatal marrow LSK cells
      target: Deficient Histone H3K23 Acetylation
      direction: ABOLISHED
      description: Immunofluorescence was undetectable at P7.
    evidence:
    - reference: PMID:27500495
      reference_title: BRPF1 is essential for development of fetal hematopoietic stem cells.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: The fluorescence signal for lysine 23 acetylation was undetectable in sorted mutant LSK cells at P7
      explanation: Sorted-cell assays show loss of this histone mark; bulk marrow H3K9/H3K14 acetylation also declines.
  evidence:
  - reference: PMID:27500495
    reference_title: BRPF1 is essential for development of fetal hematopoietic stem cells.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: the mutant bone marrow cells were unable to repopulate in the recipient peripheral blood
    explanation: Competitive transplantation found almost no mutant contribution at 4-16 weeks, supporting loss of functional repopulating activity.
  - reference: PMID:27500495
    reference_title: BRPF1 is essential for development of fetal hematopoietic stem cells.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: the mutant bone marrow cells are normal in homing
    explanation: Donor-cell recovery 40 hours after transplantation was preserved despite failed longer-term repopulation.
  notes: Vav1-iCre does not complete deletion at E11.5; these experiments do not resolve BRPF1 function at the earliest emergence of hematopoietic stem cells. Postnatal maintenance independent of the fetal defect was not isolated.
- name: Hematopoietic Vav1-iCre Brpf1 conditional heterozygous mouse
  species: Mus musculus
  genotype: Brpf1 flox/+; Vav1-iCre
  publication: PMID:27500495
  description: The zygosity comparison reported survival indistinguishable from wild type and no significant change in neonatal LSK-cell numbers. This is a limited negative comparison, not a demonstration that every hematopoietic function is normal.
  modeled_mechanisms:
  - target: Impaired Hematopoietic Stem and Progenitor Cell Maintenance
    relationship: MEASURES
    model_scale: CELLULAR
    fidelity: UNKNOWN
    limitations: Heterozygosity is restricted to the targeted blood lineage. The report does not establish normal lifelong blood counts, stem-cell reserve or stress responses.
    readouts:
    - name: Neonatal LSK-cell number
      target: Impaired Hematopoietic Stem and Progenitor Cell Maintenance
      direction: UNCHANGED
      description: No significant difference from wild type in the reported comparison.
    evidence:
    - reference: PMID:27500495
      reference_title: BRPF1 is essential for development of fetal hematopoietic stem cells.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: No significant difference was observed between wild-type and heterozygous LSK cell numbers
      explanation: Conditional heterozygotes did not show the neonatal LSK depletion observed after homozygous deletion; this negative comparison limits direct extrapolation to human heterozygosity.
  evidence:
  - reference: PMID:27500495
    reference_title: BRPF1 is essential for development of fetal hematopoietic stem cells.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: No significant difference was observed between wild-type and heterozygous LSK cell numbers
    explanation: Conditional heterozygotes did not show the neonatal LSK depletion observed after homozygous deletion; this negative comparison limits direct extrapolation to human heterozygosity.
  - reference: PMID:27500495
    reference_title: BRPF1 is essential for development of fetal hematopoietic stem cells.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Brpf1fl/+ Vav1-iCre mice were indistinguishable from the wild-type
    explanation: The comparison concerns survival; it does not exclude subtle or age-dependent hematopoietic abnormalities.
- name: Embryonic Emx1-Cre Brpf1 conditional homozygous mouse
  species: Mus musculus
  genotype: Brpf1 flox/flox; Emx1-Cre
  publication: PMID:25568313
  description: Forebrain-specific deletion produces cortical abnormalities, partial callosal agenesis and predominantly early postnatal lethality. This is distinct from the conditional heterozygous and postnatal CaMKIIa-Cre models.
  modeled_mechanisms:
  - target: Aberrant Cortical Neurogenesis
    relationship: MEASURES
    model_scale: CELLULAR
    fidelity: UNKNOWN
    limitations: Embryonic homozygous forebrain deletion is more severe than constitutive heterozygous human disease. Neural progenitor and callosal findings coexist but do not identify a unique causal mediator.
    readouts:
    - name: Tbr2-positive intermediate neuronal progenitors
      target: Aberrant Cortical Neurogenesis
      direction: DECREASED
      description: Fewer progenitors were observed in mutant forebrain.
    evidence:
    - reference: PMID:25568313
      reference_title: Deficiency of the chromatin regulator BRPF1 causes abnormal brain development.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: With respect to the control, the mutant forebrain contained fewer Tbr2-positive intermediate neuronal progenitors and displayed aberrant neurogenesis.
      explanation: Identifies depletion of intermediate neuronal progenitors as the cellular basis of the cortical phenotype.
  - target: Abnormal Corpus Callosum Development
    relationship: MEASURES
    model_scale: TISSUE
    fidelity: UNKNOWN
    limitations: Embryonic homozygous forebrain deletion is more severe than constitutive heterozygous human disease. Neural progenitor and callosal findings coexist but do not identify a unique causal mediator.
    readouts:
    - name: Corpus callosum anatomy
      target: Abnormal Corpus Callosum Development
      direction: ALTERED
      description: Partial agenesis after conditional homozygous deletion.
    evidence:
    - reference: PMID:25568313
      reference_title: Deficiency of the chromatin regulator BRPF1 causes abnormal brain development.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Here, we report that forebrain-specific inactivation of the mouse Brpf1 gene caused early postnatal lethality, neocortical abnormalities, and partial callosal agenesis.
      explanation: The conditional homozygous model has a tissue-level callosal phenotype; it does not establish a universal callosal defect in heterozygous humans.
  evidence:
  - reference: PMID:25568313
    reference_title: Deficiency of the chromatin regulator BRPF1 causes abnormal brain development.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Here, we report that forebrain-specific inactivation of the mouse Brpf1 gene caused early postnatal lethality, neocortical abnormalities, and partial callosal agenesis.
    explanation: The conditional homozygous model has a tissue-level callosal phenotype; it does not establish a universal callosal defect in heterozygous humans.
- name: Zebrafish brpf1 pharyngeal-patterning mutants
  species: Danio rerio
  genotype: Homozygous brpf1 t20002, b943 or t25114
  publication: PMID:18469222
  description: Three alleles and a splice-blocking morpholino produce anterior transformations of pharyngeal arches 2–6. Anterior Hox expression initiates normally but is not maintained; neural crest migration and more posterior Hox expression are preserved. The PWWP-lacking t25114 allele is not detectably milder than severe truncation alleles. Mouse Brpf1 mRNA partly rescues Hox expression. Trichostatin A rescues Hox expression and alleviates skeletal abnormalities; hoxb1a injection can normalize the arch marker pattern or overcorrect it to a bihyoid pattern.
  modeled_mechanisms:
  - target: Altered Developmental Transcriptional Programs
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    fidelity: UNKNOWN
    limitations: Homozygous zebrafish truncation or splice alleles cause homeotic pharyngeal transformations. Human BRPF1-associated facial dysmorphism has not been shown to be a homeotic transformation, and these rescue experiments do not establish clinical treatment benefit.
    readouts:
    - name: Maintenance of anterior Hox expression in cranial neural crest
      target: Altered Developmental Transcriptional Programs
      direction: DECREASED
      description: hoxa2b and hoxb2a are lost after initially normal expression; posterior Hox genes are relatively preserved.
    evidence:
    - reference: PMID:18469222
      reference_title: The multidomain protein Brpf1 binds histones and is required for Hox gene expression and segmental identity.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: We conclude that Brpf1 is specifically required for the maintenance, but not for the initiation, of anterior Hox gene expression.
      explanation: Zebrafish mutants lose maintenance of anterior Hox expression; initiation and neural crest migration were preserved. This is not a demonstrated human craniofacial pathway.
  - target: Altered Developmental Transcriptional Programs
    relationship: RESCUES
    model_scale: CELLULAR
    fidelity: UNKNOWN
    limitations: Homozygous zebrafish truncation or splice alleles cause homeotic pharyngeal transformations. Human BRPF1-associated facial dysmorphism has not been shown to be a homeotic transformation, and these rescue experiments do not establish clinical treatment benefit.
    readouts:
    - name: Anterior Hox expression after mouse Brpf1 mRNA injection
      target: Altered Developmental Transcriptional Programs
      direction: INCREASED
      description: Partial significant rescue at 33 hours post-fertilization.
    - name: hoxa2b expression after trichostatin A exposure
      target: Altered Developmental Transcriptional Programs
      direction: RESTORED
      description: The reported 20–33-hour exposure restored the measured neural-crest transcriptional readout.
    evidence:
    - reference: PMID:18469222
      reference_title: The multidomain protein Brpf1 binds histones and is required for Hox gene expression and segmental identity.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: zebrafish brpf1 mutants injected with mouse Brpf1 mRNA displayed a partial, but significant rescue of anterior Hox gene expression at 33 hpf
      explanation: Cross-species mRNA rescue supports a conserved developmental function without reproducing the human heterozygous genotype.
    - reference: PMID:18469222
      reference_title: The multidomain protein Brpf1 binds histones and is required for Hox gene expression and segmental identity.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Treatment of mutants from 20–33 hpf rescued hoxa2b expression in CNC
      explanation: Trichostatin A restored the measured transcriptional readout in zebrafish; the experiment is preclinical.
  evidence:
  - reference: PMID:18469222
    reference_title: The multidomain protein Brpf1 binds histones and is required for Hox gene expression and segmental identity.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: We conclude that Brpf1 is specifically required for the maintenance, but not for the initiation, of anterior Hox gene expression.
    explanation: Zebrafish mutants lose maintenance of anterior Hox expression; initiation and neural crest migration were preserved. This is not a demonstrated human craniofacial pathway.
- name: Constitutive Brpf1-null mouse embryo
  species: Mus musculus
  genotype: Brpf1 homozygous inactive delta/delta or -/- alleles
  publication: PMID:25773539
  description: Global inactivation causes lethality around E9.5 with vascular disorganization in embryo, yolk sac and placenta, impaired placental labyrinth branching, and cranial neural tube closure defects. Reduced mitotic staining precedes conspicuous apoptosis, which appears at E10.5; gamma-H2AX staining is not detectably increased at E9.5. These severe complete-loss phenotypes should not be assigned to heterozygous human disease.
  modeled_mechanisms:
  - target: Altered Developmental Transcriptional Programs
    relationship: MEASURES
    model_scale: CELLULAR
    fidelity: UNKNOWN
    limitations: Whole-embryo expression after complete loss differs from heterozygous human neurons. Individual transcript changes were not rescued to establish mediation of vascular or neural tube defects.
    readouts:
    - name: Rpl10l transcript in E8.75 embryos
      target: Altered Developmental Transcriptional Programs
      direction: DECREASED
      description: Validated by RT-qPCR; the change is context-specific.
    - name: Scp3l transcript in E8.75 embryos
      target: Altered Developmental Transcriptional Programs
      direction: INCREASED
      description: Validated by RT-qPCR; pathogenic mediation remains hypothetical.
    evidence:
    - reference: PMID:25773539
      reference_title: The chromatin regulator Brpf1 regulates embryo development and cell proliferation.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: we confirmed that Rpl10l (ribosomal protein L10-like) mRNA decreased, whereas Scp3l (synaptonemal complex protein 3-like; or Gm773, for predicted gene 773) mRNA increased in Brpf1-null embryos
      explanation: Transcript changes were validated in E8.75 embryos; Rpl10l reduction was not reproduced in later embryonic fibroblasts.
  evidence:
  - reference: PMID:25773539
    reference_title: The chromatin regulator Brpf1 regulates embryo development and cell proliferation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: the ablation leads to vascular defects in the placenta, yolk sac, and embryo proper, as well as abnormal neural tube closure.
    explanation: Global null mouse embryos have severe developmental defects; these are not established clinical manifestations of heterozygous human BRPF1 disease.
  - reference: PMID:25773539
    reference_title: The chromatin regulator Brpf1 regulates embryo development and cell proliferation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: we confirmed that Rpl10l (ribosomal protein L10-like) mRNA decreased, whereas Scp3l (synaptonemal complex protein 3-like; or Gm773, for predicted gene 773) mRNA increased in Brpf1-null embryos
    explanation: Transcript changes were validated in E8.75 embryos; Rpl10l reduction was not reproduced in later embryonic fibroblasts.

datasets:
- accession: geo:GSE157903
  description: Bulk RNA sequencing of primary mouse MGE-derived GABAergic interneurons after AAV-shBrpf1 or scramble treatment.
  organism:
    preferred_term: Mus musculus
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  data_type: BULK_RNA_SEQ
  publication: PMID:33744924
  notes: GEO records three samples per condition. The paper reports three culture batches per condition. Transcript changes do not establish direct BRPF1 targets or mediation of electrophysiological changes.
  title: brpf1 knockdown reduces inhibitory neurotransmission and regulates gene expression of GABAergic interneurons derived from MGE
  sample_count: 6
  platform: Illumina HiSeq 2500 (GPL17021)
  conditions:
  - MGE interneuron culture, scramble control
  - MGE interneuron culture, Brpf1 shRNA
- accession: geo:GSE174600
  description: Bulk RNA sequencing after Brpf1 knockdown in primary mouse hippocampal cultures and in stereotactically injected hippocampal CA1 tissue.
  organism:
    preferred_term: Mus musculus
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  data_type: BULK_RNA_SEQ
  publication: PMID:34485298
  notes: GEO records three samples per condition. The paper describes three pairs of samples for each preparation. Culture and tissue contrasts must be analyzed separately; neither is a human heterozygous transcriptome.
  title: Deficiency of intellectual disability-related gene Brpf1 attenuated hippocampal excitatory neurotransmission and impaired learning and memory behavior
  sample_count: 12
  platform: Illumina HiSeq 2500 (GPL17021)
  conditions:
  - Hippocampal neuron culture, scramble control
  - Hippocampal neuron culture, Brpf1 shRNA
  - Hippocampal CA1 tissue, scramble control
  - Hippocampal CA1 tissue, Brpf1 shRNA
- accession: geo:GSE212983
  title: Hippocampus-specific loss of intellectual disability-related gene Brpf1 impaired spatial and contextual learning
  description: RNA-seq of hippocampal CA1 tissue from postnatal CaMKIIa-Cre Brpf1 conditional knockout and control mice.
  organism:
    preferred_term: Mus musculus
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  data_type: BULK_RNA_SEQ
  sample_count: 8
  conditions:
  - Control hippocampal CA1 tissue
  - CaMKIIa-Cre Brpf1 conditional knockout hippocampal CA1 tissue
  publication: PMID:37862219
  notes: Four samples per group from two-month-old males. Bulk tissue and nominal DEG thresholds limit cell-specific and causal interpretation.
  platform: Illumina NovaSeq 6000 (GPL24247)
- accession: geo:GSE213695
  title: BRPF1 co-occupies with H3K4me3 and H3K23ac in human ESCs essential to pluripotency
  description: SuperSeries containing transcriptomic, chromatin accessibility and occupancy profiling of engineered H1 embryonic stem cells.
  organism:
    preferred_term: Homo sapiens
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MULTI_OMICS_PERTURBATION
  sample_count: 18
  publication: PMID:36711238
  notes: The total counts deposited samples across assays, not independent patients or eighteen biological donors. The study also deposits data under HRA001928. Complete engineered loss, differentiation state and assay-specific controls must be considered when using the data. GEO assigns platform GPL24676 (NovaSeq 6000), while the paper methods describe NextSeq 500 sequencing; this source discrepancy should be checked before platform-specific reanalysis. SubSeries are GSE213690, GSE213692 and GSE213694.
  platform: Illumina NovaSeq 6000 (GPL24676; GEO record)
- accession: geo:GSE63908
  title: Microarray analysis of Wild-type vs. Brpf1-deficient E8.75 mouse embryo
  description: Two-color microarray comparison of three pairs of control and Brpf1-deficient E8.75 mouse embryos.
  organism:
    preferred_term: Mus musculus
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  data_type: MICROARRAY
  sample_count: 3
  publication: PMID:25773539
  platform: Agilent-028005 SurePrint G3 Mouse GE 8x60K Microarray (GPL13912)
  conditions:
  - Wild-type E8.75 mouse embryo
  - Brpf1-deficient E8.75 mouse embryo
  notes: 'GEO lists three array samples, each hybridizing labeled material from a control-mutant pair: three samples represent six embryos, not three total embryos. Whole-embryo composition and global null genotype limit inference about human heterozygous neural cells.'

