BRPF1-Related Intellectual Disability

Mendelian MONDO:0015022 Pathograph 37 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), KAT6B (MORF), and KAT7 (HBO1) 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 patient variants impair both acylations. 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) and corpus callosum anomalies are frequent enough that dedicated ophthalmological and neuroimaging assessment is recommended. Expressivity within families is wide, extending to carriers with normal intellect.

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Classifications

Harrison's Chapter

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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 one reported sibship arose through 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 and Developmental Transcriptional Programs DIRECT

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 Chromatin Accessibility and 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

Do the mouse Brpf1 models, which are homozygous or conditional nulls with lethal phenotypes, validly model human heterozygous BRPF1 haploinsufficiency, in which life expectancy appears normal and some carriers have normal IQ?

HUMAN MODEL MISMATCH OPEN brpf1_zygosity_and_species_model_mismatch

Attached to

pathophysiology#Aberrant Cortical Neurogenesis and Callosal Development pathophysiology#Impaired Hematopoietic Stem and Progenitor Cell Maintenance pathophysiology#Impaired Learning and Memory

Most of the mechanistic BRPF1 literature uses complete loss of function: constitutive knockout is lethal around embryonic day 9.5, forebrain-specific inactivation causes early postnatal lethality with partial callosal agenesis, and blood-specific deletion causes fatal bone marrow failure. Human disease is heterozygous, non-lethal, and often mild - one reported carrier has normal intellectual development. Only the Brpf1 heterozygous mouse (PMID:31213987) matches human zygosity, and it is the model that yields the subtlest phenotype. Treating null-allele findings as the human mechanism risks systematically overstating severity, particularly for the callosal and hematopoietic arms where human evidence is a minority finding and a single family respectively.

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

Episignatures are established for KAT6A and for the KAT6B disorders but not for BRPF1. Profile genome-wide DNA methylation in blood from a variant-confirmed BRPF1 cohort against matched controls and against KAT6A and KAT6B cases. A positive result would give the first human-tissue molecular readout of heterozygous BRPF1 dosage, would resolve BRPF1 variants of uncertain significance, and would show whether the three complex members converge on one signature or separate.

Show evidence (3 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."

The human end of the spectrum includes normal cognition, which no mouse model reproduces.

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Pathophysiology

Heterozygous BRPF1 Loss-of-Function Variation

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

Downstream

BRPF1 Haploinsufficiency

Show evidence (2 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.

BRPF1 Haploinsufficiency

Loss of one functional BRPF1 allele halves the dose of the chromatin-reader scaffold. Haploinsufficiency, rather than a gain-of-function or dominant-negative product, is the accepted mechanism; the phenotypic contribution of BRPF1 dosage was isolated by comparing individuals with BRPF1-only lesions, SETD5-only lesions, and 3p25 deletions spanning both genes.

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

BRPF1 is the scaffold subunit of tetrameric MYST acetyltransferase complexes built around KAT6A (MOZ), KAT6B (MORF), or KAT7 (HBO1) plus ING4/ING5 and MEAF6. Reduced BRPF1 dose destabilizes assembly and activation of these complexes. This node is the mechanistic point at which BRPF1 disease converges with, but is not identical to, KAT6A- and KAT6B-related disorders: the enzymes have BRPF1-independent activities and BRPF1 has partners beyond KAT6A/KAT6B, which is the accepted explanation for the partial rather than complete clinical 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 (4 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 the four scaffold functions that are lost when BRPF1 dose falls: subunit bridging, enzyme stimulation, substrate targeting, and transcriptional activation.

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."

Explicitly establishes both the shared complex biology and the clinical non-identity with KAT6A/KAT6B disorders.

+ 1 more reference

Deficient Histone H3K23 Acetylation

Loss of BRPF1 scaffold activity lowers acetylation of histone H3 lysine 23, an abundant chromatin mark that BRPF1 itself also reads. In human embryonic stem cells, BRPF1, H3K4me3 and H3K23ac co-occupy open chromatin at stemness genes, so the deficit is coupled to a reader-writer circuit rather than being a bulk enzymatic loss.

H3K23 Acetylation Deficiency Branch

histone H3K23 acetyltransferase activity GO:0043994 ↓ DECREASED

Downstream

Altered Chromatin Accessibility and Developmental Transcriptional Programs

Show evidence (2 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."

Patient variants directly reduce H3K23 acetylation.

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.

Deficient Histone H3K23 Propionylation

BRPF1-KAT6 complexes also propionylate H3K23, and patient BRPF1 variants impair this acylation. Brpf1 deletion abolishes the mark in mouse embryos and fibroblasts. Because the propionylation and acetylation deficits co-occur in every patient sample studied, the independent contribution of propionylation loss to the human phenotype is unresolved.

H3K23 Propionylation Deficiency Branch

peptidyl-lysine propionylation GO:0061921 ↓ DECREASED

Downstream

Altered Chromatin Accessibility and Developmental Transcriptional Programs

Show evidence (2 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.

Altered Chromatin Accessibility and Developmental Transcriptional Programs

Loss of the BRPF1-dependent H3K23 acyl marks closes chromatin at BRPF1-occupied loci and shifts developmental gene expression. In Brpf1-deficient mouse forebrain neurons the affected transcripts are enriched for neural development, synapse function and memory genes. This is the hub from which the multisystem phenotype diverges; the individual steps from chromatin state to each organ-level endpoint are not resolved in humans.

chromatin organization GO:0006325 ⚠ ABNORMAL regulation of transcription by RNA polymerase II GO:0006357 ⚠ ABNORMAL forebrain development GO:0030900 ⚠ ABNORMAL

Downstream

Impaired Dendritic Arborization and Spine Formation

Reduced Inhibitory Neurotransmission in GABAergic Interneurons

Global Developmental Delay

Speech and Language Disorder

Infantile Hypotonia

Aberrant Cortical Neurogenesis and Callosal Development

Impaired Hematopoietic Stem and Progenitor Cell Maintenance

Congenital Cardiac Anomalies

Deregulated Ocular and Periocular Developmental Transcription Factor Programs

Show evidence (2 references)

PMID:36711238 SUPPORT In Vitro

"BRPF1, H3K4me3, and H3K23ac substantially co-occupy the open chromatin and stemness genes in hESCs."

Places BRPF1 and its mark at open chromatin over developmentally decisive genes.

PMID:37862219 SUPPORT Model Organism

"We found that Brpf1 deficiency reduced the frequency of miniature excitatory postsynaptic currents and downregulated the expression of genes Pcdhgb1, Slc16a7, Robo3, and Rho, which are related to neural development, synapse function, and memory, thereby damaging spatial and fear memory in mice."

Identifies the neurodevelopmental and synaptic gene programs dysregulated by Brpf1 loss in forebrain neurons.

Deregulated Ocular and Periocular Developmental Transcription Factor Programs

The ocular and periocular arm of the phenotype - ptosis, blepharophimosis and strabismus, the features that discriminate BRPF1 from co-deleted SETD5 - has until now had no mechanistic route in this graph. The proposed route is that BRPF1 loss deregulates transcription of the ocular developmental transcription factors Pitx2, Hmx1 and Pax6, each independently implicated in ocular developmental malformation, and that the resulting disruption of periocular morphogenesis produces the eyelid and ocular-alignment phenotypes. This is an inference drawn by the authors of the largest cohort from the animal and cell-based BRPF1 literature, not a demonstration in human periocular tissue: no BRPF1 model reproduces ptosis or blepharophimosis, so the node is marked HYPOTHETICAL and is the subject of an open HUMAN_MODEL_MISMATCH discussion.

eye development GO:0001654 ⚠ ABNORMAL regulation of transcription by RNA polymerase II GO:0006357 ⚠ ABNORMAL

Downstream

Ptosis

Blepharophimosis

Strabismus

Show evidence (3 references)

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML SUPPORT Human Clinical

"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.

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML PARTIAL Human Clinical

"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 and Callosal Development

Forebrain-specific Brpf1 inactivation in mouse produces neocortical abnormalities and partial callosal agenesis, with a reduced pool of Tbr2-positive intermediate neuronal progenitors and aberrant neurogenesis. Transcriptionally, Brpf1 loss both decreases neocortical developmental genes (Robo3, Otx1) and de-represses Hox and other transcription factors, so BRPF1 acts as both activator and silencer. This node supplies the developmental mechanism for the human corpus callosum anomalies, but the mouse model is a conditional homozygous null and is far more severe (early postnatal lethality) than human heterozygous disease.

forebrain development GO:0030900 ⚠ ABNORMAL

Downstream

Corpus Callosum Anomalies

Show evidence (2 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."

