Bainbridge-Ropers syndrome

Mendelian MONDO:0014205 Pathograph 26 Show in embeddings browser hereditary disease multiple congenital anomalies/dysmorphic syndrome-intellectual disability

Bainbridge-Ropers syndrome (BRPS), increasingly called ASXL3-related disorder, is a rare autosomal dominant neurodevelopmental syndrome caused by heterozygous, predominantly de novo protein-truncating variants in ASXL3 clustered in exons 11 and 12. It is a chromatinopathy: ASXL3 is the non-catalytic scaffolding subunit that partners the deubiquitinase BAP1 in the Polycomb repressive deubiquitinase (PR-DUB) complex, and its loss raises H2A lysine 119 monoubiquitination and broadly dysregulates transcription during neural development. The core clinical picture is moderate-to-severe intellectual disability with absent or profoundly limited speech, infantile hypotonia, severe feeding difficulties with failure to thrive, gastroesophageal reflux, autistic features, and a recognizable but nonspecific craniofacial gestalt. BRPS was originally described as a "Bohring-Opitz-like" phenotype, but it is now established as a clinically distinct entity from ASXL1-related Bohring-Opitz syndrome and ASXL2-related Shashi-Pena syndrome.

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Classifications

Harrison's Chapter

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Mappings

MONDO

MONDO:0014205 severe feeding difficulties-failure to thrive-microcephaly due to ASXL3 deficiency syndrome

Primary MONDO identifier for Bainbridge-Ropers syndrome; MONDO:0014205 xrefs OMIM:615485 and Orphanet:352577 and carries the RO:0004003 gene relation to HGNC:29357 (ASXL3), confirming the entity anchor.

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Inheritance

Autosomal dominant, typically de novo HP:0000006

BRPS is inherited in an autosomal dominant manner and is typically caused by a de novo heterozygous protein-truncating ASXL3 variant. Transmission from a mildly affected or mosaic parent is documented but uncommon, and sibling recurrence attributable to parental gonadal or gonosomal mosaicism has been reported, so recurrence risk after an apparently de novo event is low but not negligible.

Autosomal dominant inheritance

Show evidence (3 references)

PMID:33151654 SUPPORT Human Clinical

"ASXL3-related disorder is an autosomal dominant disorder typically caused by a de novo pathogenic variant."

GeneReviews states the mode of inheritance and the predominance of de novo variants.

PMID:33151654 SUPPORT Human Clinical

"Rarely, individuals diagnosed with ASXL3-related disorder have the disorder as the result of a pathogenic variant inherited from a parent."

Supports the documented but uncommon inherited route.

PMID:39833101 SUPPORT Human Clinical

"We documented recurrence in nontwin siblings due to parental mosaicism."

Directly documents sibling recurrence via parental mosaicism, the basis for the non-negligible recurrence-risk counselling point.

Discussions and Knowledge Gaps

Does the severe early neural cell-fate specification defect seen on ASXL3 knockdown in Xenopus laevis embryos actually occur in human ASXL3 haploinsufficiency, given that most affected individuals have structurally normal brain MRI?

HUMAN MODEL MISMATCH OPEN brps_human_model_mismatch_neural_fate

Attached to

pathophysiology#Disrupted Neural Cell Fate Specification

The strongest mechanistic link between the ASXL3 chromatin lesion and the neurodevelopmental phenotype comes from a morpholino knockdown in a frog embryo, which produces open neural plates and loss of hindbrain, primary neuron and neural crest markers - a far more dramatic patterning failure than anything seen in human patients, in whom GeneReviews notes that most individuals with seizures still have normal brain MRI. Two features of the model may explain the gap and limit translation: morpholino knockdown approaches a near-null state whereas human disease is heterozygous haploinsufficiency, and the human transcriptomic evidence comes from dermal fibroblasts rather than neural tissue. The translational validity of the cell-fate mechanism, not its existence in the model, is the open question.

Proposed experiments

Cortical differentiation of ASXL3 heterozygous iPSC and organoid models

brps_exp_ipsc_cortical_patterning

Differentiate ASXL3 patient-derived and isogenic heterozygous-null iPSC lines into cortical neurons and cerebral organoids, then assay regional patterning, cortical layer identity, and genome-wide H2AK119Ub1 distribution. This tests whether a human heterozygous gene dose is sufficient to produce a measurable neural cell-fate defect, which the near-null frog knockdown cannot address.