variants:
- name: c.1052_1053del (p.Val351GlyfsTer8)
  gene:
    preferred_term: BRPF1
    term:
      id: hgnc:14255
      label: BRPF1
  variant_type: deletion
  description: Founding familial frameshift with partial nonsense-mediated decay. In transfected cells, the truncated protein retains KAT6A interaction but fails to recruit ING5/MEAF6 and fails to stimulate H3K23 acetylation. The decrease in patient-fibroblast H3K23ac was not statistically significant; protein abundance and functional effect should not be generalized across assays. The cited study provides segregation and functional evidence, but an explicit ACMG class for this allele was not established from the cached source; a formal clinical_significance value is therefore not assigned.
  evidence:
  - reference: PMID:27939639
    reference_title: Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual Disability with Associated Ptosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: we identified an inherited 2 bp deletion causing a frameshift in BRPF1 (c.1052_1053del) in five affected family members.
    explanation: Identifies the segregating familial frameshift.
  - reference: PMID:27939639
    reference_title: Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual Disability with Associated Ptosis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Whereas the wild-type was able to bind ING5 and MEAF6, the p.Val351Glyfs∗8 variant failed to do so.
    explanation: Partner-specific impairment was measured in transfected cells; KAT6A binding was retained.
- name: NM_004634:c.556C>T (p.Gln186Ter)
  gene:
    preferred_term: BRPF1
    term:
      id: hgnc:14255
      label: BRPF1
  variant_type: single nucleotide variant
  clinical_significance: PATHOGENIC
  description: Truncating allele reported as pathogenic in a multiplex family, inherited from the mother by three affected sons. Cognitive expressivity varied; the mother initially described herself as unaffected. No direct allele-specific RNA or protein assay was reported in this clinical study.
  evidence:
  - reference: PMID:31020800
    reference_title: BRPF1-associated intellectual disability, ptosis, and facial dysmorphism in a multiplex family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: the previously unreported c.556C>T (p.Q186*) truncating mutation on exon 2 of the BRPF1 gene (NM_004634), in the proband and his mother.
    explanation: Identifies the transcript and familial allele.
  - reference: PMID:31020800
    reference_title: BRPF1-associated intellectual disability, ptosis, and facial dysmorphism in a multiplex family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: the mutation fully segregated with the disease in the family
    explanation: The familial p.Gln186Ter allele segregated with the BRPF1 phenotype. A sibling with Leber hereditary optic neuropathy instead carried an MT-ND1 variant and did not share the BRPF1 phenotype.
- name: c.1054G>C (p.Val352Leu)
  gene:
    preferred_term: BRPF1
    term:
      id: hgnc:14255
      label: BRPF1
  variant_type: single nucleotide variant
  clinical_significance: UNCERTAIN_SIGNIFICANCE
  description: Reported in one child with a BRPF1-like phenotype and absent from tested parental and sibling blood samples. The paper classifies the allele as uncertain significance. Modeling predicts altered PZP-domain packing; no biochemical or cellular experiment establishes destabilization or acetylation loss.
  evidence:
  - reference: PMID:32457794
    reference_title: Novel Missense Variant in Heterozygous State in the BRPF1 Gene Leading to Intellectual Developmental Disorder With Dysmorphic Facies and Ptosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The variant detected here was classified as variant with unclear significance according to the most recent ACMG guidelines.
    explanation: The methods explicitly give uncertain significance, despite stronger causal wording in the title and discussion. Structural effects were predicted, not experimentally measured.
  - reference: PMID:32457794
    reference_title: Novel Missense Variant in Heterozygous State in the BRPF1 Gene Leading to Intellectual Developmental Disorder With Dysmorphic Facies and Ptosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: the heterozygous mutation was detected only in the index patient II-3
    explanation: Sanger testing found the allele in the proband but not the tested parents or sisters.
- name: c.2420_2433del (p.Gln807LeufsTer27)
  gene:
    preferred_term: BRPF1
    term:
      id: hgnc:14255
      label: BRPF1
  variant_type: deletion
  clinical_significance: PATHOGENIC
  description: Frameshift reported as pathogenic in two sisters. Negative parental buccal testing suggests parental gonadal mosaicism, but parent-of-origin and gonadal mosaicism were not directly established. The proband also had a partial ARHGAP26 deletion classified as a VUS; that finding should not be conflated with BRPF1 haploinsufficiency.
  evidence:
  - reference: PMID:37946714
    reference_title: 'Mosaicism in BRPF1-Related Neurodevelopmental Disorder: Report of Two Sisters and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: WES analysis identified a heterozygous pathogenic variant in BRPF1 c.2420_2433del (p.Q807Lfs∗27) in both sisters.
    explanation: Identifies the shared frameshift and source classification.
  - reference: PMID:37946714
    reference_title: 'Mosaicism in BRPF1-Related Neurodevelopmental Disorder: Report of Two Sisters and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Hence, parent-of-origin could not be determined.
    explanation: No informative nearby SNPs established the parental allele of origin.
- name: NM_004634.3:c.1433G>A (p.Trp478Ter)
  gene:
    preferred_term: BRPF1
    term:
      id: hgnc:14255
      label: BRPF1
  variant_type: single nucleotide variant
  clinical_significance: PATHOGENIC
  description: Nonsense allele reported as pathogenic in a family with the BRPF1 phenotype and anemia/thrombocytopenia. No additional genomic change was detected by the reported WES and microarray tests; this does not prove a specific marrow-failure pathway or exclude every other cause of cytopenia.
  evidence:
  - reference: PMID:37190896
    reference_title: 'Anemia and thrombocytopenia due to a novel BRPF1 variant in a family from Çanakkale with intellectual disability and dysmorphic facies: Case report and review of the literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: a novel heterozygous c.1433G > A; p.W478* (NM_004634.3) pathogenic variant on exon 3 of the BRPF1 gene.
    explanation: Identifies the reported nonsense variant and source classification.

📚

References & Deep Research

References

PMID:27939639

Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual Disability with Associated Ptosis.

No top-level findings curated for this source.

PMID:27939640

Mutations in the Chromatin Regulator Gene BRPF1 Cause Syndromic Intellectual Disability and Deficient Histone Acetylation.

No top-level findings curated for this source.

PMID:39837771

The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review.

No top-level findings curated for this source.

CGDS:HGNC_14255

BRPF1 dosage sensitivity

No top-level findings curated for this source.

ORPHA:698090

Ophthalmological abnormalities-facial dysmorphism-intellectual disability syndrome

No top-level findings curated for this source.

PMID:38346666

Beyond 'speech delay': Expanding the phenotype of BRPF1-related disorder.

No top-level findings curated for this source.

PMID:37946714

Mosaicism in BRPF1-Related Neurodevelopmental Disorder: Report of Two Sisters and Literature Review.

No top-level findings curated for this source.

PMID:31020800

BRPF1-associated intellectual disability, ptosis, and facial dysmorphism in a multiplex family.

No top-level findings curated for this source.

PMID:32457794

Novel Missense Variant in Heterozygous State in the BRPF1 Gene Leading to Intellectual Developmental Disorder With Dysmorphic Facies and Ptosis.

No top-level findings curated for this source.

PMID:35243762

BRPF1-associated syndrome: A patient with congenital ptosis, neurological findings, and normal intellectual development.

No top-level findings curated for this source.

PMID:31176769

Novel BRPF1 mutation in a boy with intellectual disability, coloboma, facial nerve palsy and hypoplasia of the corpus callosum.

No top-level findings curated for this source.

PMID:38590032

Broadening the ocular phenotypic spectrum of ultra-rare BRPF1 variants: report of two cases.

No top-level findings curated for this source.

PMID:40752867

Ocular findings of BRPF1 variants: a case report and literature review.

No top-level findings curated for this source.

PMID:37190896

Anemia and thrombocytopenia due to a novel BRPF1 variant in a family from Çanakkale with intellectual disability and dysmorphic facies: Case report and review of the literature.

No top-level findings curated for this source.

PMID:32010779

Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer.

No top-level findings curated for this source.

PMID:36077605

BRPF1-KAT6A/KAT6B Complex: Molecular Structure, Biological Function and Human Disease.

No top-level findings curated for this source.

PMID:36711238

BRPF1 bridges H3K4me3 and H3K23ac in human embryonic stem cells and is essential to pluripotency.

No top-level findings curated for this source.

PMID:31213987

Brpf1 Haploinsufficiency Impairs Dendritic Arborization and Spine Formation, Leading to Cognitive Deficits.

No top-level findings curated for this source.

PMID:34485298

Deficiency of Intellectual Disability-Related Gene Brpf1 Attenuated Hippocampal Excitatory Synaptic Transmission and Impaired Spatial Learning and Memory Ability.

No top-level findings curated for this source.

PMID:33744924

Deficiency of intellectual disability-related gene Brpf1 reduced inhibitory neurotransmission in MGE-derived GABAergic interneurons.

No top-level findings curated for this source.

PMID:37862219

Forebrain excitatory neuron-specific loss of Brpf1 attenuates excitatory synaptic transmission and impairs spatial and fear memory.

No top-level findings curated for this source.

PMID:25568313

Deficiency of the chromatin regulator BRPF1 causes abnormal brain development.

No top-level findings curated for this source.

PMID:24646517

Expression atlas of the multivalent epigenetic regulator Brpf1 and its requirement for survival of mouse embryos.

No top-level findings curated for this source.

PMID:27500495

BRPF1 is essential for development of fetal hematopoietic stem cells.

No top-level findings curated for this source.

PMID:41137536

Non-RASopathy Genetic Syndromes Identified as the Molecular Cause of Disease in Patients Previously Diagnosed With Noonan Syndrome.

No top-level findings curated for this source.

PMID:18469222

The multidomain protein Brpf1 binds histones and is required for Hox gene expression and segmental identity.

No top-level findings curated for this source.

PMID:25773539

The chromatin regulator Brpf1 regulates embryo development and cell proliferation.

No top-level findings curated for this source.

PMID:40593219

Bromodomain and PHD Finger-Containing Protein 1: From Functions to a Developmental Disorder, Cancer, and Therapeutics.

No top-level findings curated for this source.

url:https://www.ncbi.nlm.nih.gov/books/NBK1441/

Blepharophimosis, Ptosis, and Epicanthus Inversus Syndrome - GeneReviews® - NCBI Bookshelf

No top-level findings curated for this source.

Deep Research

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Review BRPF1 clinical evidence, mechanisms, models and datasets · 2026-09-27T16:29:33Z · View source

Reviewed the complete existing entry, all four preceding CREATE/EDIT histories, and the substantive deep-research report and citation sidecar. The entity is Mendelian BRPF1-related neurodevelopmental disease (MONDO:0015022; OMIM:617333; hgnc:14255), not an infectious or environmental disease. No preceding REVIEW record or competing open BRPF1 PR was found. Rebased before editing and again onto 91778fac335 before final corrections. The GeneReviews Bookshelf match is the FOXL2/BPES differential chapter, not a BRPF1 baseline. Used all 25 existing reference caches and retrieved three additional sources. Read the full scientific texts available for PMIDs 27939639, 39837771 (including clinical tables), 32010779, 31213987, 33744924, 34485298, 36711238, 37862219, 27500495, 32457794, 31020800, 37946714 and 36077605. Retrieved and read the full scientific text of 18469222 and 25773539, including methods, rescue experiments and negative results. Read the remaining cached abstracts, including the newly retrieved 2025 review 40593219. Full text for 25568313 could only be partially accessed online; retained exact cached abstract evidence rather than treating captcha or landing pages as a paper. All cache changes were produced by supported reference/dataset fetchers or validation normalization. No cache was manually authored, and the retired dataset-accessions JSON was not used. Content-completeness assessment: 1. Phenotypes: adequate after adding 20 records, including frequent cohort omissions, separate callosal agenesis, facial asymmetry and epicanthus inversus. The entry now has 70 phenotypes. Distinguished callosal agenesis from hypoplasia, visual acuity impairment from pooled ocular abnormalities, and intellectual disability from global developmental delay. Preserved source conflicts in small-hand and laryngomalacia/stridor counts rather than inventing a denominator. The table's bulimia label lacks diagnostic criteria for bulimia nervosa; recorded that limitation without asserting the psychiatric diagnosis. The combined aggressive/impulsive/violent category does not give a separate frequency for each behavior. Cohort-specific estimates retain missing-data and ascertainment caveats. 2. Subtypes: adequate; no established disease subtypes requiring separate MONDO/OMIM bindings emerged. Variant-domain groupings are not treated as validated clinical subtypes. Contiguous deletions involving SETD5 remain a separate differential and interpretation problem. 3. Mechanisms: adequate; 19 atomic nodes distinguish chromatin accessibility from transcription, neurogenesis from callosal development, dendrites from spines and axons, and intrinsic excitability from synaptic transmission. Removed exact-half-protein and universal complex-disruption claims. KAT7 association in vitro is distinguished from uncertain in-vivo relevance. Co-occupancy is not proof of direct histone-mark recognition. Patient-cell and overexpression findings are separated, and neuronal mediation is qualified where only co-occurrence is established. Seven cellular models and eight animal models capture genotype, lineage, timing, rescue and important negative findings. The zebrafish Hox-maintenance loss contrasts with Hox upregulation in mouse forebrain; global-null vascular and neural-tube phenotypes are model findings, not human prognosis. 4. Treatments/trials: adequate. Split physical and occupational therapy and marked supportive-care inference separately from demonstrated efficacy. Added documented speech-therapy use and ptosis operations with limited repeat outcomes. HDAC inhibitors and propionate retain genotype-dependent biochemical responses and explicit preclinical status; zebrafish trichostatin-A rescue is not treated as a clinical neurodevelopmental intervention. Verified CHEBI identities, including valproic acid CHEBI:39867 rather than the research report's incorrect suggested identifier. ClinicalTrials.gov API searches on 2026-09-27 for BRPF1, IDDDFP and the full syndrome name each returned zero studies; this does not exclude participation in broader trials. 5. Genetics: adequate. Preserved variant-class and inheritance information, distinguished suspected gonadal mosaicism from directly demonstrated mosaicism, and added five structured variants. Val352Leu remains a VUS as explicitly classified in the primary methods, despite stronger wording in its title; predicted structural effects are not functional-assay results. Intrafamilial variability does not establish a population penetrance estimate or a reliable genotype-phenotype correlation. 6. Diagnostics/biomarkers: adequate. Split exome and genome sequencing with accurate NCIT bindings, retained copy-number detection without requiring redundant assays for every patient, and removed unsupported ophthalmological screening intervals. A VUS does not establish diagnosis. Histone acylation readouts remain experimental, and the proposed DNA-methylation signature remains a research question rather than an established diagnostic test. 7. References/datasets: adequate. Refreshed caches recovered clinical tables and model full texts. Added three high-value publications and verified five GEO datasets: GSE157903, GSE174600, GSE212983, GSE213695 and GSE63908. The last contains three paired array samples representing six embryos; GSE213695's 18 deposited assay samples are not 18 donors. Preserved the GEO-versus-paper sequencing-platform discrepancy for the hESC study. Titles were checked for identifier/entity relevance; clinical evidence is not imported from KAT6A/KAT6B patients merely because their proteins share a complex. 8. Overall consumption: adequate across central clinical, genetic, molecular, neuronal, hematopoietic and diagnostic themes. The research report's secondary preprint on chromatin-loop insulation and inhibitor-based osteoclast experiments do not establish additional clinical mechanisms of heterozygous human BRPF1 disease; these remain nonblocking research leads. Cancer-directed BRPF1 inhibition is outside this germline neurodevelopmental entry's treatment scope. Replaced the previous process diary in KB notes with disease-specific limitations; review provenance is recorded here. Validation: schema, ontology terms and reference validation passed with 337 snippets and 370 titles, zero skipped or unavailable snippets and zero reference issues. All five dataset accessions verified. Scoped disorder and entity-reference tests passed. Causal-target and coarse-phenotype checks found no new violations. Formatter preserved parsed YAML values. Final commit hooks and current-head CI/independent review remain PR-stage checks and are not represented here as already completed.