Establishes the callosal and neocortical developmental phenotype of Brpf1 loss in forebrain.

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.

Impaired Hematopoietic Stem and Progenitor Cell Maintenance

A separate organ arm. In mice, blood-specific Brpf1 deletion causes acute bone marrow failure and aplastic anemia with severe loss of hematopoietic stem cells and progenitors, raised reactive oxygen species, senescence and apoptosis, and reduced multipotency-gene expression - and BRPF1 is required for H3K23 acetylation in this compartment too. In humans only one family with anemia and thrombocytopenia has been reported, and the mouse data are homozygous conditional nulls, so this arm is biologically plausible but clinically unproven.

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

hemopoiesis GO:0030097 ↓ DECREASED

Downstream

Anemia

Thrombocytopenia

Show evidence (2 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."

Confirms that the same H3K23 acetylation lesion underlies the hematopoietic arm.

Impaired Dendritic Arborization and Spine Formation

In Brpf1 heterozygous mice, hippocampal granule cells and cortical pyramidal neurons show reduced dendritic complexity, lower spine density, and altered spine and synapse morphology. This is the best-characterized cellular substrate for the cognitive phenotype, but it has been demonstrated only in mouse; no equivalent human neuronal data exist.

hippocampal pyramidal neuron CL:1001571 hippocampal granule cell CL:0001033 cortical pyramidal neuron CL:4023111

dendrite morphogenesis GO:0048813 ⚠ ABNORMAL dendritic spine development GO:0060996 ⚠ ABNORMAL

Downstream

Reduced Excitatory Synaptic Transmission in Forebrain Neurons

Show evidence (1 reference)

PMID:31213987 SUPPORT Model Organism

"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."

Defines the dendritic and spine deficit produced by Brpf1 haploinsufficiency.

Reduced Excitatory Synaptic Transmission in Forebrain Neurons

Brpf1 loss lowers the frequency (and, in some preparations, amplitude) of miniature excitatory postsynaptic currents in hippocampal and forebrain excitatory neurons. Notably, in acute knockdown the electrophysiological deficit precedes any measurable change in dendritic morphology, indicating a partly morphology-independent synaptic effect.

excitatory postsynaptic potential GO:0060079 ↓ DECREASED

Downstream

Impaired Learning and Memory

Show evidence (2 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."

Establishes a synaptic transmission deficit that is not simply secondary to dendritic loss.

PMID:37862219 SUPPORT Model Organism

"To test this, we knocked out Brpf1 in forebrain excitatory neurons using CaMKIIa-Cre."

A cell-type-restricted knockout localizes the deficit to forebrain excitatory neurons.

Reduced Inhibitory Neurotransmission in GABAergic Interneurons

A parallel inhibitory arm: Brpf1 knockdown in mouse medial-ganglionic-eminence (MGE)-derived GABAergic interneurons raises the action-potential firing threshold, reduces evoked firing, and lowers miniature inhibitory postsynaptic current amplitude, again before any change in dendritic morphology or migration. No behavioral testing was performed on this arm, so its contribution to the cognitive phenotype is inferred rather than shown; the node is deliberately left terminal.

MGE-derived GABAergic interneuron CL:0011005

inhibitory postsynaptic potential GO:0060080 ↓ DECREASED

Show evidence (1 reference)

PMID:33744924 SUPPORT In Vitro

"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."

Quantifies the inhibitory transmission deficit and its independence from morphological change.

Impaired Learning and Memory

Brpf1-deficient mice show impaired spatial learning and memory (Morris water maze) and impaired fear memory, together with reduced anxiety. This is the organism-level readout that the mouse literature offers as a proxy for the human cognitive phenotype; its fidelity to human intellectual disability is not established, especially given that some human carriers have normal IQ.

learning or memory GO:0007611 ⚠ ABNORMAL

Downstream

Intellectual Disability

Show evidence (1 reference)

PMID:37862219 SUPPORT Model Organism

"These findings help explain the mechanisms of intellectual impairment in patients with BRPF1 mutation."

The authors position the murine spatial and fear memory deficit as the mechanistic proxy for human intellectual impairment.

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Pathograph

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

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Phenotypes

Blood 2

Anemia VERY_RARE Anemia 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)

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML 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 PARTIAL 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 Thrombocytopenia 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)

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML 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 PARTIAL 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 1

Congenital Cardiac Anomalies OCCASIONAL Abnormal heart morphology HP:0001627

Frequency derivation: Colson et al. 2025 pool the published cases and report cardiac anomalies in 9 of 49. 9/49 = 18%, which falls in the OCCASIONAL band (5-29%); their own cohort contributed 1/25 (4%).

Show evidence (2 references)

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML SUPPORT Human Clinical

"Cardiac anomalies were reported as a less common clinical finding, occurring in 9 of 49 cases."

9/49 = 18%, which falls in the OCCASIONAL band (5-29%).

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.

Digestive 3

Feeding Difficulties 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)

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML 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 Gastroesophageal reflux 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)

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML 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 Constipation 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)

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML SUPPORT Human Clinical

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

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

Eye 4

Ptosis FREQUENT Ptosis 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)

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML 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 Strabismus HP:0000486

Frequency derivation: strabismus present in 13 of 29 patients (48%) in Colson et al. 2025 (the same paper's discussion gives the strabismus denominator as 13/27). Both 48% and 13/27 = 48% fall in the FREQUENT band (30-79%).

Show evidence (2 references)

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML 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.

Hypertelorism FREQUENT Hypertelorism 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)

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML 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 FREQUENT Visual impairment HP:0000505

Frequency derivation: 41 of 53 patients (77%) in the Colson et al. 2025 literature review are reported to have visual impairments, which falls in the FREQUENT band (30-79%). The deep-phenotyping cohort reported a higher figure, 13/15 (87%, VERY_FREQUENT band); FREQUENT is retained because it rests on the much larger denominator.

Show evidence (2 references)

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML 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"

41/53 = 77%, which falls in the FREQUENT band (30-79%).

PMID:38346666 PARTIAL 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)."

13/15 = 87% in a smaller, speech-ascertained cohort; recorded as a partial counterweight that would place the phenotype one band higher.

Genitourinary 1

Cryptorchidism OCCASIONAL Cryptorchidism HP:0000028

Frequency derivation: cryptorchidism in 5 of 27 patients in Colson et al. 2025. 5/27 = 19%, which falls in the OCCASIONAL band (5-29%). The denominator is the whole cohort rather than males only, so the male-specific rate is higher.

Show evidence (1 reference)

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML SUPPORT Human Clinical

"Cryptorchidism, not previously reported in the literature, was relatively common in our cohort, occurring in 5 of 27 patients (19%)."

Cryptorchidism in 5/27 (19%) falls in the OCCASIONAL band (5-29%) and is explicitly flagged as newly described.

Head and Neck 6

Downslanted Palpebral Fissures 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.

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 PARTIAL 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.

Bulbous Nose FREQUENT Bulbous nose 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)

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML SUPPORT Human Clinical

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

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

High Palate FREQUENT High palate 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)

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML SUPPORT Human Clinical

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

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

Epicanthus FREQUENT Epicanthus 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)

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML 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.

Microcephaly OCCASIONAL Microcephaly 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)

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML 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.

Integument 2

Hypertrichosis FREQUENT Hypertrichosis 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)

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML 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.

Prominent Fingertip Pads OCCASIONAL Prominent fingertip pads 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)

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML 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%).

Musculoskeletal 2

Infantile Hypotonia FREQUENT Hypotonia 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 (40%) in Colson et al. 2025. Both fall in the FREQUENT band (30-79%).

Show evidence (3 references)

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML SUPPORT Human Clinical

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

11/29 = 40% 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)."

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 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.