Decision criterion

A reproducible shift in layer-marker proportions or regional identity in heterozygous versus isogenic control lines, accompanied by redistributed H2AK119Ub1 at developmental loci, would support translation of the frog cell-fate mechanism to human heterozygous dosage.

Quantitative volumetric and cortical-thickness MRI in an ASXL3 cohort

brps_exp_quantitative_mri

Perform quantitative volumetric and cortical-thickness MRI in a phenotyped ASXL3 cohort against matched controls, to test whether subtle structural differences exist below the threshold at which routine clinical radiology reports an abnormality.

Decision criterion

Statistically significant reduction in cortical thickness or upper-layer-associated volume relative to matched controls would reconcile the model finding with the clinical observation of "normal" MRI.

Dose-controlled heterozygous vertebrate model of Asxl3 loss

brps_exp_heterozygous_vertebrate_model

Generate and phenotype a heterozygous (rather than morpholino knockdown-null) vertebrate model to test whether the early neural patterning defect is dose-dependent and whether it attenuates at a gene dosage comparable to human disease.

Decision criterion

Persistence of a measurable patterning phenotype at heterozygous dosage would support translational relevance; complete rescue at heterozygous dosage would indicate the knockdown phenotype is a null-specific artefact.

Show evidence (1 reference)

PMID:32132929 SUPPORT Model Organism

"In this study, we utilize the frog, Xenopus laevis as a simpler and more accessible vertebrate neurodevelopmental model system to understand the embryological cause of Bainbridge-Ropers syndrome."

Identifies the model system whose translational validity to human heterozygous ASXL3 disease is the subject of this mismatch item.

Is there a genuine ASXL3-specific DNA methylation episignature that a dedicated, adequately powered study would detect, or does ASXL3 haploinsufficiency truly leave no peripheral blood methylation footprint?

KNOWLEDGE GAP OPEN brps_missing_episignature

Attached to

pathophysiology#Absence of an ASXL3 DNA Methylation Episignature

The only relevant data come from applying an ASXL1/Bohring-Opitz classifier to three ASXL3 individuals, whose profiles were control-like. That is a negative result from a classifier built for a different gene on a very small sample, not evidence of absence. The question matters clinically because without an episignature there is no functional assay to reclassify ASXL3 variants of uncertain significance, which is precisely where the missense-variant question is unresolved.

Proposed experiments

Adequately powered ASXL3-specific blood DNA methylation study

brps_exp_dedicated_episignature

Profile genome-wide blood DNA methylation in a cohort of 25 or more individuals with confirmed pathogenic ASXL3 variants against sex- and age-matched controls, powered to derive a signature de novo rather than by cross-classification with an ASXL1-derived model.

Decision criterion

Identification of a reproducible set of differentially methylated positions that classifies held-out ASXL3 cases would establish an ASXL3 episignature; failure at this sample size would substantially strengthen the negative result.

Episignature stratification by NMD class and mutational cluster region

brps_exp_episignature_by_variant_class

Stratify any candidate methylation signature by nonsense-mediated-decay versus no-NMD variant class and by MCR1 (exon 11) versus MCR2 (exon 12) location, to test whether the two proposed mechanistic classes leave different epigenomic footprints.

Decision criterion

Divergent methylation profiles between the NMD and no-NMD groups would provide molecular support for two distinct disease mechanisms rather than a single haploinsufficiency mechanism.

Clinical validation of an ASXL3 episignature for variant classification

brps_exp_episignature_vus_classification

Test any derived signature against ASXL3 missense variants and variants of uncertain significance to establish whether it has clinical utility for reclassification.

Decision criterion

Concordant classification of known pathogenic and known benign control variants would qualify the assay for clinical variant interpretation.

Show evidence (1 reference)

PMID:35361921 SUPPORT Human Clinical

"the DNAm profiles of three individuals with ASXL3 variants were control-like"

The sole empirical basis for the current belief that ASXL3 has no episignature - three individuals tested with a classifier built for a different gene - which is why this remains an open gap rather than a settled negative.

Is ASXL3-related disorder fully penetrant, and if not, is the apparent nonpenetrance in inherited-variant families genuine reduced penetrance or misclassification of variant pathogenicity?

KNOWLEDGE GAP OPEN brps_penetrance_expressivity

Attached to

genetic#ASXL3

Almost the entire published cohort consists of de novo protein-truncating variants ascertained through severely affected probands, so penetrance has never been estimated against an unbiased denominator and a reader would reasonably but wrongly infer complete penetrance. The inherited-variant series reports substantial intrafamilial and possible interfamilial variability, with transmitting parents who are mildly affected or apparently unaffected. Critically, the authors decline to attribute this to reduced penetrance, offering instead the competing explanation that the inherited variants may not be pathogenic - an ambiguity that cannot be resolved without a functional assay, which is precisely what the absent episignature denies. Systematic review lists penetrance among the explicit unresolved gaps. This matters directly for counselling families in whom an ASXL3 variant is inherited rather than de novo.