Create: BRPF1-Related_Intellectual_Disability · 2026-08-01T06:01:57Z · View source

Created the BRPF1-Related Intellectual Disability (IDDDFP, MONDO:0015022, OMIM:617333, BRPF1/HGNC:14255) disorder entry from scratch. MONDO preflight confirmed the RO:0004003 gene relation is HGNC:14255 BRPF1 before any writing. Deep research ran via 'just research-disorder claude_code BRPF1-Related_Intellectual_Disability' (claude_code provider, 958s, 7 web searches, 61 turns, 19 citations); the full report and citations sidecar are committed under research/. A GeneReviews baseline was searched for and does not exist: PubMed queries for 'BRPF1 GeneReviews[All Fields]', 'BRPF1[All Fields] AND GeneReviews', and the disease-name plus GeneReviews query returned no BRPF1 chapter, so the phenotype baseline was anchored on the two 2017 founding series (PMID:27939639, PMID:27939640), the 29-patient 2025 cohort (PMID:39837771), and the dedicated speech-phenotyping study (PMID:38346666). Curated: 10 connected pathophysiology nodes forming one graph rooted at Heterozygous BRPF1 Loss-of-Function Variation, running through BRPF1 haploinsufficiency, impaired BRPF1-KAT6 complex function, and the parallel H3K23 acetylation and propionylation deficits to chromatin/transcriptional dysregulation and then to cortical neurogenesis, dendrite/spine, excitatory and inhibitory synaptic, learning-and-memory, and hematopoietic arms; two mechanistic_hypotheses (CANONICAL H3K23 acetylation loss, EMERGING H3K23 propionylation loss); 26 phenotypes with HPO bindings and frequency bands only where a published numerator/denominator exists; a genetic section with variant spectrum, inheritance, and gonadal mosaicism; two diagnosis entries; six treatments including an explicitly-caveated preclinical acylation-restoration entry; seven differential diagnoses covering the KAT6A, KAT6B, SETD5, 3p25.3, BPES and Noonan neighbours; a harrisons_chapter classifications block; and a HUMAN_MODEL_MISMATCH discussion on the mouse-null versus human-heterozygous zygosity gap. Named-entity-confusion discipline was applied throughout because BRPF1 is the scaffold of the KAT6A/KAT6B complexes: every clinical citation was checked to confirm the described patients carry BRPF1 variants, and KAT6A/KAT6B entities appear only as differentials. Validation: 'just validate' passes clean (schema, term, and reference validation) with 115/115 snippets verified against cached references; 'just compliance' reports 96.4 percent global / 96.8 percent weighted.

Claude Code ▸

BRPF1-Related Intellectual Disability (IDDDFP) — Comprehensive Research Report

claude-haiku-4-5-20251001, claude-opus-5[1m] 19 citations 2026-07-31T22:54:21.555085

BRPF1-Related Intellectual Disability (IDDDFP) — Comprehensive Research Report

Prepared: 2026-07-31 | Target for KB entry: BRPF1-Related_Intellectual_Disability

Verification note for curators: Every abstract quote below was transcribed verbatim from the NCBI E-utilities efetch output for the stated PMID. Every HPO/MONDO/GO/UBERON identifier suggested was checked against the HPO API (ontology.jax.org), OLS4, or UniProt. Where a claim could not be sourced to a citable abstract, it is explicitly flagged as [not verifiable / gap] rather than given a citation. Per the DR guardrails in CLAUDE.md, treat this document as leads: re-run just fetch-reference PMID:X and just validate-references before committing any snippet.

1. Disease Information

1.1 Overview

BRPF1-Related Intellectual Disability — formally Intellectual Developmental Disorder with Dysmorphic Facies and Ptosis (IDDDFP) — is a rare autosomal dominant neurodevelopmental syndrome caused by heterozygous loss-of-function variants in BRPF1, a multivalent chromatin-reader/scaffold protein that assembles and activates the KAT6A/KAT6B (MOZ/MORF) lysine acetyltransferase complexes. The disorder is a chromatinopathy: haploinsufficiency reduces histone H3 lysine-23 (H3K23) acetylation and propionylation, deregulating developmental transcriptional programs.

The core clinical triad is developmental delay / mild-to-moderate intellectual disability + prominent speech and language impairment + ptosis/blepharophimosis with characteristic facial dysmorphism. Relative to other monogenic chromatin-related neurodevelopmental disorders, cognition and adaptive behavior are comparatively preserved, while speech/language involvement is near-universal.

Yan et al. (2017) established the disorder (PMID:27939640):

"Here, we describe an intellectual disability disorder in ten individuals with inherited or de novo monoallelic BRPF1 mutations. Symptoms include infantile hypotonia, global developmental delay, intellectual disability, expressive language impairment, and facial dysmorphisms. Central nervous system and spinal abnormalities are also seen in some individuals."

"These data indicate that aberrations in the chromatin regulator gene BRPF1 cause histone H3 acetylation deficiency and a previously unrecognized intellectual disability syndrome." — PMID:27939640

1.2 Key identifiers

Resource	Identifier	Label
MONDO	MONDO:0015022	intellectual developmental disorder with dysmorphic facies and ptosis
OMIM (phenotype)	617333	INTELLECTUAL DEVELOPMENTAL DISORDER WITH DYSMORPHIC FACIES AND PTOSIS; IDDDFP
OMIM (gene)	602410	BROMODOMAIN- AND PHD FINGER-CONTAINING PROTEIN; BRPF1
Orphanet	ORPHA:698090	Ophthalmological abnormalities-facial dysmorphism-intellectual disability syndrome
UMLS	C4310617	—
MedGen	934584	—
HGNC	HGNC:14255 (`hgnc:14255`)	BRPF1 — bromodomain and PHD finger containing 1
NCBI Gene	7862	BRPF1
Ensembl	ENSG00000156983	BRPF1
UniProt	P55201	Peregrin (BRPF1)
RefSeq	NM_001003694 (also NM_004634.3 used clinically)	—
Cytoband	3p25.3	—
ICD-10 / ICD-11	Not assigned a specific code in Orphanet's cross-reference set [gap]; typically coded under generic ID / congenital malformation syndrome codes	—
MeSH	No specific descriptor [gap]	—

MONDO cross-reference set retrieved from OLS4 (MONDO:0015022 → OMIM:617333, Orphanet:698090, UMLS:C4310617, MedGen:934584). Orphanet identity confirmed via api.orphadata.com/rd-cross-referencing/orphacodes/698090, which reports disorder type "Malformation syndrome" and an exact, validated OMIM:617333 mapping.

1.3 Synonyms and alternative names

Intellectual Developmental Disorder with Dysmorphic Facies and Ptosis (IDDDFP) — OMIM/MONDO preferred
BRPF1-related neurodevelopmental disorder — Orphanet synonym
Ophthalmological abnormalities–facial dysmorphism–intellectual disability syndrome — Orphanet preferred term
BRPF1-related disorder / BRPF1-associated syndrome — literature usage (PMID:38346666; PMID:35243762)
BRPF1 haploinsufficiency syndrome

⚠️ NEC (Named Entity Confusion) preflight note. BRPF1 sits in a family of closely related chromatin disorders with overlapping names — KAT6A syndrome (MONDO distinct), KAT6B-related Genitopatellar and Say-Barber-Biesecker-Young-Simpson syndromes, and the 3p25.3 microdeletion syndrome (which spans both BRPF1 and SETD5). It also phenocopies Noonan syndrome (PMID:41137536) and blepharophimosis-ptosis-epicanthus-inversus syndrome (FOXL2). Before accepting any deep-research report on this disease, confirm the report's dominant gene is BRPF1, and that the OMIM ID is 617333 (not 601358/KAT6A, 603736/KAT6B, or 110100/BPES). Run uv run runoak -i sqlite:obo:mondo info MONDO:0015022 -O obo.

1.4 Information provenance

Disease-level (aggregated) resources — OMIM, Orphanet, MONDO, ClinGen, HPO annotations — plus individual-patient case series and cohorts. There is no EHR-derived or registry-derived cohort for this disorder. The largest single patient-level source is Colson et al. 2025 (PMID:39837771, 29 new patients from 20 families + literature review). Deep-phenotyping sources: PMID:38346666 (15 participants, speech/language) and PMID:38590032 (ophthalmic OCT deep phenotyping).

2. Etiology

2.1 Disease causal factors

Genetic, monogenic, autosomal dominant. The sole established cause is heterozygous loss-of-function of BRPF1. The mechanism is haploinsufficiency — not gain of function or dominant negative — established by three converging lines of evidence:

Variant spectrum: the overwhelming majority of pathogenic variants are protein-truncating (nonsense, frameshift, canonical splice) plus whole-gene deletions (PMID:39837771).
ClinGen Dosage Sensitivity curation: haploinsufficiency score 3 (Sufficient Evidence for Haploinsufficiency); triplosensitivity score 0 (No Evidence); curated 2023-08-23 against MONDO:0015022 / OMIM:617333 (CGDS:HGNC_14255, ClinGen curation CCID:006763). ClinGen's summary: "Numerous loss-of-function mutations have been reported in intellectual developmental disorder with dysmorphic facies and ptosis (IDDDFP) patients, and functional analyses support a haploinsufficiency of the BRPF1 gene."
Functional assays: patient variants impair H3K23 acetylation (PMID:27939640) and H3K23 propionylation (PMID:32010779), and Brpf1 heterozygous mice recapitulate the cognitive phenotype (PMID:31213987).

ClinGen also records a Gene-Disease Validity classification for BRPF1; GenCC aggregates it as Definitive/Strong.

2.2 Risk factors

Genetic risk factors (causal): - De novo heterozygous BRPF1 LoF variants — the majority of cases. - Inherited variants from a mildly affected parent — well documented; five of 20 families in the 2025 cohort showed two-generation transmission (PMID:39837771). Multiplex families are reported: a 5-member family with c.1052_1053del (PMID:27939639) and a 4-member family with c.556C>T p.Q186 (PMID:31020800). - Contiguous 3p25.3 deletions encompassing BRPF1 (± SETD5*) — see §4.6.

Environmental risk factors: None identified. This is a fully penetrant-mechanism Mendelian chromatinopathy with no reported environmental, occupational, toxin, infectious, dietary, parental-age, or lifestyle risk contribution. Advanced paternal age is a generic risk factor for de novo point mutations across all dominant disorders, but has not been specifically studied in BRPF1 [gap].

Sex: Male predominance is observed in reported series (e.g. 10/15 male in PMID:38346666), but this is likely ascertainment bias, not a biological sex effect. No sex-linked mechanism exists (autosomal gene) [interpretive; not directly asserted in any abstract].

2.3 Protective factors

No genetic or environmental protective factors are established. Notably, however, there is documented variable expressivity extending to normal cognition — PMID:35243762 reports "a patient with normal intellectual development who had congenital ptosis, hypotonia, muscular weakness, atlanto-axial malformation, and pyramidal at the neurological examination," carrying "a rare nonsense variant on exon 3 of BRPF1 gene." The genetic or environmental modifiers underlying this preservation are unknown [gap — high-value research question].

A therapeutic (not protective-in-the-epidemiologic-sense) lead exists: short-chain fatty acids and HDAC inhibitors boost the deficient mark — see §12.

2.4 Gene–environment interactions

None described. No GxE studies exist for BRPF1. A mechanistically plausible but entirely untested hypothesis is that dietary short-chain fatty acid (propionate/butyrate) availability could modulate residual H3K23 acylation, given PMID:32010779's finding that "Valproate, vorinostat, propionate and butyrate promote H3K23 acylation." [hypothesis only — no human or animal GxE data]

3. Phenotypes

3.1 Frequency table — the primary evidence base

The best frequency source is Colson et al. 2025 (PMID:39837771), which reports 29 new patients (20 families) and a literature comparison cohort (~50 previously published cases). Frequencies differ substantially between the two — the newer prospectively phenotyped cohort shows lower rates of ID, speech delay, motor delay, microcephaly, short stature, and feeding difficulty, consistent with ascertainment bias in earlier case reports toward more severely affected individuals. Curators should record both and prefer the combined view.

Phenotype	New cohort (2025)	Literature cohort	Suggested HPO term	Suggested `FrequencyEnum`
Speech / language delay	13/28 (46%)	41/50 (82%)	HP:0000750 Delayed speech and language development	VERY_FREQUENT
Global developmental delay	—	10/10 (HPOA)	HP:0001263 Global developmental delay	VERY_FREQUENT
Motor delay	15/29 (52%)	39/49 (80%)	HP:0002194 Delayed gross motor development	FREQUENT
Intellectual disability	16/29 (55%); mild 6/16, moderate 10/16	35/49 (71%)	HP:0001249 Intellectual disability	FREQUENT
Ptosis	20/29 (69%)	6/10 (HPOA)	HP:0000508 Ptosis	FREQUENT
Behavioural disorder (any)	18/29 (62%)	—	HP:0000708 Behavioral abnormality	FREQUENT
Round face	17/27 (63%)	7/10 (HPOA)	HP:0000311 Round face	FREQUENT
Bulbous nose	14/28 (50%)	—	HP:0000414 Bulbous nose	FREQUENT
Wide/broad nasal bridge	—	9/10 (HPOA)	HP:0000431 Wide nasal bridge	VERY_FREQUENT
Hypertelorism	14/29 (48%)	9/10 (HPOA)	HP:0000316 Hypertelorism	FREQUENT
Strabismus	13/27 (48%)	2/10 (HPOA)	HP:0000486 Strabismus	FREQUENT
High palate	14/29 (48%)	—	HP:0000218 High palate	FREQUENT
Hypotonia	11/29 (40%)	7/8 (HPOA)	HP:0001252 Hypotonia	FREQUENT
Epicanthus	12/29 (41%)	—	HP:0000286 Epicanthus	FREQUENT
Retrognathia	12/29 (41%)	—	HP:0000278 Retrognathia	FREQUENT
Hair abnormality (any)	12/29 (41%) [novel]	—	HP:0001595 Abnormal hair morphology	FREQUENT
Synophrys	10/28 (36%) [novel]	—	HP:0000664 Synophrys	FREQUENT
Blepharophimosis	10/29 (34%)	4/8 (HPOA)	HP:0000581 Blepharophimosis	FREQUENT
ADHD	9/27 (33%)	—	HP:0007018 Attention deficit hyperactivity disorder	FREQUENT
Gastroesophageal reflux	9/29 (31%)	—	HP:0002020 Gastroesophageal reflux	FREQUENT
Sleep disturbance	9/29 (31%)	—	HP:0002360 Sleep disturbance	FREQUENT
Hypertrichosis	9/29 (31%) [novel]	—	HP:0000998 Hypertrichosis	FREQUENT
Low hanging columella	9/29 (31%) [novel]	—	HP:0009765 Low hanging columella	FREQUENT
Clinodactyly of 5th finger	8/27 (30%)	—	HP:0004209 Clinodactyly of the 5th finger	FREQUENT
Low frustration tolerance	8/28 (29%)	—	HP:0000722 Obsessive-compulsive behavior (no exact term — use free-text)	FREQUENT
Palpebral edema	8/29 (28%) [novel]	—	HP:0100540 Palpebral edema	OCCASIONAL
Laterally extended eyebrows	8/29 (28%) [novel]	—	HP:0011230 Laterally extended eyebrow	OCCASIONAL
Distal joint laxity	7/27 (26%)	6/10 joint hypermobility (HPOA)	HP:0001388 Joint laxity / HP:0001382 Joint hypermobility	OCCASIONAL
Refractive error	7/29 (24%) — myopia 5/29 (17%), hypermetropia 2/29 (7%)	—	HP:0000539 Abnormality of refraction; HP:0000545 Myopia; HP:0000540 Hypermetropia	OCCASIONAL
Prominent fingertip pads	6/27 (22%)	—	HP:0001212 Prominent fingertip pads	OCCASIONAL
Anxiety	6/29 (21%)	—	HP:0000739 Anxiety	OCCASIONAL
Short stature	6/29 (21%)	17/42 (40%)	HP:0004322 Short stature	OCCASIONAL–FREQUENT
Cryptorchidism	5/27 (19%) [not previously reported]	—	HP:0000028 Cryptorchidism	OCCASIONAL
Epicanthus inversus	5/29 (17%)	—	HP:0000537 Epicanthus inversus	OCCASIONAL
Small hands	4/23 (17%)	—	HP:0200055 Small hand	OCCASIONAL
Autistic behavior	4/26 (15%)	—	HP:0000729 Autistic behavior	OCCASIONAL
Broad hallux	4/27 (15%)	—	HP:0010055 Broad hallux	OCCASIONAL
Seizures	4/29 (14%)	5/10 (HPOA)	HP:0001250 Seizure	OCCASIONAL–FREQUENT
Obesity	4/28 (14%)	—	HP:0001513 Obesity	OCCASIONAL
Constipation	4/29 (14%)	—	HP:0002019 Constipation	OCCASIONAL
Recurrent infections	4/28 (14%)	—	HP:0002719 Recurrent infections	OCCASIONAL
Inappropriate laughter	4/25 (14%)	—	HP:0000748 Inappropriate laughter	OCCASIONAL
Feeding difficulties	3/26 (12%)	24/42 (57%)	HP:0011968 Feeding difficulties	OCCASIONAL–FREQUENT
Agenesis of corpus callosum	2/17 with MRI (12%)	1/7 thin CC (HPOA)	HP:0001274 Agenesis of corpus callosum; HP:0033725 Thin corpus callosum	OCCASIONAL
Facial asymmetry	3/28 (11%)	—	HP:0000324 Facial asymmetry	OCCASIONAL
Amblyopia	3/29 (10%)	—	HP:0000646 Amblyopia	OCCASIONAL
Hematologic abnormality (anemia, thrombocytopenia)	2/25 (8%)	—	HP:0001903 Anemia; HP:0001873 Thrombocytopenia	OCCASIONAL
Microcephaly	2/29 (7%)	14/52 (27%)	HP:0000252 Microcephaly	OCCASIONAL
Nystagmus	2/29 (7%)	—	HP:0000639 Nystagmus	OCCASIONAL
Laryngomalacia	2/28 (7%)	—	HP:0001601 Laryngomalacia	OCCASIONAL
White matter hyperintensities	1/17 (6%)	1/7 (HPOA)	HP:0030890 Hyperintensity of cerebral white matter on MRI	OCCASIONAL
Cardiac defect	1/25 (4%)	subset (PMID:32010779)	HP:0001627 Abnormal heart morphology	OCCASIONAL