Nervous System 12

Global Developmental Delay FREQUENT Global developmental delay HP:0001263

Frequency derivation: Colson et al. 2025 (29 patients, 20 families) state "ID/DD was observed in the majority of patients" and quantify the ID component at 16/29 (55%). 55% falls in the FREQUENT band (30-79%), and the authors' own wording "majority" maps to FREQUENT under the DisMech qualitative mapping.

Show evidence (3 references)

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML SUPPORT Human Clinical

"ID/DD was observed in the majority of patients."

Author wording "majority" maps to FREQUENT under the DisMech qualitative mapping; the paired quantitative statement (16/29, 55%) places the same claim in the FREQUENT band (30-79%).

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.

PMID:39837771 SUPPORT Human Clinical

"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."

The largest cohort (29 patients) confirms developmental delay as a core feature.

Intellectual Disability FREQUENT Intellectual disability HP:0001249

Severity: MILD

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)

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML 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 PARTIAL 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 VERY_FREQUENT Delayed speech and language development HP:0000750

Frequency derivation: the dedicated speech-pathology cohort found language disorder in 11/12 assessed (92%), which falls in the VERY_FREQUENT band (80-99%), and describes involvement as universal. The band is retained against a lower figure in Colson et al. 2025, where "delayed speech and language development" was recorded as a reported developmental-milestone item in 13/29 (46%, FREQUENT band) rather than by formal speech-language assessment; the two numbers measure different things and only the former is a direct measurement of the phenotype.

Show evidence (3 references)

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML PARTIAL Human Clinical

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

13/29 = 46% (FREQUENT band) in the largest cohort, lower than the 92% found on formal speech-language assessment; recorded here as a partial, band-lowering counterweight rather than as support for VERY_FREQUENT.

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."

11 of 12 assessed (92%) had language disorder, supporting the VERY_FREQUENT band.

PMID:38346666 SUPPORT Human Clinical

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

The dedicated speech-pathology study describes involvement as universal against an otherwise variable phenotype.

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 Motor delay 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)

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML 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.

Corpus Callosum Anomalies OCCASIONAL Hypoplasia of the corpus callosum HP:0002079

Frequency derivation: of the 17 Colson et al. 2025 patients who had brain MRI, two (12%) had agenesis of the corpus callosum; 12% falls in the OCCASIONAL band (5-29%). An independent review found structural brain abnormalities in 5 of 22 previously reported patients (23%), also OCCASIONAL. Both denominators are restricted to those imaged, and MRI was ordered on clinical indication rather than systematically.

Show evidence (3 references)

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML 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."

2/17 = 12% among those imaged, which falls in the OCCASIONAL band (5-29%).

PMID:39837771 SUPPORT Human Clinical

"Structural abnormalities such as agenesis of the corpus callosum and ocular defects were noted, consistent with previous studies but with some differences."

Confirms callosal agenesis among the structural abnormalities in the largest cohort.

PMID:31176769 SUPPORT Human Clinical

"However, only 5 of 22 previously reported patients show structural brain abnormalities."

5 of 22 (23%) with structural brain abnormalities supports the OCCASIONAL band.

Seizures OCCASIONAL Seizure 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)

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML 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 Attention deficit hyperactivity disorder 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)

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML 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.

Show evidence (1 reference)

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML SUPPORT Human Clinical

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

Anxiety OCCASIONAL Anxiety 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)

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML SUPPORT Human Clinical

"anxiety (21%)"

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

Autistic Behavior OCCASIONAL Autistic behavior 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)

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML SUPPORT Human Clinical

"autistic behaviour (15%)"

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

PMID:32010779 PARTIAL 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 Sleep disturbance 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)

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML SUPPORT Human Clinical

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

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

Growth 2

Short Stature 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)

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML 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 Obesity 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)

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML 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%).

Other 15

Blepharophimosis FREQUENT Blepharophimosis 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)

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML 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.

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 Retrognathia 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)

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML 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 Palpebral edema 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)

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML 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.

Amblyopia OCCASIONAL Amblyopia 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)

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML 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 Iris coloboma 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)

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML SUPPORT Human Clinical

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 PARTIAL 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 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 PARTIAL 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.

Round Face FREQUENT Round face 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)

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML 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.

Synophrys FREQUENT Synophrys 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)

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML SUPPORT Human Clinical

"synophrys (10/28; 36%)"

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

Laterally Extended Eyebrows OCCASIONAL Laterally extended eyebrow 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)

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML 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 Low hanging columella 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)

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML SUPPORT Human Clinical

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

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

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)

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML 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%).

Chiari Type I Malformation 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.

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML 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.

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)

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML 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.

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)

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML 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.

🧬

Genetic Associations

BRPF1 Pathogenic Variants (Causative)

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

Autosomal dominant inheritance

Show evidence (7 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.

+ 4 more references

💊

Medical Actions

Multidisciplinary Supportive and Developmental Care

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

There is no disease-modifying therapy. Management is symptomatic and developmental, coordinating early intervention, physiotherapy and occupational therapy for hypotonia and motor delay, feeding support in infancy, educational support, and ophthalmological and behavioural care.

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 frames management as multi-domain surveillance and care rather than targeted therapy.

Speech and Language Therapy

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

Speech and language therapy is the highest-yield intervention given the near universal speech and language disorder. Because childhood apraxia of speech is present in a substantial minority, therapy should be selected on the basis of a formal differential speech diagnosis rather than a generic "speech delay" label - the explicit message of the dedicated speech-pathology study.

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

Show evidence (1 reference)

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.

Ptosis Repair Surgery

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

Surgical correction of ptosis addresses the syndrome's defining sign and, more importantly, removes an amblyogenic visual-axis obstruction. Because vision impairment is reported in the large majority of patients and amblyopia is documented, timing relative to visual development matters. Direct outcome data for ptosis surgery specifically in BRPF1 patients have not been published; the rationale is the documented ptosis plus amblyopia risk rather than a BRPF1-specific surgical series.

Target Phenotypes: Ptosis HP:0000508 Amblyopia HP:0000646

Show evidence (1 reference)

PMID:38346666 PARTIAL 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)."

Establishes the high burden of vision impairment that motivates timely eyelid surgery; the paper does not itself report surgical outcomes.

Physical and Occupational Therapy

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

Physiotherapy and occupational therapy target infantile hypotonia, fine and gross motor delay, muscular weakness, and feeding and daily-living skills. The prognosis for the motor domain is comparatively good, since motor delays frequently resolve in later childhood.

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 the motor-domain targets and their favourable natural history.

Genetic Counseling

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

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 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."

Gonadal mosaicism materially changes recurrence-risk counselling for a seemingly de novo variant.

PMID:39837771 SUPPORT Human Clinical

"Familial analysis revealed variability in clinical expression."

Intrafamilial variability is a key counselling point.

Experimental Pharmacologic Restoration of H3K23 Acylation

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

Agent: butyrate CHEBI:17968 propionate CHEBI:17272 vorinostat CHEBI:45716

Preclinical only. Because the molecular lesion is a deficit of H3K23 acetylation and propionylation, agents that raise histone acylation - propionate and butyrate as acyl-CoA precursors, and the histone deacetylase inhibitors valproate and vorinostat - were shown to promote H3K23 acylation in cell systems, and the authors proposed mutation-based therapy on that basis. There is no clinical trial, no in vivo efficacy data, and no evidence of benefit in BRPF1 patients; valproate in particular is a known human teratogen and neurodevelopmental risk and must not be inferred as a treatment for this disorder from these data.

Mechanism Target:

RESTORES Deficient Histone H3K23 Acetylation

RESTORES Deficient Histone H3K23 Propionylation

Show evidence (2 references)

PMID:32010779 PARTIAL In Vitro

"Valproate, vorinostat, propionate and butyrate promote H3K23 acylation."

Cell-based demonstration that these agents raise H3K23 acylation; no patient-level efficacy is claimed.

PMID:32010779 PARTIAL In Vitro

"suggest mutation-based therapy for medical conditions with deficient histone acylation"

The therapeutic proposal is explicitly a suggestion arising from in vitro data.