Proposed experiments

Unselected-cohort penetrance estimation for ASXL3 truncating variants

brps_exp_biobank_penetrance

Ascertain ASXL3 protein-truncating variants in large unselected population biobanks with linked phenotype data, rather than through clinically referred probands, and measure the proportion of carriers meeting neurodevelopmental diagnostic criteria.

Decision criterion

A carrier frequency substantially exceeding the expected disease prevalence, with a meaningful fraction of carriers lacking a neurodevelopmental diagnosis, would establish reduced penetrance for at least some variant classes.

Deep phenotyping and mosaicism testing of transmitting parents

brps_exp_family_deep_phenotyping

Systematically deep-phenotype apparently unaffected transmitting parents in inherited ASXL3 families and apply ultra-deep sequencing of multiple tissues to distinguish true germline heterozygosity with reduced penetrance from low-level parental mosaicism.

Decision criterion

Demonstration of constitutional heterozygosity in a rigorously phenotyped unaffected parent would establish genuine nonpenetrance; detection of mosaicism would instead explain the mild parental phenotype without invoking reduced penetrance.

Show evidence (3 references)

PMID:42494517 SUPPORT Human Clinical

"substantial intrafamilial phenotypic variability, as well as the possibility of interfamilial phenotypic variability"

Establishes variable expressivity across and within families carrying inherited ASXL3 variants.

PMID:42494517 SUPPORT Human Clinical

"The family reports emphasize the possibility of additional, yet currently unidentified, factors influencing phenotypic expression or, alternatively, may reflect uncertainty about the pathogenicity of inherited ASXL3 variants."

The authors explicitly refuse to separate reduced penetrance or modifier effects from pathogenicity uncertainty, which is why this is curated as an open gap rather than as a penetrance estimate.

PMID:38420660 SUPPORT Human Clinical

"Several gaps in our knowledge of this disorder were identified, namely, underlying pathophysiology and disease mechanism, disease contribution of missense variants, relevance of variant location, prevalence and penetrance data."

A systematic review names penetrance data as an explicit, unresolved knowledge gap.

Do ASXL3 missense variants contribute to disease, and if so to which phenotype - autism spectrum disorder without syndromic features, a recessive congenital heart phenotype, or nothing at all?

KNOWLEDGE GAP OPEN brps_missense_contribution

Attached to

genetic#ASXL3

Every established BRPS variant is protein-truncating. Missense ASXL3 variants have been reported in autism cohorts without the severe syndromic features, and biallelic missense variants have been reported in a small number of individuals with congenital heart defects, but neither association is established. Systematic reviews list the disease contribution of missense variants as an explicit unresolved gap. Without an episignature or another functional assay there is currently no way to resolve individual missense variants of uncertain significance.

Proposed experiments

Deep mutational scanning of the ASXL3 DEUBAD domain

brps_exp_deubad_deep_mutational_scan

Perform saturation mutagenesis of the ASXL3 DEUBAD (BAP1-binding) domain and measure BAP1 binding and PR-DUB H2A deubiquitinase activity for each substitution, generating a functional score for every possible missense change in the domain.

Decision criterion

A bimodal functional score distribution separating known pathogenic truncating-equivalent losses from tolerated substitutions would provide a calibrated assay for missense variant interpretation.

Rare ASXL3 missense burden analysis in neurodevelopmental cohorts

brps_exp_missense_burden

Conduct a case-control burden analysis of rare ASXL3 missense variants in large autism and neurodevelopmental-disorder cohorts against population reference data.

Decision criterion

Significant excess of rare missense variants in cases after correction would support a genuine, phenotypically milder missense contribution distinct from the truncating BRPS phenotype.

Segregation and functional follow-up of biallelic missense congenital heart defect families

brps_exp_biallelic_missense_chd

Re-examine segregation and perform functional assays in the reported families with biallelic ASXL3 missense variants and congenital heart defects, to determine whether this represents a genuinely distinct recessive allelic disorder or an incidental finding.

Decision criterion

Consistent biallelic segregation with a shared functional deficit across independent families would support a distinct recessive ASXL3-related cardiac phenotype.