HPOA-only features (from ontology.jax.org/api/network/annotation/OMIM:617333, derived from the original OMIM curation, not in the 2025 cohort):

HPO ID	Term	HPOA frequency
HP:0001762	Talipes equinovarus	10/20
HP:0000343	Long philtrum	10/20
HP:0012368	Flat face	7/9
HP:0010862	Delayed fine motor development	6/8
HP:0031936	Delayed ability to walk	5/9
HP:0004602	Cervical C2/C3 vertebral fusion	3/10
HP:0000322	Short philtrum	3/10
HP:0000337	Broad forehead	3/10
HP:0000160	Narrow mouth	3/10
HP:0000494	Downslanted palpebral fissures	4/10
HP:0034295	Reduced cerebral white matter volume	2/10
HP:0000369	Low-set ears	2/10
HP:0001511	Intrauterine growth retardation	2/20
HP:0002714	Downturned corners of mouth	1/10
HP:0000154	Wide mouth	1/10
HP:0012385	Camptodactyly	(no frequency)
HP:0001510	Growth delay	Occasional
HP:0003577 / HP:0003623	Congenital onset / Neonatal onset	10/10 / 4/4

3.2 Speech and language — the most consistent domain

PMID:38346666 provides the only systematic speech/language characterization (15 participants, median age 7y4m, 14 distinct variants):

"Language disorders were common (11/12), and most had mild to moderate deficits across receptive, expressive, written, and social-pragmatic domains. Speech disorders were frequent (7/9), including phonological delay (6/9) and disorder (3/9), and childhood apraxia of speech (3/9). All those tested for cognitive abilities had a FSIQ ≥70 (4/4). Participants had vision impairment (13/15), fine (8/15) and gross motor delay (10/15) which often resolved in later childhood, infant feeding impairment (8/15), and infant hypotonia (9/15)."

"We have implicated BRPF1-related disorder as causative for speech and language disorder, including childhood apraxia of speech. Adaptive behavior and cognition were strengths when compared to other monogenic neurodevelopmental chromatin-related disorders. The universal involvement of speech and language impairment is noteable, relative to the high degree of phenotypic variability in BRPF1-related disorder." — PMID:38346666

Suggested HPO terms: HP:0000750 Delayed speech and language development; HP:0011098 Speech apraxia (childhood apraxia of speech; verified label is "Speech apraxia"); HP:0002465 Poor speech.

Two curation-relevant nuances from this paper: - Vision impairment 13/15 (87%) — the highest ocular frequency in any series. - Motor delay is often transient ("which often resolved in later childhood") — argues for clinical_course annotation rather than PROGRESSIVE.

3.3 Ophthalmological phenotype — the syndrome's signature

Ocular involvement is the defining feature and is why Orphanet names the syndrome "Ophthalmological abnormalities–facial dysmorphism–intellectual disability syndrome." Mattioli et al. established that this arm is specifically BRPF1-driven within the 3p25 contiguous deletion:

"We conclude that both genes contribute to the phenotypic severity of 3p25 deletion syndrome but that some specific features, such as ptosis and blepharophimosis, are mostly driven by BRPF1 haploinsufficiency." — PMID:27939639

An important 2024 expansion added subclinical optic neuropathy, detectable only on OCT (PMID:38590032):

"Interestingly, P1 had a Chiari Malformation type I and a subclinical optic neuropathy, which could not be explained by variations in other genes. Having detected a peculiar ocular phenotype in P1, we suggested optical coherence tomography (OCT) for P2; such an exam also detected bilateral subclinical optic neuropathy in this case. To date, only a few patients with BRPF1 variants have been described, and none were reported to have optic neuropathy. Since subclinical optic nerve alterations can go easily undetected, our experience highlights the importance of a more detailed ophthalmologic evaluation in patients with BRPF1 variant."

Additional HPO terms: HP:0001098 Abnormal fundus morphology / HP:0000648 Optic atrophy (for optic neuropathy — no exact "subclinical optic neuropathy" term exists; use a more specific preferred_term per the dismech convention); HP:0007099 Chiari type I malformation.

3.4 Phenotype characteristics (onset, severity, progression)

Age of onset: Congenital / neonatal — HPOA records HP:0003577 Congenital onset 10/10 and HP:0003623 Neonatal onset 4/4. Ptosis is congenital (PMID:35243762). Hypotonia and feeding difficulty present in infancy (PMID:38346666).
Severity: Predominantly mild to moderate. PMID:39837771: "Neuropsychological assessment reveals a predominance of mild to moderate ID, with cognitive profiles showing variability in verbal and visual processing." In the 2025 cohort, of 16 with ID, 6 were mild and 10 moderate — no severe/profound ID reported. PMID:38346666: FSIQ ≥70 in all 4 formally tested.
Progression: Non-progressive / static. This is a developmental (neurodevelopmental) disorder, not a neurodegenerative one. Motor delay frequently improves ("often resolved in later childhood," PMID:38346666). No abstract reports regression or neurodegeneration. Curate as clinical_course: STABLE for the neurological phenotype, not PROGRESSIVE.
Variable expressivity: Marked, including intrafamilial. PMID:39837771: "Among the five families reported here, phenotypic differences were observed between family members carrying the same pathogenic variant, affecting intellectual ability, dysmorphic features and malformations, suggesting an intrafamilial variability." At the extreme, PMID:35243762 reports normal intellect with isolated congenital ptosis and neurological signs.

3.5 Quality of life impact

No disease-specific QoL instrument, EQ-5D, SF-36, or PROMIS data exist for BRPF1-related disorder [gap]. Per-phenotype functional impact can be inferred:

Speech/language disorder + childhood apraxia of speech — the dominant functional burden; drives communication, literacy ("written" domain affected), and social-pragmatic participation (PMID:38346666).
Ptosis/blepharophimosis — visual-axis obstruction risk, amblyopia (3/29), plus cosmetic/psychosocial impact; surgically correctable.
Vision impairment (13/15) — affects learning and mobility.
Behavioral phenotype (62% any; ADHD 33%, anxiety 21%, sleep disturbance 31%) — significant caregiver burden.
Adaptive behavior is a relative strength — PMID:38346666: "Adaptive behavior and cognition were strengths when compared to other monogenic neurodevelopmental chromatin-related disorders." This is an important positive prognostic message.

4. Genetic / Molecular Information

4.1 Causal gene

BRPF1 (bromodomain and PHD finger containing 1), hgnc:14255, 3p25.3, OMIM 602410, Ensembl ENSG00000156983, NCBI Gene 7862. Protein: Peregrin, UniProt P55201, 1,214 aa, ~137.5 kDa. Clinical transcript commonly NM_004634.3; also NM_001003694 (RefSeq Select). Note the literature also uses ENST00000383829.

Domain architecture (UniProt P55201, verified):

Feature	Positions
C2H2-type zinc finger	21–47
PHD-type zinc finger 1	273–323
C2HC pre-PHD-type zinc finger	327–360
PHD-type zinc finger 2	384–448
Bromodomain	628–732
PWWP domain	1,085–1,168

PMID:27939640 describes this as "a multivalent chromatin regulator possessing three histone-binding domains, one non-specific DNA-binding module, and several motifs for interacting with and activating three lysine acetyltransferases."

4.2 Pathogenic variants — spectrum

Classification & mechanism: Pathogenic/likely pathogenic per ACMG/AMP, mechanism loss of function / haploinsufficiency (ClinGen HI score 3).

Variant types. From the 29-patient / 17-unique-variant 2025 cohort (PMID:39837771):

Type	Count	Examples (protein)
Frameshift	7	p.(Asp190MetfsTer14), p.(Ala396LeufsTer69), p.(Ser660ArgfsTer2), p.(Arg593AlafsTer5), p.(Leu779CysfsTer14), p.(Tyr387LeufsTer79), p.(Lys820ArgfsTer2)
Nonsense	4	p.(Gln302Ter), p.(Ser1007Ter), p.(Arg251Ter), p.(Gln645Ter)
Missense	2	p.(Cys23Arg), p.(Arg548Trp) — both at conserved residues
Canonical splice	2	c.599+1G>T, c.2311+1G>A
Whole-gene deletion	2	—

Landmark individual variants (well-documented, good for KB evidence anchors):

Variant	Consequence	Context	PMID
c.1052_1053del	p.Val351Glyfs*8	5 affected members, large AD family; index variant of Mattioli et al.	27939639
c.556C>T	p.Gln186 (p.Q186)	4 affected members, multiplex Jewish family	31020800
c.1433G>A	p.Trp478 (p.W478), exon 3	First Turkish family; anemia + thrombocytopenia	37190896
c.1054G>C	p.Val352Leu, exon 3	Novel missense, Saudi family; absent in 100 ethnically matched controls	32457794

Original series composition: Yan et al. reported 10 individuals from 9 unrelated families with 1 missense, 3 nonsense, and 6 frameshift variants; Mattioli et al. reported the index family plus "BRPF1 deletions or point mutations in six additional individuals with a similar phenotype" (PMID:27939639). Yan et al. 2020 added "BRPF1 variants in 12 previously unidentified cases of syndromic intellectual disability" (PMID:32010779).

Total reported cases: Orphanet's epidemiology record cites 79 cases (worldwide, validated, "Cases/families"). PMID:39837771 adds 29 new patients on top of "over 50 previously published cases."

Somatic vs germline: IDDDFP variants are germline (de novo or inherited). BRPF1 also carries somatic mutations in cancer — "the BRPF1 gene is mutated in childhood leukemia and adult medulloblastoma" (PMID:25920810) — and "H3K23 acylation is also impaired by cancer-derived somatic BRPF1 mutations" (PMID:32010779). These are mechanistically related but a distinct disease context; do not conflate them in the disorder entry.

4.3 Population allele frequency and constraint

gnomAD constraint: BRPF1 is highly LoF-constrained — pLI = 1, LOEUF ≈ 0.21. (Retrieved via web search; the gnomAD GraphQL endpoint requires POST and could not be queried directly. Curators should re-verify the exact pLI/LOEUF/o-e values against gnomAD v4 before citing.)
DECIPHER Haploinsufficiency Index (%HI): 15.78 (lower = more haploinsufficient), per the ClinGen gene page.
Pathogenic BRPF1 LoF variants are absent or vanishingly rare in gnomAD — consistent with pLI 1. PMID:32457794 independently excluded their missense variant in 100 ethnically matched controls by Sanger sequencing.
ClinVar: 577 total submitted BRPF1 variant records; 269 with a pathogenic or likely pathogenic clinical significance assertion (NCBI E-utilities esearch db=clinvar, retrieved 2026-07-31). Note: the P/LP count includes multi-gene CNV records overlapping BRPF1, so it overstates the number of BRPF1-specific sequence-level P/LP variants — do not quote it as "269 pathogenic BRPF1 variants."

4.4 Functional consequences

Loss of function is the established mechanism. For the index frameshift, PMID:27939639 found: "The mRNA transcript was not significantly reduced in affected fibroblasts and most likely produces a truncated protein (p.Val351Glyfs8). The protein variant shows an aberrant cellular location, loss of certain protein interactions, and decreased histone H3K23 acetylation." — i.e. the truncated protein escapes nonsense-mediated decay* but is functionally null/mislocalized.
Molecular readouts of pathogenicity: reduced H3K23 acetylation (PMID:27939640; PMID:27939639) and reduced H3K23 propionylation (PMID:32010779). Both are usable as functional assays.
Mislocalization: nuclear localization of BRPF1 depends on KAT6A, ING5, and MEAF6 (UniProt P55201); truncating variants that remove interaction motifs mislocalize.

4.5 Modifier genes

No validated modifier genes. The strongest candidate is the neighboring SETD5 in contiguous deletions (§4.6) — a contiguous-gene effect rather than a true modifier. Intrafamilial variability with an identical variant (PMID:39837771) implies unidentified genetic and/or stochastic modifiers [gap — explicit open question].

4.6 Chromosomal abnormalities — the 3p25 / 3p25.3 deletion connection

BRPF1 lies within the 3p25 deletion syndrome region, adjacent to SETD5. Mattioli et al. dissected the contributions (PMID:27939639):

"Deletions of the 3p25 region, containing BRPF1 and SETD5, cause a defined ID syndrome where most of the clinical features are attributed to SETD5 deficiency. We compared the clinical symptoms of individuals carrying mutations or small deletions of BRPF1 alone or SETD5 alone with those of individuals with deletions encompassing both BRPF1 and SETD5. We conclude that both genes contribute to the phenotypic severity of 3p25 deletion syndrome but that some specific features, such as ptosis and blepharophimosis, are mostly driven by BRPF1 haploinsufficiency."

This is a strong candidate for a dismech Grouping or comorbidity/contiguous-gene entry — it is a clean worked example of dissecting a contiguous-gene syndrome into per-gene phenotype attribution.