Behavioural and ADHD Management

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

A behavioural disorder is present in 18/29 (62%) of the largest cohort and is a leading source of caregiver burden, yet it is the phenotype least served by the otherwise developmental focus of care. Management is symptom-directed and follows generic neurodevelopmental practice: behavioural assessment and counselling for the attention/hyperactivity, low frustration tolerance, anxiety and agitation components, sleep hygiene for the 31% with sleep disturbance, and standard ADHD pharmacotherapy where behavioural measures are insufficient. No BRPF1-specific behavioural intervention or drug-selection evidence exists, so nothing here is disorder-specific beyond the indication.

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

Show evidence (2 references)

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML SUPPORT Human Clinical

Establishes the indication - a behavioural phenotype in the majority of patients, itemized into the targets this intervention addresses. The evidence supports the need for behavioural management, not the efficacy of any particular regimen in BRPF1 disease.

url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML SUPPORT Human Clinical

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

Quantifies the sleep component of the behavioural burden addressed by this intervention.

🔀

Differential Diagnoses

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

Arboleda-Tham syndrome (KAT6A) MONDO:0014558

Overlapping Features The closest mechanistic neighbour: KAT6A is one of the acetyltransferases BRPF1 scaffolds, and much of the "BRPF1-KAT6A complex" literature reports KAT6A patients rather than BRPF1 patients. Clinically the two are separable. Arboleda-Tham syndrome is almost always de novo, features near-universal intellectual disability with profound expressive speech delay, microcephaly, congenital cardiac septal defects, and gastrointestinal dysmotility. BRPF1-related disorder is frequently inherited, intellectual disability is milder and sometimes absent, and ptosis with blepharophimosis dominates the facial gestalt. The founding BRPF1 paper states the overlap is partial rather than identical.

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 The second, allelic KAT6B phenotype. Distinguished by patellar agenesis or hypoplasia, flexion contractures, genital anomalies, agenesis of the corpus callosum, microcephaly and renal cysts, with severe developmental delay - a much more severe and skeletally distinctive presentation than BRPF1-related disorder, which lacks the patellar and genital findings.

Show evidence (1 reference)

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.

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 A documented real-world confusion rather than a theoretical one. Facial dysmorphism, short stature and developmental delay can prompt a clinical Noonan diagnosis; in a series of clinically diagnosed Noonan patients who were RASopathy-panel negative, exome sequencing established BRPF1 among the alternative diagnoses. Ptosis is common to both, so the discriminators are the RASopathy-typical pulmonary valve stenosis, hypertrophic cardiomyopathy, webbed neck and lymphatic anomalies, which BRPF1 does not produce.

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 BPES (FOXL2) is the primary non-syndromic-ID differential when ptosis and blepharophimosis are the presenting signs. BPES adds epicanthus inversus and, in type I, premature ovarian insufficiency, but does not cause intellectual disability or the wider neurodevelopmental phenotype - so cognitive and speech assessment is the discriminator.

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 specific to BPES and has no BRPF1 counterpart.
Developmental delay and intellectual disability in BPES occur only with contiguous FOXL2 deletions that take in neighbouring genes, not with intragenic FOXL2 variants; in BRPF1 disease the neurodevelopmental phenotype is intrinsic.

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"

In BPES these BRPF1-like features appear only in the contiguous-gene deletion setting and are attributed to neighbouring genes, so their presence with an intragenic FOXL2 variant argues against BPES and for an alternative diagnosis such as BRPF1-related disorder.

{ }

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), KAT6B (MORF), and KAT7 (HBO1) 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
  patient variants impair both acylations. 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) and corpus callosum anomalies are frequent enough that dedicated
  ophthalmological and neuroimaging assessment is recommended. 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 one reported sibship arose through 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."

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
  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.
  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: >-
    Loss of one functional BRPF1 allele halves the dose of the chromatin-reader
    scaffold. Haploinsufficiency, rather than a gain-of-function or
    dominant-negative product, is the accepted mechanism; the phenotypic
    contribution of BRPF1 dosage was isolated by comparing individuals with
    BRPF1-only lesions, SETD5-only lesions, and 3p25 deletions spanning both
    genes.
  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
  description: >-
    BRPF1 is the scaffold subunit of tetrameric MYST acetyltransferase complexes
    built around KAT6A (MOZ), KAT6B (MORF), or KAT7 (HBO1) plus ING4/ING5 and
    MEAF6. Reduced BRPF1 dose destabilizes assembly and activation of these
    complexes. This node is the mechanistic point at which BRPF1 disease
    converges with, but is not identical to, KAT6A- and KAT6B-related disorders:
    the enzymes have BRPF1-independent activities and BRPF1 has partners beyond
    KAT6A/KAT6B, which is the accepted explanation for the partial rather than
    complete clinical 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 the four scaffold functions that are lost when BRPF1 dose falls:
      subunit bridging, enzyme stimulation, substrate targeting, and
      transcriptional activation.
  - 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: >-
      Explicitly establishes both the shared complex biology and the clinical
      non-identity with KAT6A/KAT6B disorders.
  - 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 mislocalizes and loses protein interactions, i.e. fails to
      scaffold the complex.
  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
  description: >-
    Loss of BRPF1 scaffold activity lowers acetylation of histone H3 lysine 23,
    an abundant chromatin mark that BRPF1 itself also reads. In human embryonic
    stem cells, BRPF1, H3K4me3 and H3K23ac co-occupy open chromatin at stemness
    genes, so the deficit is coupled to a reader-writer circuit rather than being
    a bulk enzymatic loss.
  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: >-
      Patient variants directly reduce H3K23 acetylation.
  - 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.
  downstream:
  - target: Altered Chromatin Accessibility and Developmental Transcriptional Programs
    causal_link_type: DIRECT
    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: >-
        Directly links loss of BRPF1-dependent H3K23ac to reduced chromatin
        accessibility and altered differentiation.

- name: Deficient Histone H3K23 Propionylation
  description: >-
    BRPF1-KAT6 complexes also propionylate H3K23, and patient BRPF1 variants
    impair this acylation. Brpf1 deletion abolishes the mark in mouse embryos and
    fibroblasts. Because the propionylation and acetylation deficits co-occur in
    every patient sample studied, 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.
  downstream:
  - target: Altered Chromatin Accessibility and 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: PARTIAL
      evidence_source: IN_VITRO
      snippet: >-
        Immunofluorescence microscopy and ATAC-See revealed the association of
        this modification with active chromatin.
      explanation: >-
        H3K23 propionylation marks active chromatin, making an effect on
        transcriptional programs plausible; the causal steps are not demonstrated.

- name: Altered Chromatin Accessibility and Developmental Transcriptional Programs
  description: >-
    Loss of the BRPF1-dependent H3K23 acyl marks closes chromatin at
    BRPF1-occupied loci and shifts developmental gene expression. In
    Brpf1-deficient mouse forebrain neurons the affected transcripts are
    enriched for neural development, synapse function and memory genes. This is
    the hub from which the multisystem phenotype diverges; the individual steps
    from chromatin state to each organ-level endpoint are not resolved in humans.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  biological_processes:
  - preferred_term: chromatin organization
    term:
      id: GO:0006325
      label: chromatin organization
    modifier: ABNORMAL
  - preferred_term: regulation of transcription by RNA polymerase II
    term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
    modifier: ABNORMAL
  - preferred_term: forebrain development
    term:
      id: GO:0030900
      label: forebrain development
    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, H3K4me3, and H3K23ac substantially co-occupy the open chromatin and
      stemness genes in hESCs.
    explanation: >-
      Places BRPF1 and its mark at open chromatin over developmentally decisive
      genes.
  - 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 Brpf1 deficiency reduced the frequency of miniature
      excitatory postsynaptic currents and downregulated the expression of genes
      Pcdhgb1, Slc16a7, Robo3, and Rho, which are related to neural development,
      synapse function, and memory, thereby damaging spatial and fear memory in
      mice.
    explanation: >-
      Identifies the neurodevelopmental and synaptic gene programs dysregulated by
      Brpf1 loss in forebrain neurons.
  downstream:
  - target: Impaired Dendritic Arborization and Spine Formation
    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 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.
      explanation: >-
        Brpf1 dosage loss produces a dendritic and spine phenotype; the
        intervening transcriptional steps are not individually mapped.
  - 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: MODEL_ORGANISM
      snippet: >-
        Our results demonstrated a key role of Brpf1 in inhibitory
        neurotransmission and related gene expression of GABAergic interneurons.
      explanation: >-
        Brpf1 loss alters gene expression and inhibitory function in GABAergic
        interneurons, a parallel arm to the excitatory deficit.
  - 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 and Callosal Development
    causal_link_type: DIRECT
    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: >-
        Directly ties the transcriptional dysregulation to the neocortical
        developmental program.
  - 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: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
      reference_title: "The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      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.