Show evidence (1 reference)

PMID:38420660 SUPPORT Human Clinical

A systematic review names the disease contribution of missense variants as an explicit, unresolved knowledge gap.

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Pathophysiology

ASXL3 Haploinsufficiency from Protein-Truncating Variants

A heterozygous nonsense, frameshift, or canonical splice-site variant, almost always falling in the two large coding exons 11 and 12, is the initiating lesion. For variants predicted to trigger nonsense-mediated decay the mutant transcript is degraded and total ASXL3 message and protein fall, producing true haploinsufficiency. A second class of truncating variants escapes decay and yields a truncated protein, and the two classes are associated with measurably different clinical severity, which argues that reduced dosage is the dominant but not the only mechanism.

patient dermal fibroblast CL:0000057

ASXL3 hgnc:29357

nonsense-mediated decay of the mutant ASXL3 transcript GO:0000184 ↑ INCREASED

Downstream

Impaired PR-DUB Deubiquitinase Complex Function Reduced ASXL3 protein limits assembly of the ASXL3-BAP1 PR-DUB complex, of which ASXL3 is an obligate scaffolding subunit.

Show evidence (4 references)

PMID:23383720 SUPPORT Human Clinical

"Using genome-wide sequencing, we identified heterozygous, de novo truncating mutations in ASXL3, a transcriptional repressor related to ASXL1, in four unrelated probands."

Establishes heterozygous de novo truncating ASXL3 variants as the initiating molecular lesion.

PMID:26647312 SUPPORT In Vitro

"ASXL3 mRNA transcripts from the mutated allele are prone to nonsense-mediated decay, and expression of ASXL3 is reduced."

Patient fibroblasts directly demonstrate NMD of the mutant allele and reduced ASXL3 expression, the molecular definition of haploinsufficiency.

PMID:38420660 SUPPORT Human Clinical

"The majority of genetic variants were de novo truncating variants in exon 11 or 12 of the ASXL3 gene."

A systematic review confirms the exon 11/12 clustering of the causal truncating variants.

+ 1 more reference

Impaired PR-DUB Deubiquitinase Complex Function

ASXL3 is a non-catalytic scaffolding subunit of the Polycomb repressive deubiquitinase (PR-DUB) complex, binding the ubiquitin C-terminal hydrolase BAP1 through its DEUBAD module. BAP1 has little activity on nucleosomes on its own and depends on an ASXL partner, so reduced ASXL3 dosage limits assembly of functional ASXL3-BAP1 PR-DUB and blunts its catalytic output. The ASXL paralogs are epigenetic scaffolds more generally, also engaging EZH2, nuclear receptors and other partners.

ASXL3-BAP1 PR-DUB complex GO:0035517

histone H2A deubiquitinase activity of the PR-DUB complex GO:0140950 ↓ DECREASED

Downstream

Elevated H2A Lysine 119 Monoubiquitination Loss of PR-DUB catalytic output leaves the repressive H2AK119 monoubiquitin mark abnormally elevated.

Show evidence (3 references)

PMID:26647312 SUPPORT In Vitro

"We found that ASXL3 interacts with BAP1, a hydrolase that removes mono-ubiquitin from histone H2A lysine 119 (H2AK119Ub1) as a component of the Polycomb repressive deubiquitination (PR-DUB) complex."

Directly establishes the ASXL3-BAP1 PR-DUB interaction that this node describes.

PMID:25835095 SUPPORT Other

"ASXL1, ASXL2 and ASXL3 are epigenetic scaffolds for BAP1, EZH2, NCOA1, nuclear receptors and WTIP."

A functional-proteomics review supports the scaffolding role of ASXL3 for BAP1 and additional chromatin and nuclear-receptor partners.

PMID:32132929 SUPPORT Model Organism

"ASXL3 protein is a component of the polycomb deubiquitinase complex that removes mono-ubiquitin from Histone H2A."

Independently confirms ASXL3 membership in the H2A-directed Polycomb deubiquitinase complex.

Elevated H2A Lysine 119 Monoubiquitination

Loss of PR-DUB output leaves H2AK119 monoubiquitination abnormally high. This mark is the repressive output of Polycomb repressive complex 1, and its dynamic removal by PR-DUB is required for normal derepression of developmental target genes. BRPS was the first single-gene disorder attributed to a defect in H2AK119Ub1 deubiquitination, making this the defining chromatin lesion of the syndrome.

patient dermal fibroblast CL:0000057

PR-DUB-mediated histone H2A deubiquitination GO:0016579 ↓ DECREASED chromatin organization at Polycomb target loci GO:0006325 ⚠ ABNORMAL

Downstream

Absence of an ASXL3 DNA Methylation Episignature The chromatin lesion does not propagate into a detectable peripheral blood DNA methylation signature: ASXL3 patients profile as control-like on the ASXL1/Bohring-Opitz classifier. The steps that would connect an elevated H2AK119Ub1 mark to a blood DNAm readout are unknown, and this edge asserts the absence of a detectable downstream signature rather than a positive effect.