Whole-gene BRPF1 deletions were also recovered from exome CNV analysis in a dystonia cohort (PMID:33611074) — "Within the deletion intervals, BRPF1, CHD8, DJ1, EFTUD2, FGF14, GCH1, PANK2, SGCE, UBE3A, VPS16, WARS2, and WDR45 were determined as the most clinically relevant genes" — indicating BRPF1 CNVs are detectable by exome read-depth analysis (ExomeDepth).

4.7 Epigenetic information

BRPF1 is itself an epigenetic regulator; the disease is an epigenetic lesion (see §6). Two curation-relevant points:

Histone acylation marks affected: H3K23ac and H3K23pr (propionylation). PMID:32010779 reports the propionylation discovery: "We report that these complexes also catalyze H3K23 propionylation in vitro and in vivo. Immunofluorescence microscopy and ATAC-See revealed the association of this modification with active chromatin."
DNA methylation episignature: Distinct EpiSign episignatures are established for KAT6A and for the two KAT6B disorders (PMID:37249002). A BRPF1-specific DNA methylation episignature has not been reported [gap]. Given BRPF1's obligate partnership with KAT6A/KAT6B, testing whether BRPF1 patients carry a shared or distinct episignature is a high-value, tractable research question — and would be diagnostically useful for VUS resolution. Do not curate a BRPF1 episignature as if it exists.

5. Environmental Information

Environmental factors: None. No toxin, radiation, pollution, or occupational exposure is implicated.
Lifestyle factors: None implicated in causation. (Diet is relevant only as a speculative therapeutic lever — §12.)
Infectious agents: None. Not applicable.

Recurrent infections were noted in 4/28 (14%) of the 2025 cohort (PMID:39837771), but these are a consequence of the disorder (possibly related to the hematopoietic/immune arm), not an etiologic environmental factor.

6. Mechanism / Pathophysiology

6.1 Causal chain (upstream → downstream)

[MOLECULAR] Heterozygous BRPF1 loss-of-function variant (3p25.3)
↓
[MOLECULAR] BRPF1 haploinsufficiency — reduced scaffold available to assemble
    KAT6A/KAT6B(/KAT7)–BRPF1–ING4/5–MEAF6 tetrameric HAT complexes
↓
[MOLECULAR] Impaired complex assembly, substrate targeting, and enzymatic
    stimulation; mislocalization of truncated protein
↓
[MOLECULAR] Deficient histone H3K23 acetylation AND H3K23 propionylation
    at active chromatin / transcription start sites
↓
[CELLULAR] Deregulated transcription of developmental programs
   (Hox cluster, Robo3, Otx1, Pitx2, Hmx1, Pax6, Runx1/2,
    multipotency genes Slamf1/Mecom/Hoxa9/Hlf/Gfi1/Egr/Gata3)
↓
   ┌───────────────────────┬──────────────────────┬─────────────────────┐
   ↓                       ↓                      ↓                     ↓
[CELLULAR]            [CELLULAR]             [CELLULAR]           [CELLULAR]
Reduced Tbr2+          Reduced dendritic      Impaired GABAergic   Impaired HSC/
intermediate           arborization &         interneuron          progenitor
neuronal progenitors;  spine density;         excitability         self-renewal;
aberrant neurogenesis  altered spine/synapse  (↑ firing threshold, ↑ROS, senescence,
       morphology             ↓ mIPSC amplitude)   apoptosis
   ↓                       ↓                      ↓                     ↓
[TISSUE] Neocortical   [TISSUE] ↓ excitatory  [TISSUE] E/I         [TISSUE] Marrow
abnormality; partial   synaptic transmission  imbalance in         hypoplasia
callosal agenesis      (↓ mEPSC freq & amp)   cortex/hippocampus   (mouse KO)
   ↓                       ↓                      ↓                     ↓
   └───────────────────────┴──────────────────────┘                     ↓
           ↓                                            ↓
[ORGANISM] Intellectual disability, speech/language              [ORGANISM] Anemia,
disorder, hypotonia, seizures, behavioral phenotype               thrombocytopenia
                                                  (rare in humans)

  ‖ parallel developmental arm ‖
[CELLULAR] Deregulated Pitx2/Hmx1/Pax6 in ocular/craniofacial primordia
↓
[TISSUE] Abnormal periocular and craniofacial morphogenesis
↓
[ORGANISM] Ptosis, blepharophimosis, strabismus, optic neuropathy,
   characteristic facial dysmorphism

6.2 Molecular pathways

Primary pathway: MOZ/MORF (KAT6A/KAT6B) histone acetyltransferase complex — lysine acetylation and acylation of histone H3.

BRPF1 is the obligate scaffold. PMID:36077605:

"It functions in the form of a tetrameric complex with a monocytic leukemia zinc finger protein (MOZ or KAT6A), MOZ-related factor (MORF or KAT6B) or HAT bound to ORC1 (HBO1 or KAT7) and two small non-catalytic proteins, the inhibitor of growth 5 (ING5) or the paralog ING4 and MYST/Esa1-associated factor 6 (MEAF6)."

BRPF1's four functions within the complex (PMID:24646517):

"Within these complexes, BRPF1 serves as a scaffold for bridging subunit interaction, stimulating acetyltransferase activity, governing substrate specificity and stimulating gene expression."

Trithorax-group / Hox maintenance pathway. From zebrafish (PMID:18469222):

"brpf1 mutants display anterior transformations of pharyngeal arches due to progressive loss of anterior Hox gene expression. Brpf1 functions in association with the histone acetyltransferase Moz (Myst3), an interaction mediated by the N-terminal domain of Brpf1, and promotes histone acetylation in vivo. Brpf1 recruits Moz to distinct sites of active chromatin and remains at chromosomes during mitosis, mediated by direct histone binding of its bromodomain, which has a preference for acetylated histones, and its PWWP domain, which binds histones independently of their acetylation status. This is the first demonstration of histone binding for PWWP domains."

Emerging: 3D genome / loop-extrusion interplay. A 2025 bioRxiv CRISPR screen implicates the MORF complex including Brpf1 in antagonizing CTCF/cohesin insulation (PMID:40060486): "Among them were the MORF acetyltransferase complex members (Kat6b, Ing5, Brpf1), which could antagonize the transcriptional insulation mediated by CTCF and cohesin complex at developmental genes." [preprint; not peer-reviewed — mark as EMERGING hypothesis if curated]

Suggested GO terms (biological process):

GO ID	Label	Modifier
GO:0016573	histone acetylation	DECREASED
GO:0043966	histone H3 acetylation	DECREASED
GO:0006355	regulation of DNA-templated transcription	ABNORMAL
GO:0045893	positive regulation of DNA-templated transcription	DECREASED
GO:0007399	nervous system development	ABNORMAL
GO:0021895	cerebral cortex neuron differentiation	DECREASED
GO:0048813	dendrite morphogenesis	DECREASED
GO:0060996	dendritic spine development	DECREASED
GO:0007268 / GO:0060079	chemical synaptic transmission / excitatory postsynaptic potential	DECREASED
GO:0060080	inhibitory postsynaptic potential	DECREASED
GO:0030097	hemopoiesis	DECREASED
GO:0001525	angiogenesis (vascular defects in KO)	ABNORMAL
GO:0001843	neural tube closure	ABNORMAL

Suggested GO molecular function terms (UniProt P55201, verified): GO:0010698 acetyltransferase activator activity; GO:0140566 histone reader activity; GO:0003677 DNA binding.

Suggested GO cellular component terms (verified): GO:0070776 MOZ/MORF histone acetyltransferase complex (the most specific and informative), GO:0000123 histone acetyltransferase complex, GO:0005634 nucleus.

6.3 Cellular processes

Neurodevelopmental (cortex/hippocampus). Forebrain-conditional KO (PMID:25568313):

"Here, we report that forebrain-specific inactivation of the mouse Brpf1 gene caused early postnatal lethality, neocortical abnormalities, and partial callosal agenesis. With respect to the control, the mutant forebrain contained fewer Tbr2-positive intermediate neuronal progenitors and displayed aberrant neurogenesis. Molecularly, Brpf1 loss led to decreased transcription of multiple genes, such as Robo3 and Otx1, important for neocortical development. Surprisingly, elevated expression of different Hox genes and various other transcription factors, such as Lhx4, Foxa1, Tbx5, and Twist1, was also observed. These results thus identify an important role of Brpf1 in regulating forebrain development and suggest that it acts as both an activator and a silencer of gene expression in vivo."

Synaptic / dendritic (the haploinsufficiency-specific model — most disease-relevant). PMID:31213987:

"Brpf1 heterozygotes showed reduced dendritic complexity in both hippocampal granule cells and cortical pyramidal neurons, accompanied by reduced spine density and altered spine and synapse morphology. An in vitro study of Brpf1 haploinsufficiency also demonstrated decreased frequency and amplitude of miniature EPSCs that may subsequently contribute to abnormal behaviors, including decreased anxiety levels and defective learning and memory."

Excitatory transmission (hippocampus). PMID:34485298:

"We found that mild knockdown of Brpf1 reduced mEPSC frequency of cultured hippocampal neurons, before any significant changes of dendritic morphology showed. We also found that Brpf1 mild knockdown in the hippocampus showed a decreasing trend on the spatial learning and memory ability of mice. Finally, mRNA-Seq analyses showed that genes related to learning, memory, and synaptic transmission (such as C1ql1, Gpr17, Htr1d, Glra1, Cxcl10, and Grin2a) were dysregulated upon Brpf1 knockdown."

Inhibitory transmission (GABAergic interneurons) — E/I imbalance. PMID:33744924:

"Moreover, increased firing threshold, decreased number of evoked action potentials, and a reduced amplitude of miniature inhibitory postsynaptic currents were observed before any significant change of MAP2+ dendritic morphology and in vivo migration ability appeared. Finally, mRNA-Seq analysis revealed that genes related to neurodevelopment and synaptic transmission such as Map2k7 were dysregulated. Our results demonstrated a key role of Brpf1 in inhibitory neurotransmission and related gene expression of GABAergic interneurons."

"Intellectual disability is closely related to impaired GABA neurotransmission. Brpf1 was specifically expressed in medial ganglionic eminence (MGE), a developmental niche of GABAergic interneurons, and patients with BRPF1 mutations showed intellectual disability." — PMID:33744924

Together, PMID:34485298 and PMID:33744924 establish a bidirectional excitation/inhibition disturbance — both excitatory (mEPSC) and inhibitory (mIPSC) synaptic transmission are attenuated. This is a candidate conformance point for epilepsy_excitation_inhibition_imbalance#Excitation-Inhibition Imbalance in the dismech module set (seizures 14–50%), though note the evidence is MODEL_ORGANISM/IN_VITRO, not human.

Hematopoietic. PMID:27500495:

"Brpf1-deficient pups experienced early lethality due to acute bone marrow failure and aplastic anemia. The mutant bone marrow and fetal liver exhibited severe deficiency in HSCs and hematopoietic progenitors, along with elevated reactive oxygen species, senescence, and apoptosis. BRPF1 deficiency also reduced the expression of multipotency genes, including Slamf1, Mecom, Hoxa9, Hlf, Gfi1, Egr, and Gata3. Furthermore, BRPF1 was required for acetylation of histone H3 at lysine 23, a highly abundant but not well-characterized epigenetic mark."

Cell cycle / proliferation / embryonic vascular development. PMID:25773539:

"Here we present systematic analyses of the mutant animals and demonstrate that the ablation leads to vascular defects in the placenta, yolk sac, and embryo proper, as well as abnormal neural tube closure. At the cellular level, Brpf1 loss inhibits proliferation of embryonic fibroblasts and hematopoietic progenitors. Molecularly, the loss reduces transcription of a ribosomal protein L10 (Rpl10)-like gene and the cell cycle inhibitor p27, and increases expression of the cell-cycle inhibitor p16 and a novel protein homologous to Scp3..."

Skeletal / osteoclast. BRPF bromodomain inhibition "impaired RANKL-induced differentiation of primary murine bone marrow cells and human primary monocytes into bone resorbing osteoclasts by specifically repressing transcriptional programs required for osteoclastogenesis" (PMID:28849908) — relevant to the skeletal features and to BRPF1's known role in "skeletal patterning" (PMID:36077605).

6.4 Protein dysfunction

Loss of a multivalent reader/scaffold, not an enzyme. The truncated protein escapes NMD but shows "aberrant cellular location, loss of certain protein interactions, and decreased histone H3K23 acetylation" (PMID:27939639). No misfolding/aggregation mechanism. Nuclear localization is dependent on KAT6A, ING5, and MEAF6 (UniProt P55201).

Interaction partners (UniProt P55201): KAT6A, KAT6B, KAT7/HBO1, ING5 (and paralog ING4), MEAF6, histones H2AC17 and H4C9.

6.5 Metabolic changes

No primary metabolic defect. One indirect but therapeutically important link: short-chain fatty acid (propionate, butyrate) metabolism intersects with H3K23 acylation, since propionyl-CoA is the donor for propionylation (PMID:32010779). This is a metabolism–epigenome coupling, not a metabolic disease. CHEBI terms: CHEBI:17272 propionate; CHEBI:17968 butyrate; CHEBI:39549 valproic acid; CHEBI:45716 vorinostat.

6.6 Immune system involvement

Not an immunologic disease. Two peripheral observations: recurrent infections in 4/28 (14%) (PMID:39837771), and the hematopoietic arm (bone marrow failure in mouse KO, PMID:27500495; anemia + thrombocytopenia in a human family, PMID:37190896). Whether human BRPF1 haploinsufficiency causes clinically meaningful immune dysfunction is unresolved [gap].

6.7 Tissue damage mechanisms

In the hematopoietic compartment, mouse KO shows elevated reactive oxygen species, senescence, and apoptosis (PMID:27500495). No oxidative-stress, ischemic, fibrotic, or necrotic mechanism is described in the CNS. The CNS phenotype is developmental (hypoplastic/miswired) rather than degenerative.

6.8 Biochemical abnormalities

The core biochemical lesion is a quantitative deficit in two histone acyl marks: - H3K23 acetylation ↓ (PMID:27939640, PMID:27939639, PMID:27500495) - H3K23 propionylation ↓ (PMID:32010779)

There is no measurable serum/urine biochemical abnormality; these are chromatin-level assays on patient fibroblasts/cells. No enzyme deficiency, receptor dysfunction, or ion-channel defect in the classical sense — though the functional consequence in neurons is altered excitability (PMID:33744924).

6.9 Molecular profiling

Transcriptomics: mRNA-Seq in Brpf1-knockdown hippocampal neurons — dysregulation of C1ql1, Gpr17, Htr1d, Glra1, Cxcl10, Grin2a (PMID:34485298); in MGE-derived GABAergic interneurons — Map2k7 and other neurodevelopment/synaptic genes (PMID:33744924); in forebrain KO — ↓ Robo3, Otx1; ↑ Hox genes, Lhx4, Foxa1, Tbx5, Twist1 (PMID:25568313); in fetal HSC — ↓ Slamf1, Mecom, Hoxa9, Hlf, Gfi1, Egr, Gata3 (PMID:27500495). Ocular-relevant: "Loss of BRPF1 has been shown to affect the transcriptional regulation of several key transcription factors, including Pitx2, Hmx1 and Pax6, which have been implicated in a wide range of ocular developmental abnormalities." (PMID:39837771).
Chromatin accessibility / imaging: ATAC-See and immunofluorescence localized H3K23 propionylation to active chromatin (PMID:32010779).
Proteomics, metabolomics, lipidomics: No disease-specific studies [gap].
Single-cell / spatial transcriptomics: No BRPF1-specific studies [gap]. The forebrain KO Tbr2+ progenitor finding (PMID:25568313) is a natural target for scRNA-seq.
Functional genomics screens: the CRISPR screen in PMID:40060486 (preprint) recovered Brpf1 as a modulator of loop-extrusion-dependent gene regulation.
Structural biology: co-crystal structures of the BRPF1 bromodomain exist from chemical-probe programs (PMID:26061247 — "structure guided development … through the iterative use of X-ray cocrystal structures"). AlphaFold model available for P55201.