- name: Deregulated Ocular and Periocular Developmental Transcription Factor Programs
  description: >-
    The ocular and periocular arm of the phenotype - ptosis, blepharophimosis
    and strabismus, the features that discriminate BRPF1 from co-deleted SETD5 -
    has until now had no mechanistic route in this graph. The proposed route is
    that BRPF1 loss deregulates transcription of the ocular developmental
    transcription factors Pitx2, Hmx1 and Pax6, each independently implicated in
    ocular developmental malformation, and that the resulting disruption of
    periocular morphogenesis produces the eyelid and ocular-alignment
    phenotypes. This is an inference drawn by the authors of the largest cohort
    from the animal and cell-based BRPF1 literature, not a demonstration in
    human periocular tissue: no BRPF1 model reproduces ptosis or
    blepharophimosis, so the node is marked HYPOTHETICAL and is the subject of
    an open HUMAN_MODEL_MISMATCH discussion.
  biological_scale: CELLULAR
  mechanism_confidence: HYPOTHETICAL
  biological_processes:
  - preferred_term: eye development
    term:
      id: GO:0001654
      label: eye development
    modifier: ABNORMAL
  - 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: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
    reference_title: "The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    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: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
    reference_title: "The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    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: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
      reference_title: "The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review."
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      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: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
      reference_title: "The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review."
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      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: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
      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 and Callosal Development
  description: >-
    Forebrain-specific Brpf1 inactivation in mouse produces neocortical
    abnormalities and partial callosal agenesis, with a reduced pool of
    Tbr2-positive intermediate neuronal progenitors and aberrant neurogenesis.
    Transcriptionally, Brpf1 loss both decreases neocortical developmental genes
    (Robo3, Otx1) and de-represses Hox and other transcription factors, so BRPF1
    acts as both activator and silencer. This node supplies the developmental
    mechanism for the human corpus callosum anomalies, but the mouse model is a
    conditional homozygous null and is far more severe (early postnatal
    lethality) than human heterozygous disease.
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  biological_processes:
  - preferred_term: forebrain development
    term:
      id: GO:0030900
      label: forebrain development
    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: >-
      Here, we report that forebrain-specific inactivation of the mouse Brpf1
      gene caused early postnatal lethality, neocortical abnormalities, and
      partial callosal agenesis.
    explanation: >-
      Establishes the callosal and neocortical developmental phenotype of Brpf1
      loss in forebrain.
  - 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.
  downstream:
  - target: Corpus Callosum Anomalies
    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: >-
        Structural abnormalities such as agenesis of the corpus callosum and
        ocular defects were noted, consistent with previous studies but with some
        differences.
      explanation: >-
        The mouse callosal phenotype has a human counterpart in the largest
        cohort; the link across species and zygosity is not formally established.

- name: Impaired Hematopoietic Stem and Progenitor Cell Maintenance
  description: >-
    A separate organ arm. In mice, blood-specific Brpf1 deletion causes acute
    bone marrow failure and aplastic anemia with severe loss of hematopoietic
    stem cells and progenitors, raised reactive oxygen species, senescence and
    apoptosis, and reduced multipotency-gene expression - and BRPF1 is required
    for H3K23 acetylation in this compartment too. In humans only one family with
    anemia and thrombocytopenia has been reported, and the mouse data are
    homozygous conditional nulls, so this arm is biologically plausible but
    clinically unproven.
  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: >-
      Confirms that the same H3K23 acetylation lesion underlies the hematopoietic
      arm.
  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: PARTIAL
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Brpf1-deficient pups experienced early lethality due to acute bone marrow
        failure and aplastic anemia.
      explanation: >-
        Provides a mechanism for the single 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: PARTIAL
      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; human evidence is a single family.

- name: Impaired Dendritic Arborization and Spine Formation
  description: >-
    In Brpf1 heterozygous mice, hippocampal granule cells and cortical pyramidal
    neurons show reduced dendritic complexity, lower spine density, and altered
    spine and synapse morphology. This is the best-characterized cellular
    substrate for the cognitive phenotype, but it has been demonstrated only in
    mouse; no equivalent human neuronal data exist.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  cell_types:
  - preferred_term: hippocampal pyramidal neuron
    term:
      id: CL:1001571
      label: hippocampal pyramidal neuron
  - 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
  - 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 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.
    explanation: >-
      Defines the dendritic and spine deficit produced by Brpf1 haploinsufficiency.
  downstream:
  - target: Reduced Excitatory Synaptic Transmission in Forebrain Neurons
    causal_link_type: DIRECT
    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: >-
        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.
      explanation: >-
        The structural deficit is accompanied by reduced miniature excitatory
        postsynaptic currents.

- name: Reduced Excitatory Synaptic Transmission in Forebrain Neurons
  description: >-
    Brpf1 loss lowers the frequency (and, in some preparations, amplitude) of
    miniature excitatory postsynaptic currents in hippocampal and forebrain
    excitatory neurons. Notably, in acute knockdown the electrophysiological
    deficit precedes any measurable change in dendritic morphology, indicating a
    partly morphology-independent synaptic effect.
  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: >-
      Establishes a synaptic transmission deficit that is not simply secondary to
      dendritic loss.
  - 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: >-
      To test this, we knocked out Brpf1 in forebrain excitatory neurons using
      CaMKIIa-Cre.
    explanation: >-
      A cell-type-restricted knockout localizes the deficit to forebrain
      excitatory neurons.
  downstream:
  - target: Impaired Learning and Memory
    causal_link_type: DIRECT
    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: >-
        Our results showed that Brpf1 mild knockdown attenuated hippocampal
        excitatory synaptic transmission and reduced spatial learning and memory
        ability, which helps explain the symptoms of patients with BRPF1
        mutations.
      explanation: >-
        Links the synaptic deficit to a behavioral learning and memory deficit in
        the same animals.

- name: Reduced Inhibitory Neurotransmission in GABAergic Interneurons
  description: >-
    A parallel inhibitory arm: Brpf1 knockdown in mouse medial-ganglionic-eminence
    (MGE)-derived GABAergic interneurons raises the action-potential firing
    threshold, reduces evoked firing, and lowers miniature inhibitory
    postsynaptic current amplitude, again before any change in dendritic
    morphology or migration. No behavioral testing was performed on this arm, so
    its contribution to the cognitive phenotype is inferred rather than shown;
    the node is deliberately left terminal.
  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: >-
      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.
    explanation: >-
      Quantifies the inhibitory transmission deficit and its independence from
      morphological change.