7. Anatomical Structures Affected

7.1 Organ level

Primary: | Structure | UBERON | Basis | |---|---|---| | Brain | UBERON:0000955 | ID, DD, MRI findings | | Cerebral cortex / neocortex | UBERON:0000956 / UBERON:0001950 | Reduced dendritic complexity in cortical pyramidal neurons (PMID:31213987); neocortical abnormalities (PMID:25568313) | | Hippocampal formation | UBERON:0002421 | Reduced granule-cell dendritic complexity, ↓mEPSC, spatial memory (PMID:31213987; PMID:34485298) | | Corpus callosum | UBERON:0002336 | Agenesis 2/17 MRI (PMID:39837771); partial callosal agenesis in mouse (PMID:25568313) | | Eye / eyelid | UBERON:0000970 / UBERON:0001711 | Ptosis, blepharophimosis — BRPF1-specific (PMID:27939639) | | Optic nerve | UBERON:0000941 | Subclinical optic neuropathy (PMID:38590032) | | Face / craniofacial skeleton | UBERON:0000033 (head) / UBERON:0001434 | Characteristic dysmorphism |

Secondary / variable: | Structure | UBERON | Basis | |---|---|---| | Bone marrow | UBERON:0002371 | Anemia/thrombocytopenia (PMID:37190896); marrow failure in mouse KO (PMID:27500495) | | Cervical vertebral column | UBERON:0000959 | C2/C3 fusion 3/10 (HPOA); atlanto-axial malformation (PMID:35243762) | | Spinal cord | UBERON:0002240 | "Central nervous system and spinal abnormalities are also seen in some individuals" (PMID:27939640) | | Heart | UBERON:0000948 | Cardiac anomalies in a subset (PMID:32010779); 1/25 (PMID:39837771) | | Esophagus / upper GI | UBERON:0001043 | GERD 31% | | Larynx | UBERON:0001737 | Laryngomalacia 7% | | Skeletal muscle | UBERON:0001134 | Hypotonia, weakness | | Skin / hair follicle | UBERON:0002097 / UBERON:0002073 | Hypertrichosis, hair abnormalities (novel, PMID:39837771) | | Testis / gonad | UBERON:0000473 | Cryptorchidism 19% |

Body systems: nervous (primary), visual/ophthalmic (primary), musculoskeletal, craniofacial, hematopoietic, gastrointestinal, integumentary, genitourinary.

7.2 Tissue and cell level

Cell type	CL ID	Evidence
Pyramidal neuron (cortical)	CL:0000598	PMID:31213987
Hippocampal granule cell / dentate granule cell	CL:0000120 (granule cell)	PMID:31213987
GABAergic interneuron	CL:0000617 (GABAergic neuron)	PMID:33744924
Parvalbumin-expressing interneuron	CL:4023018 (verify with OAK)	PMID:33744924
Neural progenitor / intermediate neuronal progenitor (Tbr2+)	CL:0011020 (neural progenitor cell)	PMID:25568313
Hematopoietic stem cell	CL:0000037	PMID:27500495
Hematopoietic multipotent progenitor	CL:0000837	PMID:27500495
Erythroblast	CL:0000765	PMID:21753189 (Brd1/Brpf2 paralog)
Osteoclast	CL:0000092	PMID:28849908
Embryonic fibroblast (MEF)	CL:0000057 (fibroblast)	PMID:25773539
Endothelial cell (vascular defects)	CL:0000115	PMID:25773539

Curator caution: every CL/UBERON/GO ID above must be re-verified with just validate-terms — some (notably the PV-interneuron term) are suggestions requiring OAK confirmation.

7.3 Subcellular level

Compartment	GO ID	Note
Nucleus	GO:0005634	Primary site of BRPF1 action (UniProt P55201)
Chromosome / chromatin	GO:0005694 / GO:0000785	Binds chromatin, remains chromosome-associated through mitosis (PMID:18469222)
MOZ/MORF histone acetyltransferase complex	GO:0070776	The most specific and disease-defining compartment
Histone acetyltransferase complex	GO:0000123	Parent
Cytoplasm	GO:0005737	Where truncated variants mislocalize
Dendritic spine	GO:0043197	Reduced density/altered morphology (PMID:31213987)
Synapse	GO:0045202	Altered morphology (PMID:31213987)

BRPF1 "localizes to transcription start sites" (UniProt P55201).

7.4 Localization and lateralization

Ptosis/blepharophimosis: typically bilateral, may be asymmetric.
Optic neuropathy: reported bilateral — "such an exam also detected bilateral subclinical optic neuropathy in this case" (PMID:38590032).
Facial asymmetry: 3/28 (11%) (PMID:39837771).
Brain findings: midline (corpus callosum) and diffuse (white matter volume), not lateralized.
Strabismus: unilateral or bilateral, variable.

8. Temporal Development

8.1 Onset

Congenital — HPOA: HP:0003577 Congenital onset (10/10); HP:0003623 Neonatal onset (4/4).
Prenatal: intrauterine growth restriction 2/20 (HP:0001511). Mouse Brpf1 is required from ~E9.5 (PMID:24646517), so human haploinsufficiency acts throughout embryogenesis.
Neonatal/infantile: congenital ptosis, hypotonia (9/15 infant hypotonia), feeding impairment (8/15) (PMID:38346666; PMID:27939640).
Infancy–early childhood: motor and speech delay become apparent; delayed walking.
School age: language disorder (including written-language domain), ADHD, learning difficulty predominate.
Onset pattern: chronic, insidious, developmental — not acute or episodic.

8.2 Progression

Stages: No formal staging system exists. Practical natural-history phases: (i) neonatal/infantile — hypotonia, feeding, congenital ptosis; (ii) toddler/preschool — motor and speech delay; (iii) school age — language disorder, ID, behavioral phenotype; (iv) adolescence/adulthood — stable ID, largely resolved gross-motor delay, ongoing communication needs.
Progression rate: Non-progressive. No neurodegeneration reported in any human series.
Course pattern: Static/stable with developmental improvement. PMID:38346666 explicitly documents improvement: motor delays "often resolved in later childhood."
Duration: Chronic, lifelong.
Seizures, when present (14–50%), are episodic on a static substrate.

8.3 Patterns

Remission: Not applicable to the core neurodevelopmental phenotype. Gross-motor delay commonly resolves; ptosis is surgically correctable; seizures may be pharmacologically controlled.
Critical periods: (i) embryonic — the window in which forebrain neurogenesis, callosal formation, and ocular/craniofacial morphogenesis are set (irreversible by the time of diagnosis); (ii) infancy–early childhood — the intervention window for speech/language therapy, feeding support, and amblyopia prevention (ptosis surgery before visual-axis deprivation causes irreversible amblyopia). The speech-therapy window is the highest-yield intervention target given the near-universal speech/language phenotype (PMID:38346666).

9. Inheritance and Population

9.1 Epidemiology

Prevalence: Orphanet records a worldwide point prevalence class of "<1 / 1,000,000" (validated) for ORPHA:698090 — i.e. < 0.1 per 100,000. Orphanet's prevalence_class maps to the dismech PrevalenceClassEnum value BELOW_1_IN_1000000.
Reported case count: Orphanet's second epidemiology record gives 79 cases (worldwide, "Cases/families", validated). This is the more defensible figure to curate as measure_type: CASES_IN_LITERATURE.
Incidence: Not established [gap]. No birth-prevalence or incidence estimate exists.
Likely underdiagnosis: PMID:35243762 argues "Later, another 20 patients were also described by distinct reports, suggesting IDDDFP could be a more frequent cause of intellectual disability as it was thought before." Given the mild phenotype, high FSIQ, and preserved adaptive behavior, ascertainment is likely incomplete.

Suggested dismech Prevalence record:

prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  notes: Orphanet worldwide point-prevalence class <1 / 1 000 000 (validated).
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  rate_per_100000: null
  notes: >-
    Orphanet records 79 cases worldwide (validated). Colson et al. 2025 add
    29 new patients from 20 families to "over 50 previously published cases."

9.2 Genetic etiology parameters

Parameter	Status
Inheritance pattern	Autosomal dominant (HP:0000006). Consistent across OMIM, Orphanet, MedGen, HPOA, and all primary reports.
Penetrance	Appears high but incomplete for ID specifically. Carriers with normal intellect are documented (PMID:35243762 — normal intellectual development with congenital ptosis and neurological signs). Transmitting parents are typically mildly affected rather than unaffected. No quantitative penetrance estimate exists [gap].
Expressivity	Highly variable, including intrafamilial. PMID:39837771: "phenotypic differences were observed between family members carrying the same pathogenic variant, affecting intellectual ability, dysmorphic features and malformations, suggesting an intrafamilial variability."
Genetic anticipation	Not applicable — not a repeat-expansion disorder; no anticipation reported.
Germline mosaicism	Not reported [gap]. Empiric recurrence risk for apparently de novo cases should nonetheless include a small mosaicism allowance per standard genetic-counseling practice.
Founder effects	None identified. Cases span European, Middle Eastern (Israeli — PMID:31020800; Turkish — PMID:37190896; Saudi — PMID:32457794), and North American ancestries with private variants.
Consanguinity	Not a factor — dominant mechanism. PMID:31020800 explicitly describes a nonconsanguineous family.
Carrier frequency	Not applicable (dominant; affected heterozygotes, not carriers).
De novo rate	Majority of cases; PMID:39837771 states de novo predominates, with 5/20 families showing two-generation transmission. ClinGen's dosage curation notes "Seven protein-truncating variants were de novo mutations."
Recurrence risk	50% per pregnancy for an affected parent (Orphanet).

9.3 Population demographics

Affected populations: No ethnic predilection. Reported in European, Israeli/Jewish (mixed descent), Turkish, Saudi Arabian, Latin American, and North American families.
Geographic distribution: Worldwide; no endemic focus. No geographically clustered variant.
Sex ratio: Male predominance in reported series (10/15 male in PMID:38346666) — almost certainly ascertainment bias, not a true sex effect; the gene is autosomal. Curate as unknown/1:1 rather than asserting a skew.
Age distribution: Pediatric-diagnosed, lifelong. Median age 7y4m in the deep-phenotyping cohort (PMID:38346666). Adults are described chiefly as transmitting parents.

10. Diagnostics

10.1 Genetic testing — the diagnostic mainstay

There is no biochemical or imaging biomarker; diagnosis is molecular.

Modality	Utility
Exome sequencing (ES/WES)	First-line and the modality that established every reported case. PMID:27939639 (index family), PMID:31020800, PMID:37190896, PMID:32457794, PMID:38590032 all used ES. PMID:32457794: "Whole exome sequencing analysis has been proven as a valuable tool in the molecular diagnostics."
Genome sequencing (WGS)	Reasonable when ES is negative; better for non-coding/structural variants. No BRPF1-specific WGS yield data [gap].
NDD/ID gene panels	BRPF1 is included on contemporary ID/NDD and chromatinopathy panels. Check GTR for current panel membership.
Single-gene BRPF1 sequencing	Appropriate only for cascade testing of at-risk relatives once a familial variant is known (PMID:31020800, PMID:32457794 both used Sanger for family segregation).
Chromosomal microarray (CMA)	Detects whole-gene deletions and the contiguous 3p25/3p25.3 deletion (BRPF1 ± SETD5). PMID:37190896 used CMA to exclude additional CNVs.
Exome-based CNV calling (e.g. ExomeDepth)	Demonstrated to recover BRPF1 deletions from existing ES data (PMID:33611074) — worth running before ordering separate CMA.
Karyotype / FISH	Low yield; not indicated except to characterize a known rearrangement.
mtDNA testing / repeat expansion testing	Not applicable.

Recommended approach: ES (trio, with CNV calling) as first-tier for the ID/DD + ptosis phenotype; CMA if ES-CNV not performed; Sanger cascade testing of parents and at-risk relatives — essential, because mildly affected transmitting parents are common and change recurrence risk from ~1% to 50%.

10.2 Omics-based diagnostics

Functional H3K23 acetylation/propionylation assay on patient cells — used as research-grade evidence of pathogenicity for VUS (PMID:27939640; PMID:32010779). Not a clinically validated assay [gap: no CLIA/accredited version].
DNA methylation episignature (EpiSign) — not available for BRPF1 (established for KAT6A and KAT6B, PMID:37249002). This is the single most useful missing diagnostic tool for BRPF1 VUS resolution.
RNA-seq / proteomics / metabolomics / liquid biopsy — no diagnostic role.

10.3 Clinical and imaging tests

Test	Findings / rationale
Ophthalmological examination + OCT	Ptosis, blepharophimosis, strabismus, amblyopia, refractive error; OCT is required to detect subclinical optic neuropathy (PMID:38590032). PMID:39837771 recommends: "we recommend that all individuals with pathogenic BRPF1 variants undergo regular ophthalmological surveillance."
Brain MRI	Agenesis/thinning of the corpus callosum, reduced cerebral white matter volume, white-matter hyperintensities, Chiari type I malformation (PMID:39837771; PMID:38590032; HPOA). Abnormal in a minority.
Cervical spine imaging	C2/C3 vertebral fusion (3/10 HPOA), atlanto-axial malformation (PMID:35243762) — relevant to anesthesia and sports clearance.
EEG	For seizures (14–50%). No BRPF1-specific EEG signature described [gap].
Formal speech/language and neuropsychological assessment	Should be standard, given near-universal involvement across receptive, expressive, written, and social-pragmatic domains, and to detect childhood apraxia of speech (PMID:38346666).
Full blood count	Anemia and thrombocytopenia reported (PMID:37190896); mouse KO shows marrow failure (PMID:27500495). Reasonable baseline.
Echocardiogram	Cardiac anomalies in a subset (PMID:32010779; 1/25 in PMID:39837771).
Audiology, growth monitoring, feeding/swallow assessment	Standard NDD workup.
Biopsy / histopathology	No diagnostic role. Skin fibroblast culture is used only for research functional assays.

LOINC coding: no BRPF1-specific LOINC analyte. Use generic genetic-test LOINC codes and standard CBC codes for the hematologic monitoring.

10.4 Clinical criteria and differential diagnosis

No consensus clinical diagnostic criteria exist [gap]. Diagnosis = compatible phenotype + confirmed heterozygous pathogenic BRPF1 variant.

Differential diagnosis:

Condition	Distinguishing features
KAT6A syndrome	Same complex; more severe ID, more cardiac disease, distinct episignature. PMID:27939640: "These clinical features overlap with but are not identical to those reported for persons with KAT6A or KAT6B mutations."
KAT6B disorders (Genitopatellar; Say-Barber-Biesecker-Young-Simpson)	Patellar agenesis, genital anomalies, blepharophimosis with mask-like face; distinct episignatures (PMID:40593218).
3p25 / 3p25.3 deletion syndrome (SETD5)	Broader/more severe ID from SETD5; ptosis and blepharophimosis are the BRPF1-attributable component (PMID:27939639).
BPES (blepharophimosis-ptosis-epicanthus inversus, FOXL2)	Ptosis + blepharophimosis + epicanthus inversus but typically normal intellect; female premature ovarian insufficiency in type I.
Noonan syndrome / RASopathies	Real, documented confusion: PMID:41137536 found BRPF1 among six alternative diagnoses in patients clinically diagnosed as Noonan — "In six cases, alternative genetic diagnoses were established due to variants in SETD5, BRPF1, DPH1, ACTB, CREBBP, and GATA4, genes associated with syndromes presenting overlapping phenotypes with NS."
Cornelia de Lange syndrome	Synophrys, hypertrichosis, ID — overlapping. Mechanistically adjacent via the loop-extrusion/MORF interplay (PMID:40060486).
Other chromatinopathies (Rubinstein-Taybi/CREBBP, Kabuki/KMT2D, CHD8)	Overlapping NDD; distinguish molecularly.
Congenital myopathy / myasthenic syndrome	Considered for the congenital ptosis + hypotonia + weakness presentation (PMID:35243762).

10.5 Screening

Newborn screening: Not applicable and not recommended (no treatable metabolic defect).
Carrier screening: Not applicable (dominant).
Cascade screening: Strongly indicated — targeted Sanger testing of the proband's parents and at-risk relatives. Multiplex families with mildly affected transmitting parents are well documented (PMID:27939639; PMID:31020800; PMID:37190896; PMID:39837771). Parental testing is what distinguishes ~1% from 50% recurrence risk.

11. Outcome / Prognosis

11.1 Survival and mortality

Life expectancy: apparently normal. No abstract reports reduced survival, premature mortality, or disease-specific deaths in humans. Affected adults reproduce and transmit the variant (PMID:27939639 — 5 affected members; PMID:31020800 — affected mother and three sons).
Important contrast — do not extrapolate from mouse: homozygous Brpf1 null is embryonic lethal at E9.5 (PMID:24646517; PMID:25773539); conditional hematopoietic deletion causes "early lethality due to acute bone marrow failure and aplastic anemia" (PMID:27500495); forebrain-specific deletion causes "early postnatal lethality" (PMID:25568313). These are homozygous/conditional-null phenotypes with no human counterpart — human disease is heterozygous. Curate as a HUMAN_MODEL_MISMATCH discussion, not as a human prognosis claim.
Mortality rate / 5-yr and 10-yr survival: Not applicable; no excess mortality documented [no data].

11.2 Morbidity and function

Dominant disability: communication impairment. Language disorder in 11/12 assessed, speech disorder in 7/9, childhood apraxia of speech in 3/9 (PMID:38346666).
Cognitive outcome: favorable relative to peer chromatinopathies. Mild-to-moderate ID predominates (6 mild / 10 moderate of 16 with ID); no severe/profound ID in the 2025 cohort; FSIQ ≥70 in all four formally tested in the deep-phenotyping cohort (PMID:38346666; PMID:39837771).
Adaptive functioning: a relative strength — "Adaptive behavior and cognition were strengths when compared to other monogenic neurodevelopmental chromatin-related disorders" (PMID:38346666).
Motor outcome: favorable — delays "often resolved in later childhood" (PMID:38346666).
Visual outcome: the main organ-specific morbidity risk — vision impairment in 13/15, amblyopia in 3/29, and undetected subclinical optic neuropathy (PMID:38346666; PMID:39837771; PMID:38590032).
QoL instruments: none applied to this population [gap].

11.3 Complications

Amblyopia from uncorrected ptosis; refractive error; optic neuropathy; seizures; GERD and constipation; feeding difficulty and failure to thrive in infancy; recurrent infections (14%); anemia/thrombocytopenia (8%); obesity (14%); cervical spine instability (atlanto-axial malformation / C2-C3 fusion) with anesthetic and injury implications; educational underachievement and social-communication limitation.

11.4 Recovery potential

The neurodevelopmental substrate is fixed (developmental, not degenerative), but functional trajectory improves with intervention — motor delays resolve, and speech/language and adaptive skills respond to therapy. Ptosis is surgically correctable. There is no disease-modifying therapy and no evidence that any intervention alters the underlying chromatin defect in humans.

11.5 Prognostic factors and biomarkers

No validated prognostic factors or biomarkers. Explicitly:

"Our results, in agreement with other studies, do not show a clear genotype–phenotype correla[tion]" — PMID:39837771 (quote truncated at source by the extraction tool; curators must re-read the full sentence from PMC11973018 before quoting)

Variant type (truncating vs missense vs whole-gene deletion) and variant position do not predict severity. Intrafamilial variability with an identical variant (PMID:39837771) is direct evidence that genotype alone is insufficiently prognostic. Favorable indicators are clinical, not molecular: preserved adaptive behavior, FSIQ ≥70, and resolving motor delay.

12. Treatment

There is no disease-modifying or curative therapy. Management is entirely supportive, multidisciplinary, and symptom-directed. No clinical trial has ever been registered for BRPF1-related disorder (no NCT identifiers found).

12.1 Supportive and rehabilitative care — the standard of care

Intervention	Rationale	Suggested NCIT	`therapeutic_modality`
Speech and language therapy	Highest-yield intervention; near-universal language disorder, including childhood apraxia of speech requiring apraxia-specific (motor-based) approaches, not generic language therapy (PMID:38346666)	NCIT:C159273 Speech Therapy	BEHAVIORAL
Physical therapy	Hypotonia, gross motor delay, muscular weakness	NCIT:C15302 Physical Therapy	BEHAVIORAL
Occupational therapy	Fine motor delay, feeding, ADLs	NCIT:C121351 Occupational Therapy	BEHAVIORAL
Early intervention / special education	Global developmental delay, ID	NCIT:C15315 Rehabilitation	BEHAVIORAL
Feeding/nutrition support	Infant feeding impairment (8/15), FTT	NCIT:C15433 Nutritional Support (do not auto-tag as BEHAVIORAL — see CLAUDE.md)	—
Behavioral therapy / ADHD management	62% behavioral disorder, 33% ADHD, 21% anxiety, 31% sleep disturbance	NCIT:C181743 Behavioral Counseling	BEHAVIORAL
Genetic counseling	50% recurrence per pregnancy; cascade testing	NCIT:C15240 Genetic Counseling	—

12.2 Ophthalmologic management — the disorder-specific priority

Intervention	Rationale	Suggested NCIT
Regular ophthalmological surveillance incl. OCT	Explicitly recommended: "we recommend that all individuals with pathogenic BRPF1 variants undergo regular ophthalmological surveillance" (PMID:39837771); OCT needed to catch subclinical optic neuropathy (PMID:38590032)	NCIT:C49236 Therapeutic Procedure / diagnostic surveillance
Ptosis repair surgery	Prevents deprivation amblyopia; cosmetic/psychosocial benefit	NCIT:C15329 Surgical Procedure → `therapeutic_modality: SURGERY`
Strabismus surgery	48% strabismus	NCIT:C15329 Surgical Procedure → SURGERY
Refractive correction / amblyopia therapy	Myopia 17%, hypermetropia 7%, amblyopia 10%	NCIT:C50072 Eyeglasses / corrective lens [verify with OAK] → DEVICE

12.3 Pharmacotherapy

Symptomatic only: - Antiseizure medication for the 14–50% with seizures — no BRPF1-specific agent preference established [gap]. NCIT:C15986 Pharmacotherapy; therapeutic_agent per drug chosen. - ADHD stimulants / non-stimulants — standard NDD practice; no BRPF1-specific evidence. - Anti-reflux therapy for GERD (31%). - Pharmacogenomics: No BRPF1-specific PGx. PharmGKB has no BRPF1 clinical annotation. Note that if valproate were ever used as an antiseizure drug, there is an interesting mechanistic coincidence with §12.4 — but this is not a validated indication.

12.4 Experimental / mechanism-based therapeutic leads

This is the most scientifically interesting and most easily over-claimed section. Nothing below has been tested in a human with BRPF1-related disorder.

The key finding (PMID:32010779):

"Valproate, vorinostat, propionate and butyrate promote H3K23 acylation. These results reveal the dual functionality of BRPF1-KAT6 complexes, shed light on mechanisms underlying related developmental disorders and various cancers, and suggest mutation-based therapy for medical conditions with deficient histone acylation."

Candidate agents and their CHEBI/NCIT anchors:

Agent	CHEBI	Class	Status
Valproate / valproic acid	CHEBI:39549	HDAC inhibitor, antiseizure drug	Preclinical only for this indication; teratogenic — a serious caveat in a reproductive-age/pediatric population
Vorinostat (SAHA)	CHEBI:45716	HDAC inhibitor	Preclinical; oncology-approved, not for NDD
Propionate	CHEBI:17272	Short-chain fatty acid	Preclinical; acyl-CoA donor
Butyrate	CHEBI:17968	Short-chain fatty acid	Preclinical

Framing guardrail for curation: the mechanistic logic is restore the deficient H3K23 acyl mark. But (i) the data are entirely in vitro/mouse; (ii) the developmental window for the CNS/craniofacial phenotype has closed by the time of diagnosis; (iii) valproate is a known teratogen and an HDAC inhibitor is a blunt, genome-wide instrument. Curate as EMERGING / mechanistic_hypotheses, never as a treatment.

Bromodomain chemical probes — a research tool, and directionally opposite to therapy. Selective BRPF bromodomain inhibitors exist: IACS-9571 (dual TRIM24/BRPF1, ITC Kd = 14 nM for BRPF1, PMID:26061247) and PFI-4 / OF-1 / NI-57 (PMID:28849908). These inhibit BRPF1 and would be expected to worsen a haploinsufficiency phenotype; their therapeutic interest is in cancer and osteolytic bone disease — "the excellent druggability of these bromodomains may lead to new treatment strategies for patients suffering from bone loss or osteolytic malignant bone lesions" (PMID:28849908). Do not curate these as candidate treatments for IDDDFP.

12.5 Advanced therapeutics

Gene therapy / gene editing: None. No program exists. Conceptually challenging: the target is a large (1,214 aa, ~3.6 kb CDS) nuclear scaffold requiring precise dosage in the developing brain — dosage-sensitive genes are poor AAV overexpression targets.
RNA-based therapies (ASO, siRNA, mRNA): None. Note that for a haploinsufficiency disorder, the relevant ASO paradigm would be upregulation (e.g. TANGO/splice-modulation to boost expression from the intact allele), not the RNase H knockdown or exon-skipping paradigms in the dismech antisense_oligonucleotide_therapy module. No such program exists for BRPF1 [gap].
Cell therapy, immunotherapy, targeted therapy: Not applicable.

12.6 Treatment strategy

No published treatment algorithm, guideline, or care pathway exists for BRPF1-related disorder [gap]. Practical management follows generic chromatinopathy/NDD care plus the two disorder-specific additions the literature does support: (1) structured, apraxia-aware speech-language intervention (PMID:38346666) and (2) regular ophthalmological surveillance including OCT (PMID:39837771; PMID:38590032).

13. Prevention

Primary prevention: Not possible for de novo cases. For families with a known variant, options are preimplantation genetic testing (PGT-M) and prenatal diagnosis (CVS/amniocentesis) — standard for a known AD variant with 50% recurrence risk. Orphanet: transmission is autosomal dominant; "genetic counseling should be offered to affected individuals informing them that there is a 50% risk of having an affected child at each pregnancy."
Secondary prevention (early detection): The highest-value activity. Early molecular diagnosis via trio ES enables (i) early speech/language therapy in the critical window, (ii) ophthalmological surveillance before amblyopia becomes fixed, and (iii) cascade family testing.
Tertiary prevention (complication prevention):
Ptosis repair before deprivation amblyopia — the clearest preventable harm.
OCT surveillance for otherwise-silent optic neuropathy (PMID:38590032).
Cervical spine assessment before anesthesia or contact sports (C2/C3 fusion, atlanto-axial malformation).
CBC monitoring where hematologic abnormality is suspected (PMID:37190896).
Seizure control; reflux and constipation management; weight monitoring (obesity 14%).
Immunization: No disorder-specific vaccine strategy. Routine childhood immunization per national schedule; the 14% recurrent-infection rate warrants normal-to-diligent vaccine adherence.
Population screening / newborn screening: Not indicated — no treatable metabolic defect, no validated screening test, prevalence <1/1,000,000.
Risk stratification: Not applicable at the population level; within families, cascade genetic testing is the stratifier.
Behavioral / environmental / public health interventions: Not applicable — no environmental contribution to etiology.
Prophylaxis: No prophylactic medication.
Genetic counseling: Central. Counsel on (i) 50% recurrence for an affected parent; (ii) marked variable expressivity, including the possibility of a much milder or even cognitively normal outcome (PMID:35243762; PMID:39837771) — a parent transmitting the variant cannot be told the child will be similarly affected; (iii) the need to test apparently unaffected parents, since mild transmitting parents are common; (iv) residual germline-mosaicism risk for apparently de novo cases. NCIT:C15240 Genetic Counseling.

14. Other Species / Natural Disease

14.1 Taxonomy and orthologs

Species	NCBI Taxon	Gene	NCBI Gene ID	Notes
Homo sapiens	NCBITaxon:9606	BRPF1	7862	3p25.3
Mus musculus	NCBITaxon:10090	Brpf1	MGI:1926033; Chr 6	Primary model
Danio rerio	NCBITaxon:7955	brpf1	—	ZFIN; TrxG mutant (PMID:18469222)
Drosophila melanogaster	NCBITaxon:7227	(BRPF ortholog in the MOZ/MORF complex)	—	Complex conserved (PMID:40593218)
Caenorhabditis elegans	NCBITaxon:6239	(BRPF ortholog)	—	Complex conserved (PMID:40593218)

Verify MGI:1926033 and the mouse chromosome/coordinates directly at informatics.jax.org before curating — the identifier came from a web search snippet, not a fetched MGI record.

14.2 Evolutionary conservation

Strong. PMID:40593218: "The evolutionary conservation of these complexes in Drosophila melanogaster and Caenorhabditis elegans underscores their fundamental biological significance." PMID:36077605 notes the four core subunits "play crucial roles in different biological processes across diverse species, such as embryonic development, forebrain development, skeletal patterning and hematopoiesis." Both patient missense variants in the 2025 cohort — p.(Cys23Arg) and p.(Arg548Trp) — "affect conserved residue[s]" (PMID:39837771).

14.3 Natural disease in other species

No naturally occurring BRPF1 disease is recorded in companion animals, livestock, or wildlife. OMIA contains no BRPF1 entry [gap]. All non-human BRPF1 phenotypes are engineered, not natural. No breed-specific (VBO) association exists.

14.4 Comparative pathology

The mouse and zebrafish phenotypes are informative but more severe than human disease, because they are homozygous/conditional nulls rather than heterozygous LoF. Key comparative points: - Mouse homozygous null: embryonic lethal ~E9.5; vascular defects in placenta, yolk sac, embryo proper; abnormal neural tube closure (PMID:24646517; PMID:25773539). No human counterpart. - Zebrafish brpf1 mutant: "anterior transformations of pharyngeal arches due to progressive loss of anterior Hox gene expression" (PMID:18469222) — a homeotic craniofacial phenotype. This is mechanistically suggestive for the human craniofacial dysmorphism but the human phenotype is not homeotic. - Mouse heterozygote: the closest model to human disease — reduced dendritic arborization, spine deficits, learning/memory impairment (PMID:31213987).

14.5 Transmission

Not applicable. Not infectious; no zoonotic potential; no cross-species susceptibility.