- name: Impaired Learning and Memory
  description: >-
    Brpf1-deficient mice show impaired spatial learning and memory (Morris water
    maze) and impaired fear memory, together with reduced anxiety. This is the
    organism-level readout that the mouse literature offers as a proxy for the
    human cognitive phenotype; its fidelity to human intellectual disability is
    not established, especially given that some human carriers have normal IQ.
  biological_scale: ORGANISM
  mechanism_confidence: PROVISIONAL
  biological_processes:
  - preferred_term: learning or memory
    term:
      id: GO:0007611
      label: learning or memory
    modifier: ABNORMAL
  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: >-
      These findings help explain the mechanisms of intellectual impairment in
      patients with BRPF1 mutation.
    explanation: >-
      The authors position the murine spatial and fear memory deficit as the
      mechanistic proxy for human intellectual impairment.
  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: PARTIAL
      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: >-
    Frequency derivation: Colson et al. 2025 (29 patients, 20 families) state
    "ID/DD was observed in the majority of patients" and quantify the ID
    component at 16/29 (55%). 55% falls in the FREQUENT band (30-79%), and the
    authors' own wording "majority" maps to FREQUENT under the DisMech
    qualitative mapping.
  evidence:
  - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
    reference_title: "The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ID/DD was observed in the majority of patients."
    explanation: >-
      Author wording "majority" maps to FREQUENT under the DisMech qualitative
      mapping; the paired quantitative statement (16/29, 55%) places the same
      claim in the FREQUENT band (30-79%).
  - 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 is a population frequency, not
    an obligate feature.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
    severity: MILD
  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: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
    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: PARTIAL
    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: PARTIAL
    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 impairment is the most consistent feature of the
    disorder, present essentially universally and often disproportionate to
    general cognition. Deficits span receptive, expressive, written and
    social-pragmatic domains and are usually mild to moderate. Phonological delay
    and disorder are the commonest speech diagnoses.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  frequency: VERY_FREQUENT
  notes: >-
    Frequency derivation: the dedicated speech-pathology cohort found language
    disorder in 11/12 assessed (92%), which falls in the VERY_FREQUENT band
    (80-99%), and describes involvement as universal. The band is retained
    against a lower figure in Colson et al. 2025, where "delayed speech and
    language development" was recorded as a reported developmental-milestone
    item in 13/29 (46%, FREQUENT band) rather than by formal speech-language
    assessment; the two numbers measure different things and only the former is
    a direct measurement of the phenotype.
  evidence:
  - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
    reference_title: "The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Delayed speech and language development were noted in 13 patients (46%)."
    explanation: >-
      13/29 = 46% (FREQUENT band) in the largest cohort, lower than the 92%
      found on formal speech-language assessment; recorded here as a partial,
      band-lowering counterweight rather than as support for VERY_FREQUENT.
  - 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: >-
      11 of 12 assessed (92%) had language disorder, supporting the
      VERY_FREQUENT band.
  - 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 is noteable,
      relative to the high degree of phenotypic variability in BRPF1-related
      disorder.
    explanation: >-
      The dedicated speech-pathology study describes involvement as universal
      against an otherwise variable phenotype.

- 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.
    Its recognition changes therapy targets, since apraxia requires
    motor-programming-focused intervention rather than generic language therapy.
  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. It is generally non-progressive and improves
    with age.
  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 (40%) in Colson et al. 2025. Both fall in the FREQUENT
    band (30-79%).
  evidence:
  - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
    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: >-
      11/29 = 40% 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: >-
      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: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
    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: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
    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: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
    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: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
    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: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
    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: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
    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: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
    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: >-
    Frequency derivation: strabismus present in 13 of 29 patients (48%) in
    Colson et al. 2025 (the same paper's discussion gives the strabismus
    denominator as 13/27). Both 48% and 13/27 = 48% fall in the FREQUENT band
    (30-79%).
  evidence:
  - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
    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: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
    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: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
    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: PARTIAL
    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: PARTIAL
    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: Corpus Callosum Anomalies
  description: >-
    Structural brain findings, notably agenesis or hypoplasia of the corpus
    callosum, occur in a minority of patients. In an early review only 5 of 22
    reported patients had structural brain abnormalities, and the largest cohort
    confirms callosal anomalies while noting differences from earlier series.
  phenotype_term:
    preferred_term: Hypoplasia of the corpus callosum
    term:
      id: HP:0002079
      label: Hypoplasia of the corpus callosum
  frequency: OCCASIONAL
  notes: >-
    Frequency derivation: of the 17 Colson et al. 2025 patients who had brain
    MRI, two (12%) had agenesis of the corpus callosum; 12% falls in the
    OCCASIONAL band (5-29%). An independent review found structural brain
    abnormalities in 5 of 22 previously reported patients (23%), also
    OCCASIONAL. Both denominators are restricted to those imaged, and MRI was
    ordered on clinical indication rather than systematically.
  evidence:
  - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
    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: >-
      2/17 = 12% among those imaged, which 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: >-
      Structural abnormalities such as agenesis of the corpus callosum and ocular
      defects were noted, consistent with previous studies but with some
      differences.
    explanation: >-
      Confirms callosal agenesis among the structural abnormalities in the largest
      cohort.
  - 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: >-
      However, only 5 of 22 previously reported patients show structural brain
      abnormalities.
    explanation: >-
      5 of 22 (23%) with structural brain abnormalities supports the OCCASIONAL
      band.

- 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: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
    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: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
    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: OCCASIONAL
  notes: >-
    Frequency derivation: Colson et al. 2025 pool the published cases and report
    cardiac anomalies in 9 of 49. 9/49 = 18%, which falls in the OCCASIONAL band
    (5-29%); their own cohort contributed 1/25 (4%).
  evidence:
  - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
    reference_title: "The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cardiac anomalies were reported as a less common clinical finding,
      occurring in 9 of 49 cases.
    explanation: >-
      9/49 = 18%, which 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: 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 described in a single Turkish family with a novel BRPF1 nonsense
    variant and had not previously been reported in IDDDFP. BRPF1 has an
    established role in fetal and adult hematopoietic stem cell biology, which
    makes the observation biologically plausible, but it rests on one family and
    should not be treated as an established feature.
  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: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
    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: PARTIAL
    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 together with anemia in the same single Turkish
    family and, like the anemia, is a novel and unreplicated observation.
  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: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
    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: PARTIAL
    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: PARTIAL
    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: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
    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: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
    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: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
    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: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
    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: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
    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: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
    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: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
    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: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
    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: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
    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.
  evidence:
  - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
    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: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
    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: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
    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: PARTIAL
    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: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
    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: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
    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: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
    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: >-
    Visual impairment - the composite of strabismus, refractive error,
    amblyopia and, when specifically sought, optic neuropathy - is the dominant
    organ-specific morbidity and the reason systematic ophthalmological
    surveillance is recommended.
  phenotype_term:
    preferred_term: Visual impairment
    term:
      id: HP:0000505
      label: Visual impairment
  frequency: FREQUENT
  notes: >-
    Frequency derivation: 41 of 53 patients (77%) in the Colson et al. 2025
    literature review are reported to have visual impairments, which falls in
    the FREQUENT band (30-79%). The deep-phenotyping cohort reported a higher
    figure, 13/15 (87%, VERY_FREQUENT band); FREQUENT is retained because it
    rests on the much larger denominator.
  evidence:
  - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
    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: >-
      41/53 = 77%, which falls in the FREQUENT band (30-79%).
  - reference: PMID:38346666
    reference_title: "Beyond 'speech delay': Expanding the phenotype of BRPF1-related disorder."
    supports: PARTIAL
    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: >-
      13/15 = 87% in a smaller, speech-ascertained cohort; recorded as a partial
      counterweight that would place the phenotype one band higher.

- category: Ophthalmologic
  name: Refractive Error
  description: >-
    Myopia and hypermetropia are common and are amblyogenic when uncorrected,
    which is why refraction belongs in the baseline ophthalmological assessment.
  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: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
    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: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
    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: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
    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: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
    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: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
    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 was not reported before the 2025 cohort but was relatively
    common in it, making it a newly described component of the phenotype that
    warrants examination in affected males.
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  frequency: OCCASIONAL
  notes: >-
    Frequency derivation: cryptorchidism in 5 of 27 patients in Colson et al.
    2025. 5/27 = 19%, which falls in the OCCASIONAL band (5-29%). The
    denominator is the whole cohort rather than males only, so the male-specific
    rate is higher.
  evidence:
  - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
    reference_title: "The Phenotypic and Genotypic Spectrum of BRPF1-Related Disorder: 29 New Patients and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cryptorchidism, not previously reported in the literature, was relatively
      common in our cohort, occurring in 5 of 27 patients (19%).
    explanation: >-
      Cryptorchidism in 5/27 (19%) falls in the OCCASIONAL band (5-29%) and is
      explicitly flagged as newly described.

- category: Musculoskeletal
  name: Clinodactyly of the Fifth Finger
  description: >-
    Clinodactyly of the fifth digit is the commonest limb finding; extremities
    are otherwise largely unaffected in the prospectively phenotyped cohort.
  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: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
    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: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
    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%).

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: >-
    Cumulative published case count rather than a population rate. BRPF1
    variants were present in 40 cases of syndromic intellectual disability as of
    2020; the 2025 cohort added 29 new patients from 20 families on top of its
    literature comparison group, bringing the reported total to roughly 100
    individuals. Orphanet also holds a validated worldwide "Cases/families"
    epidemiology record for ORPHA:698090, but the cached Orphadata release
    carries no count in that row, so no Orphanet case number is quoted here.
  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: >-
      Adds 29 further published patients from 20 families to the cumulative
      count.

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 one sibship is explained by
    parental gonadal mosaicism. A contiguous 3p25 deletion may remove BRPF1 with
    the neighbouring SETD5; in that setting both genes contribute to severity,
    but ptosis and blepharophimosis track with BRPF1 loss specifically. 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.
  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: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: >-
        Intellectual developmental disorder with dysmorphic facies and ptosis is
        an autosomal dominant condition characterized by delayed psychomotor
        development, intellectual disability, delayed speech, and dysmorphic
        facial features, mostly ptosis.
      explanation: >-
        States the autosomal dominant mode of inheritance for the entity.
  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: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
    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 a heterozygous missense allele, showing the spectrum extends
      beyond truncating variants.
  - 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: >-
      Establishes parental gonadal mosaicism as a recurrence-risk mechanism
      relevant to counselling.

diagnosis:
- name: Exome or genome sequencing
  description: >-
    Diagnosis is molecular. The facial gestalt is suggestive but not
    pathognomonic and the ID is often mild, so the disorder is typically
    identified by trio exome or genome sequencing rather than targeted testing.
    Chromosomal microarray identifies the 3p25 deletion subset.
  diagnosis_term:
    preferred_term: trio exome or genome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  results: >-
    A heterozygous pathogenic or likely pathogenic BRPF1 variant, or a 3p25
    deletion encompassing BRPF1, establishes 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: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: >-
      In this study, whole exome sequencing (WES) was performed as a molecular
      diagnostic test.
    explanation: >-
      Confirms exome sequencing as the diagnostic modality in an independent
      family.

- name: Chromosomal microarray or exome-based copy-number analysis
  description: >-
    Sequence-level analysis alone misses a real fraction of cases. Whole-gene
    BRPF1 deletions and contiguous 3p25.3 deletions spanning BRPF1 and the
    neighbouring SETD5 are an established route to the phenotype: two of the 17
    unique alleles in the largest cohort were complete gene deletions, detected
    by array CGH rather than by sequencing, and the founding series identified
    BRPF1 deletions alongside point mutations. Copy-number analysis is therefore
    required in parallel with sequencing - either as read-depth CNV calling on
    the exome or genome data, or as a chromosomal microarray when the sequencing
    pipeline does not call CNVs. Segregation of a detected deletion can be
    confirmed by qPCR.
  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, establishes the diagnosis; a
    deletion spanning SETD5 as well predicts a more severe intellectual
    phenotype than BRPF1 loss alone.
  evidence:
  - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
    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 including OCT
  description: >-
    Detailed ophthalmological assessment is recommended at diagnosis and
    periodically thereafter. Beyond ptosis and blepharophimosis, patients may
    have strabismus, amblyopia, refractive error, coloboma, and subclinical optic
    neuropathy that is detectable only on optical coherence tomography.
  diagnosis_term:
    preferred_term: ophthalmological evaluation including optical coherence tomography
    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: >-
    There is no disease-modifying therapy. Management is symptomatic and
    developmental, coordinating early intervention, physiotherapy and
    occupational therapy for hypotonia and motor delay, feeding support in
    infancy, educational support, and ophthalmological and behavioural care.
  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 frames management as multi-domain surveillance and care rather
      than targeted therapy.
  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 is the highest-yield intervention given the near
    universal speech and language disorder. Because childhood apraxia of speech
    is present in a substantial minority, therapy should be selected on the basis
    of a formal differential speech diagnosis rather than a generic "speech
    delay" label - the explicit message of the dedicated speech-pathology study.
  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.
  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: >-
    Surgical correction of ptosis addresses the syndrome's defining sign and,
    more importantly, removes an amblyogenic visual-axis obstruction. Because
    vision impairment is reported in the large majority of patients and
    amblyopia is documented, timing relative to visual development matters.
    Direct outcome data for ptosis surgery specifically in BRPF1 patients have
    not been published; the rationale is the documented ptosis plus amblyopia
    risk rather than a BRPF1-specific surgical series.
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: ptosis repair surgery
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  therapeutic_modality: SURGERY
  evidence:
  - reference: PMID:38346666
    reference_title: "Beyond 'speech delay': Expanding the phenotype of BRPF1-related disorder."
    supports: PARTIAL
    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: >-
      Establishes the high burden of vision impairment that motivates timely
      eyelid surgery; the paper does not itself report surgical outcomes.
  target_phenotypes:
  - preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  - preferred_term: Amblyopia
    term:
      id: HP:0000646
      label: Amblyopia

- name: Physical and Occupational Therapy
  description: >-
    Physiotherapy and occupational therapy target infantile hypotonia, fine and
    gross motor delay, muscular weakness, and feeding and daily-living skills.
    The prognosis for the motor domain is comparatively good, since motor delays
    frequently resolve in later childhood.
  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 the motor-domain targets and their favourable natural history.
  target_phenotypes:
  - preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  - 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 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: >-
      Gonadal mosaicism materially changes recurrence-risk counselling for a
      seemingly de novo variant.
  - 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 Pharmacologic Restoration of H3K23 Acylation
  description: >-
    Preclinical only. Because the molecular lesion is a deficit of H3K23
    acetylation and propionylation, agents that raise histone acylation -
    propionate and butyrate as acyl-CoA precursors, and the histone deacetylase
    inhibitors valproate and vorinostat - were shown to promote H3K23 acylation
    in cell systems, and the authors proposed mutation-based therapy on that
    basis. There is no clinical trial, no in vivo efficacy data, and no evidence
    of benefit in BRPF1 patients; valproate in particular is a known human
    teratogen and neurodevelopmental risk and must not be inferred as a treatment
    for this disorder from these data.
  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: propionate
      term:
        id: CHEBI:17272
        label: propionate
    - preferred_term: vorinostat
      term:
        id: CHEBI:45716
        label: vorinostat
  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: PARTIAL
    evidence_source: IN_VITRO
    snippet: "Valproate, vorinostat, propionate and butyrate promote H3K23 acylation."
    explanation: >-
      Cell-based demonstration that these agents raise H3K23 acylation; no
      patient-level efficacy is claimed.
  - reference: PMID:32010779
    reference_title: "Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer."
    supports: PARTIAL
    evidence_source: IN_VITRO
    snippet: >-
      suggest mutation-based therapy for medical conditions with deficient
      histone acylation
    explanation: >-
      The therapeutic proposal is explicitly a suggestion arising from in vitro
      data.
  notes: >-
    Listed for mechanistic completeness and to document the rationale, not as a
    recommended intervention. Valproate is contraindicated in pregnancy and
    carries neurodevelopmental risk; nothing in the cited work supports its
    clinical use in BRPF1-related disorder.

- name: Behavioural and ADHD Management
  description: >-
    A behavioural disorder is present in 18/29 (62%) of the largest cohort and
    is a leading source of caregiver burden, yet it is the phenotype least
    served by the otherwise developmental focus of care. Management is
    symptom-directed and follows generic neurodevelopmental practice: behavioural
    assessment and counselling for the attention/hyperactivity, low frustration
    tolerance, anxiety and agitation components, sleep hygiene for the 31% with
    sleep disturbance, and standard ADHD pharmacotherapy where behavioural
    measures are insufficient. No BRPF1-specific behavioural intervention or
    drug-selection evidence exists, so nothing here is disorder-specific beyond
    the indication.
  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: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
    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: >-
      Establishes the indication - a behavioural phenotype in the majority of
      patients, itemized into the targets this intervention addresses. The
      evidence supports the need for behavioural management, not the efficacy of
      any particular regimen in BRPF1 disease.
  - reference: url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML
    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: >-
      Quantifies the sleep component of the behavioural burden addressed by this
      intervention.
  notes: >-
    No BRPF1-specific efficacy data exist for any behavioural or
    pharmacological intervention; no clinical trial has been registered for this
    disorder. The entry records the indication and the standard-of-care
    response, not disorder-specific evidence of benefit.

differential_diagnoses:
- name: Arboleda-Tham syndrome (KAT6A)
  description: >-
    The closest mechanistic neighbour: KAT6A is one of the acetyltransferases
    BRPF1 scaffolds, and much of the "BRPF1-KAT6A complex" literature reports
    KAT6A patients rather than BRPF1 patients. Clinically the two are separable.
    Arboleda-Tham syndrome is almost always de novo, features near-universal
    intellectual disability with profound expressive speech delay, microcephaly,
    congenital cardiac septal defects, and gastrointestinal dysmotility.
    BRPF1-related disorder is frequently inherited, intellectual disability is
    milder and sometimes absent, and ptosis with blepharophimosis dominates the
    facial gestalt. The founding BRPF1 paper states the overlap is partial rather
    than identical.
  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: >-
    The second, allelic KAT6B phenotype. Distinguished by patellar agenesis or
    hypoplasia, flexion contractures, genital anomalies, agenesis of the corpus
    callosum, microcephaly and renal cysts, with severe developmental delay -
    a much more severe and skeletally distinctive presentation than
    BRPF1-related disorder, which lacks the patellar and genital findings.
  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.