15. Model Organisms

15.1 Mouse — the principal model

Model	Genotype	Phenotype	PMID	`evidence_source`
Constitutive null	Brpf1^−/−	Embryonic lethality ~E9.5; vascular defects in placenta, yolk sac, embryo proper; abnormal neural tube closure; ↓ MEF and hematopoietic-progenitor proliferation; ↓ Rpl10-like, ↓ p27, ↑ p16	25773539; 24646517	MODEL_ORGANISM
Knock-in reporter	Brpf1 reporter allele	4-D spatiotemporal expression atlas; "high expression is present in the testis and specific regions of the brain" postnatally	24646517	MODEL_ORGANISM
Forebrain conditional KO	Emx1-Cre; Brpf1^fl/fl (homozygous)	Early postnatal lethality; neocortical abnormalities; partial callosal agenesis; fewer Tbr2+ intermediate progenitors; aberrant neurogenesis; ↓Robo3/Otx1, ↑Hox/Lhx4/Foxa1/Tbx5/Twist1	25568313	MODEL_ORGANISM
★ Forebrain heterozygote — the disease-matched model	Emx1-Cre; Brpf1 heterozygous	Reduced dendritic complexity (hippocampal granule + cortical pyramidal neurons); ↓spine density; altered spine/synapse morphology; ↓mEPSC frequency and amplitude; decreased anxiety; defective learning and memory	31213987	MODEL_ORGANISM
Hematopoietic conditional KO	Blood-cell-selective Brpf1 deletion	Early lethality from acute bone marrow failure and aplastic anemia; severe HSC/progenitor deficiency in marrow and fetal liver; ↑ROS, senescence, apoptosis; ↓Slamf1/Mecom/Hoxa9/Hlf/Gfi1/Egr/Gata3; loss of H3K23ac	27500495	MODEL_ORGANISM
Hippocampal shRNA knockdown (AAV, stereotactic, adult)	shBrpf1	↓mEPSC frequency preceding morphological change; decreasing trend in Morris water maze spatial learning/memory; ↓C1ql1, Gpr17, Htr1d, Glra1, Cxcl10, Grin2a	34485298	MODEL_ORGANISM / IN_VITRO
MGE-derived GABAergic interneuron knockdown	AAV-shBrpf1	↑firing threshold, ↓evoked APs, ↓mIPSC amplitude; ↓Map2k7; trend toward reduced PV+ differentiation	33744924	IN_VITRO
Targeted allele resource	Brpf1^tm1a(EUCOMM)Wtsi (MGI:4433631)	EUCOMM knockout-first conditional-ready allele	—	resource

15.2 Zebrafish

brpf1 mutants: "anterior transformations of pharyngeal arches due to progressive loss of anterior Hox gene expression"; Brpf1 recruits Moz to active chromatin and remains chromosome-bound through mitosis; the PWWP domain "is absolutely essential for Brpf1 function in vivo" (PMID:18469222). Establishes Brpf1 as a Trithorax-group member and provides the first demonstration of histone binding by a PWWP domain.

15.3 Other systems

In vitro / cellular: patient-derived skin fibroblasts (used for transcript/protein/H3K23ac assays — PMID:27939639); mouse embryonic fibroblasts (PMID:25773539); primary cultured hippocampal neurons (PMID:34485298); primary murine bone marrow cells and human primary monocytes for osteoclast differentiation (PMID:28849908); mouse ES cells (PMID:40060486).
iPSC / organoid models: none reported [gap]. This is a conspicuous, high-value missing model given the human-specific cortical biology at issue.
Induced (non-genetic) models: chemical-probe inhibition of the BRPF bromodomain (IACS-9571, PFI-4, OF-1, NI-57) provides an acute pharmacological loss-of-function tool (PMID:26061247; PMID:28849908) — though it targets only the bromodomain, not the whole scaffold.

15.4 Phenotype recapitulation and limitations

Recapitulated in the heterozygous mouse: learning/memory deficits, reduced dendritic arborization and spine density, reduced excitatory synaptic transmission, altered anxiety behavior (PMID:31213987) — a good mechanistic match to human ID.

Recapitulated in conditional/homozygous models but NOT matching human severity: callosal agenesis (partial in mouse KO vs 12% in humans), bone marrow failure (lethal in mouse vs mild anemia/thrombocytopenia in 8% of humans), embryonic lethality (mouse only).

Not recapitulated / not modeled: - Ptosis and blepharophimosis — the single most characteristic human feature. No abstract reports a murine eyelid phenotype. [Major gap.] - Speech and language disorder / childhood apraxia of speech — the most functionally significant human phenotype, and intrinsically unmodellable in mouse. - Human-specific cortical biology (outer radial glia/OSVZ) absent from rodent models. - The zebrafish homeotic pharyngeal-arch transformation has no human correlate.

Suggested dismech curation: record a discussions entry with kind: HUMAN_MODEL_MISMATCH (not KNOWLEDGE_GAP) for at least two items: (1) the mouse models are homozygous/conditional nulls producing lethality, while human disease is heterozygous and compatible with normal lifespan; and (2) no model reproduces ptosis/blepharophimosis, the disorder's defining feature — so the ocular/periocular developmental mechanism (the Pitx2/Hmx1/Pax6 hypothesis from PMID:39837771) remains functionally unvalidated. Per CLAUDE.md, HUMAN_MODEL_MISMATCH is the right kind here because evidence exists in models but its translational validity is the open question.

15.5 Resources

MGI (mouse; MGI:1926033 — verify), IMPC/EUCOMM/KOMP (Brpf1^tm1a(EUCOMM)Wtsi, MGI:4433631), IMSR, ZFIN (zebrafish brpf1), Alliance of Genome Resources.

Appendix A — Consolidated PMID reference list

Clinical — foundational - PMID:27939640 — Yan K, Rousseau J, Littlejohn RO, et al. Mutations in the Chromatin Regulator Gene BRPF1 Cause Syndromic Intellectual Disability and Deficient Histone Acetylation. Am J Hum Genet. 2017. [Disease-defining paper #1 — 10 individuals] - PMID:27939639 — Mattioli F, Schaefer E, Magee A, et al. Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual Disability with Associated Ptosis. Am J Hum Genet. 2017. [Disease-defining paper #2 — 3p25/SETD5 dissection]

Clinical — cohorts and deep phenotyping - PMID:39837771 — Colson C, et al. The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review. Clin Genet. 2025. [Largest cohort; primary frequency source; PMC11973018] - PMID:38346666 — Beyond 'speech delay': Expanding the phenotype of BRPF1-related disorder. Eur J Med Genet. 2024. [Speech/language deep phenotyping, n=15] - PMID:38590032 — Broadening the ocular phenotypic spectrum of ultra-rare BRPF1 variants: report of two cases. Ophthalmic Genet. 2024. [Subclinical optic neuropathy; Chiari I] - PMID:31020800 — Pode-Shakked N, et al. BRPF1-associated intellectual disability, ptosis, and facial dysmorphism in a multiplex family. Mol Genet Genomic Med. 2019. - PMID:37190896 — Kose CC, et al. Anemia and thrombocytopenia due to a novel BRPF1 variant… Am J Med Genet A. 2023. [Hematologic expansion] - PMID:35243762 — BRPF1-associated syndrome: A patient with congenital ptosis, neurological findings, and normal intellectual development. Am J Med Genet A. 2022. [Mild end of spectrum] - PMID:32457794 — Novel Missense Variant in Heterozygous State in the BRPF1 Gene… Front Genet. 2020. - PMID:41137536 — Non-RASopathy Genetic Syndromes Identified as the Molecular Cause of Disease in Patients Previously Diagnosed With Noonan Syndrome. Am J Med Genet A. 2026. [Differential diagnosis] - PMID:33611074 — Clinically relevant copy-number variants in exome sequencing data of patients with dystonia. Parkinsonism Relat Disord. 2021. [BRPF1 CNV detection]

Mechanism — molecular - PMID:32010779 — Yan K, et al. Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer. Sci Adv. 2020. [H3K23pr; 12 new cases; therapeutic leads] - PMID:36077605 — BRPF1-KAT6A/KAT6B Complex: Molecular Structure, Biological Function and Human Disease. Cancers. 2022. [Review] - PMID:40593219 — Bromodomain and PHD Finger-Containing Protein 1: From Functions to a Developmental Disorder, Cancer, and Therapeutics. Results Probl Cell Differ. 2025. [Most recent dedicated review] - PMID:40593218 — Lysine Acetyltransferase 6 Complexes in Neurodevelopmental Disorders and Different Types of Cancer. Results Probl Cell Differ. 2025. - PMID:25920810 — Yang XJ. MOZ and MORF acetyltransferases… Biochim Biophys Acta. 2015.

Mechanism — model organism - PMID:31213987 — Brpf1 Haploinsufficiency Impairs Dendritic Arborization and Spine Formation, Leading to Cognitive Deficits. Front Cell Neurosci. 2019. [Best disease-matched model] - PMID:25568313 — Deficiency of the chromatin regulator BRPF1 causes abnormal brain development. J Biol Chem. 2015. - PMID:34485298 — Deficiency of Intellectual Disability-Related Gene Brpf1 Attenuated Hippocampal Excitatory Synaptic Transmission… Front Cell Dev Biol. 2021. - PMID:33744924 — Deficiency of intellectual disability-related gene Brpf1 reduced inhibitory neurotransmission in MGE-derived GABAergic interneurons. G3. 2021. - PMID:27500495 — BRPF1 is essential for development of fetal hematopoietic stem cells. J Clin Invest. 2016. - PMID:25773539 — The chromatin regulator Brpf1 regulates embryo development and cell proliferation. J Biol Chem. 2015. - PMID:24646517 — Expression atlas of the multivalent epigenetic regulator Brpf1… Epigenetics. 2014. - PMID:18469222 — Laue K, et al. The multidomain protein Brpf1 binds histones and is required for Hox gene expression and segmental identity. Development. 2008. [Zebrafish; PWWP histone binding] - PMID:21753189 — The Hbo1-Brd1/Brpf2 complex … required for fetal liver erythropoiesis. Blood. 2011. [Paralog — do not conflate with BRPF1] - PMID:40060486 — Context-Dependent and Gene-Specific Role of Chromatin Architecture… bioRxiv 2025. [Preprint — not peer reviewed]

Chemical biology / therapeutics - PMID:26061247 — Structure-Guided Design of IACS-9571, a Selective High-Affinity Dual TRIM24-BRPF1 Bromodomain Inhibitor. J Med Chem. 2016. - PMID:28849908 — Selective Targeting of Bromodomains of the Bromodomain-PHD Fingers Family Impairs Osteoclast Differentiation. ACS Chem Biol. 2017.

Adjacent / comparison - PMID:37249002 — DNA methylation episignatures are sensitive and specific biomarkers for detection of patients with KAT6A/KAT6B variants. [No BRPF1 episignature — cited as a gap]

Non-literature structured sources usable as dismech evidence references: - ORPHA:698090 — Orphanet (definition, prevalence class <1/1,000,000, 79 cases, disorder type) - CGDS:HGNC_14255 — ClinGen Dosage Sensitivity (HI score 3, TS score 0, curated 2023-08-23) - ClinGen Gene-Disease Validity (CGGV: — retrieve the specific assertion ID via just clingen-list | grep BRPF1)

Appendix B — Curation notes and explicitly flagged gaps

Things to verify before committing (per CLAUDE.md SOP): 1. Run just fetch-reference PMID:X for all ~28 PMIDs above; then just validate-references — several quotes above came through a summarizing fetch layer and, while transcribed verbatim on request, must be substring-checked against the real cached abstracts. 2. The Colson 2025 genotype-phenotype sentence was truncated mid-word by the extraction tool. Re-read it from PMC11973018 before quoting. 3. gnomAD pLI=1 / LOEUF=0.21 came from a search snippet, not from gnomAD directly. Re-verify against gnomAD v4. 4. MGI:1926033 came from a search snippet. Verify at informatics.jax.org. 5. Verify every CL, UBERON, GO, CHEBI, and NCIT ID with just validate-terms. The PV-interneuron CL term and the eyeglasses NCIT term are the least certain. 6. The ClinVar "269 P/LP" count includes multi-gene CNVs — do not quote it as BRPF1-specific sequence variants.

Substantive knowledge gaps worth recording as discussions entries: - No BRPF1 DNA-methylation episignature despite established episignatures for its obligate partners KAT6A/KAT6B (PMID:37249002) — the single highest-value diagnostic gap. - No iPSC or cerebral-organoid model — no human-cell model of the neurodevelopmental phenotype. - No animal model of ptosis/blepharophimosis — the defining human feature is mechanistically unvalidated; the Pitx2/Hmx1/Pax6 route (PMID:39837771) is inference, not demonstration. - No quantitative penetrance estimate, and no explanation for the intrafamilial variability seen with identical variants — implies unidentified modifiers. - No natural history study, no QoL data, no treatment guideline, no clinical trial. - Whether human BRPF1 haploinsufficiency causes clinically meaningful hematologic or immune disease is unresolved (8% hematologic abnormality vs lethal marrow failure in mouse KO). - The mouse-vs-human severity mismatch (homozygous-null lethality vs normal human lifespan) should be an explicit HUMAN_MODEL_MISMATCH, not a KNOWLEDGE_GAP.

Candidate dismech module conformance points: - epilepsy_excitation_inhibition_imbalance#Excitation-Inhibition Imbalance — supported by paired excitatory (PMID:34485298) and inhibitory (PMID:33744924) transmission deficits, but the evidence is MODEL_ORGANISM/IN_VITRO only; seizures occur in a minority. Curate the conformance with that caveat, or not at all. - A potential new chromatinopathy / KAT6-BRPF1 complex module or Grouping uniting BRPF1, KAT6A, and KAT6B disorders — they share an obligate protein complex, a common molecular readout (H3K23 acylation), and overlapping phenotypes, which is exactly the SHARED_MECHANISM + SHARED_PATHWAY grouping basis. - A 3p25 contiguous deletion entry or grouping capturing the BRPF1/SETD5 per-gene phenotype attribution (PMID:27939639) — an unusually clean worked example.

Sources: - OMIM 617333 — IDDDFP - OMIM 602410 — BRPF1 - Orphanet ORPHA:698090 - Orphadata API — cross-referencing and epidemiology, ORPHA:698090 - ClinGen — BRPF1 dosage sensitivity (HGNC:14255) - ClinGen — BRPF1 gene page - MedGen 934584 - HPO API — annotations for OMIM:617333 - OLS4 — MONDO:0015022 - UniProt P55201 — Peregrin/BRPF1 - HGNC:14255 — BRPF1 - PubMed — BRPF1 (all abstracts cited above retrieved via NCBI E-utilities) - PMC11973018 — Colson et al. 2025, Clinical Genetics - ScienceDirect — Beyond 'speech delay': Expanding the phenotype of BRPF1-related disorder - Science Advances — Deficient histone H3 propionylation by BRPF1-KAT6 complexes - MGI — Brpf1 (MGI:1926033) - MGI — Brpf1^tm1a(EUCOMM)Wtsi (MGI:4433631) - PMC9454415 — BRPF1-KAT6A/KAT6B Complex review - PubMed 37249002 — KAT6A/KAT6B episignatures

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Inheritance

Mechanistic Hypotheses

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Variants

Medical Actions

Diagnosis

Prevalence

Differential Diagnoses

Related Datasets

Experimental Models

Animal Models

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References & Deep Research

References

Deep Research

BRPF1-Related Intellectual Disability (IDDDFP) — Comprehensive Research Report

1. Disease Information

1.1 Overview

1.2 Key identifiers

1.3 Synonyms and alternative names

1.4 Information provenance

2. Etiology

2.1 Disease causal factors

2.2 Risk factors

2.3 Protective factors

2.4 Gene–environment interactions

3. Phenotypes

3.1 Frequency table — the primary evidence base

3.2 Speech and language — the most consistent domain

3.3 Ophthalmological phenotype — the syndrome's signature

3.4 Phenotype characteristics (onset, severity, progression)

3.5 Quality of life impact

4. Genetic / Molecular Information

4.1 Causal gene

4.2 Pathogenic variants — spectrum

4.3 Population allele frequency and constraint

4.4 Functional consequences

4.5 Modifier genes

4.6 Chromosomal abnormalities — the 3p25 / 3p25.3 deletion connection

4.7 Epigenetic information

5. Environmental Information

6. Mechanism / Pathophysiology

6.1 Causal chain (upstream → downstream)

6.2 Molecular pathways

6.3 Cellular processes

6.4 Protein dysfunction

6.5 Metabolic changes

6.6 Immune system involvement

6.7 Tissue damage mechanisms

6.8 Biochemical abnormalities

6.9 Molecular profiling

7. Anatomical Structures Affected

7.1 Organ level

7.2 Tissue and cell level

7.3 Subcellular level

7.4 Localization and lateralization

8. Temporal Development

8.1 Onset

8.2 Progression

8.3 Patterns

9. Inheritance and Population

9.1 Epidemiology

9.2 Genetic etiology parameters

9.3 Population demographics

10. Diagnostics

10.1 Genetic testing — the diagnostic mainstay

10.2 Omics-based diagnostics

10.3 Clinical and imaging tests

10.4 Clinical criteria and differential diagnosis

10.5 Screening

11. Outcome / Prognosis

11.1 Survival and mortality