- 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: >-
    A documented real-world confusion rather than a theoretical one. Facial
    dysmorphism, short stature and developmental delay can prompt a clinical
    Noonan diagnosis; in a series of clinically diagnosed Noonan patients who
    were RASopathy-panel negative, exome sequencing established BRPF1 among the
    alternative diagnoses. Ptosis is common to both, so the discriminators are
    the RASopathy-typical pulmonary valve stenosis, hypertrophic cardiomyopathy,
    webbed neck and lymphatic anomalies, which BRPF1 does not produce.
  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: >-
    BPES (FOXL2) is the primary non-syndromic-ID differential when ptosis and
    blepharophimosis are the presenting signs. BPES adds epicanthus inversus and,
    in type I, premature ovarian insufficiency, but does not cause intellectual
    disability or the wider neurodevelopmental phenotype - so cognitive and
    speech assessment is the discriminator.
  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 specific to BPES and has no BRPF1 counterpart.
  - Developmental delay and intellectual disability in BPES occur only with contiguous FOXL2 deletions that take in neighbouring genes, not with intragenic FOXL2 variants; in BRPF1 disease the neurodevelopmental phenotype is intrinsic.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1441/
    reference_title: "Blepharophimosis, Ptosis, and Epicanthus Inversus Syndrome - GeneReviews"
    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"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      intellectual disability, microcephaly, speech delay, ventricular septum
      defect, cleft palate, and subtle skeletal features
    explanation: >-
      In BPES these BRPF1-like features appear only in the contiguous-gene
      deletion setting and are attributed to neighbouring genes, so their
      presence with an intragenic FOXL2 variant argues against BPES and for an
      alternative diagnosis such as BRPF1-related disorder.

discussions:
- discussion_id: brpf1_zygosity_and_species_model_mismatch
  prompt: >-
    Do the mouse Brpf1 models, which are homozygous or conditional nulls with
    lethal phenotypes, validly model human heterozygous BRPF1 haploinsufficiency,
    in which life expectancy appears normal and some carriers have normal IQ?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Aberrant Cortical Neurogenesis and Callosal Development
  - pathophysiology#Impaired Hematopoietic Stem and Progenitor Cell Maintenance
  - pathophysiology#Impaired Learning and Memory
  rationale: >-
    Most of the mechanistic BRPF1 literature uses complete loss of function:
    constitutive knockout is lethal around embryonic day 9.5, forebrain-specific
    inactivation causes early postnatal lethality with partial callosal agenesis,
    and blood-specific deletion causes fatal bone marrow failure. Human disease is
    heterozygous, non-lethal, and often mild - one reported carrier has normal
    intellectual development. Only the Brpf1 heterozygous mouse
    (PMID:31213987) matches human zygosity, and it is the model that yields the
    subtlest phenotype. Treating null-allele findings as the human mechanism risks
    systematically overstating severity, particularly for the callosal and
    hematopoietic arms where human evidence is a minority finding and a single
    family respectively.
  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: >-
      Episignatures are established for KAT6A and for the KAT6B disorders but not
      for BRPF1. Profile genome-wide DNA methylation in blood from a
      variant-confirmed BRPF1 cohort against matched controls and against KAT6A
      and KAT6B cases. A positive result would give the first human-tissue
      molecular readout of heterozygous BRPF1 dosage, would resolve BRPF1
      variants of uncertain significance, and would show whether the three
      complex members converge on one signature or separate.
    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: >-
      The human end of the spectrum includes normal cognition, which no mouse
      model reproduces.

notes: >-
  Named-entity-confusion discipline. BRPF1 is the non-catalytic scaffold of the
  KAT6A/KAT6B/KAT7 acetyltransferase complexes, so a large part of the
  "BRPF1 complex" literature reports patients carrying KAT6A or KAT6B variants,
  not BRPF1 variants. Every clinical citation in this entry was checked to
  confirm the described patients carry BRPF1 variants; KAT6A (Arboleda-Tham
  syndrome, curated separately as kb/disorders/Arboleda-Tham_Syndrome.yaml) and
  KAT6B (SBBYS, genitopatellar syndrome) appear only as differentials.
  PMID:32010779 is a partial exception handled deliberately: it is a
  KAT6A/KAT6B/BRPF1 biochemistry paper, but the clinical claims cited here
  ("12 previously unidentified cases", "Cardiac anomalies are present in a
  subset of the cases") refer explicitly to its BRPF1-variant cases.
  No GeneReviews chapter exists for BRPF1 or IDDDFP. PubMed searches for
  "BRPF1 GeneReviews[All Fields]", "BRPF1[All Fields] AND GeneReviews", and
  "intellectual developmental disorder with dysmorphic facies and ptosis AND
  GeneReviews[All Fields]" returned no BRPF1 chapter (the only hits were the
  unrelated Coffin-Siris, Noonan-with-multiple-lentigines and PPP2R1A
  chapters). The GeneReviews baseline step is therefore not applicable, and the
  phenotype baseline is instead 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).
  Prevalence. An earlier version of this entry stated that prevalence was not
  curated because no population-level estimate had been published. That was
  wrong: Orphanet holds a validated worldwide point-prevalence class of
  <1 / 1 000 000 for ORPHA:698090, now curated with the Orphadata row quoted
  directly. Orphanet also holds a validated worldwide "Cases/families"
  epidemiology record, but the row carries no count in the cached Orphadata
  release, so the cumulative case total is instead sourced to the primary
  literature (40 published cases as of PMID:32010779, plus the 29 new patients
  of PMID:39837771).
  Full-text sourcing. The frequency denominators from the largest cohort
  (Colson et al. 2025) live in the article body, not the abstract. The
  PMID:39837771 reference cache is abstract-only because the NCBI PMC route
  returns a restricted record for this Wiley article, so body-text quotes are
  cited against the Europe PMC full-text endpoint
  (url:https://www.ebi.ac.uk/europepmc/webservices/rest/PMC11973018/fullTextXML),
  following the existing precedent in this repository. Both identifiers point at
  the same paper; the PMID is retained wherever the abstract suffices.
  Known gaps. No genotype-phenotype correlation is asserted because none is
  established. gnomAD constraint values (pLI, LOEUF) are not curated: no cached,
  quotable source for the exact figures was available, so the claim was dropped
  rather than approximated. Frequency bands are given only where a published
  numerator and denominator exist, and are deliberately omitted - with the
  reason recorded in each phenotype's notes - where the published denominators
  straddle two bands (feeding difficulties, short stature) or where no cohort
  tabulates the feature at all (downslanted palpebral fissures, wide nasal
  bridge, muscle weakness, subclinical optic neuropathy, facial nerve palsy,
  Chiari type I malformation). Bands sourced to the 15-participant,
  speech-ascertained cohort (PMID:38346666) are susceptible to ascertainment
  bias toward communication phenotypes and should be read as provisional.
  The Pitx2/Hmx1/Pax6 ocular-transcription-factor node is the authors'
  inference from animal and cell data, not a demonstration in human periocular
  tissue, and is marked HYPOTHETICAL accordingly.
  The entire cellular and synaptic arm of the pathophysiology graph
  (dendritic arborization, excitatory and inhibitory transmission, learning and
  memory) rests on mouse and cultured-neuron data; no human neuronal or iPSC
  evidence exists, and the human phenotype includes carriers with normal IQ,
  which the mouse models do not model. The GABAergic-interneuron node is left
  terminal for this reason: no behavioural testing accompanied that arm.

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References & Deep Research

References

PMID:27939639

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