Genome-Wide Transcriptional Dysregulation The altered chromatin state produces widespread bidirectional changes in gene expression in patient-derived cells.

Show evidence (2 references)

PMID:26647312 SUPPORT In Vitro

"A significant increase in H2AK119Ub1 was observed in ASXL3 patient fibroblasts, highlighting an important functional role for ASXL3 in PR-DUB mediated deubiquitination."

Directly measures the elevated H2AK119Ub1 mark in patient-derived cells.

PMID:26647312 SUPPORT In Vitro

"This is the first single gene disorder linked to defects in deubiquitination of H2AK119Ub1"

Establishes the H2AK119Ub1 deubiquitination defect as the defining molecular lesion of this disorder.

Genome-Wide Transcriptional Dysregulation

The aberrant chromatin state translates into widespread transcriptional change. Patient fibroblast transcriptomes show hundreds of differentially expressed genes split almost evenly between up- and downregulated, which is more consistent with loss of a chromatin scaffold that tunes both repression and activation than with loss of a pure repressor. The affected genes are enriched for transcriptional regulation, development, and proliferation.

patient dermal fibroblast CL:0000057

dysregulated transcription of developmental target genes GO:0006355 ⚠ ABNORMAL

Downstream

Disrupted Neural Cell Fate Specification Transcriptional dysregulation during early neural patterning is inferred to derail cell-fate specification. The specific intermediate target genes in human neural tissue are not known, and the direct evidence is model-organism only.

Show evidence (1 reference)

PMID:26647312 SUPPORT In Vitro

"Out of 564 significantly differentially expressed genes (DEGs) in ASXL3 patient fibroblasts, 52% were upregulated and 48% downregulated. DEGs were enriched in molecular processes impacting transcriptional regulation, development and proliferation, consistent with the features of BRS."

Quantifies the transcriptional consequence and its near-symmetric up/down distribution in patient cells.

Disrupted Neural Cell Fate Specification

The developmental consequence of ASXL3 loss falls on early neural patterning. In a vertebrate embryo model, ASXL3 depletion severely perturbs specification of neural cell fates, with reduced expression of hindbrain, primary neuron, and neural crest markers, while spinal-cord identity is relatively spared. This positions ASXL3 as a chromatin regulator required during the earliest steps of nervous system induction and anteroposterior patterning, which is when the human phenotype is determined.

developing neuron CL:0000540

neural cell fate commitment GO:0045165 ⚠ ABNORMAL nervous system development GO:0007399 ⚠ ABNORMAL neuron differentiation GO:0030182 ↓ DECREASED

Downstream

Neurodevelopmental and Multisystem Clinical Phenotype Disrupted early neural specification is inferred to produce the clinical neurodevelopmental phenotype. Because most affected individuals have structurally normal brain imaging, the intervening steps between a patterning defect and the clinical picture are unresolved.

Show evidence (2 references)

PMID:32132929 SUPPORT Model Organism

"We have found that ASXL3 protein knockdown during early embryo development highly perturbs neural cell fate specification, potentially resembling the Bainbridge-Ropers syndrome phenotype in humans."

Directly demonstrates that ASXL3 depletion disrupts early neural cell fate specification in a vertebrate embryo.

PMID:32132929 SUPPORT Model Organism

"Dynamic chromatin modifications play important roles in the specification of cell fates during early neural patterning and development."

Provides the mechanistic rationale linking the chromatin lesion to a cell-fate specification defect.

Neurodevelopmental and Multisystem Clinical Phenotype

The terminal node: a static (non-degenerative) neurodevelopmental phenotype comprising moderate-to-severe intellectual disability, absent or profoundly limited speech, autistic features, central hypotonia evolving toward limb hypertonia, severe infantile feeding difficulty with failure to thrive, gastroesophageal reflux, and a nonspecific craniofacial gestalt, with generalized epilepsy in a minority.

Show evidence (2 references)

PMID:38420660 SUPPORT Human Clinical

"Common phenotypic features comprised global developmental delay or intellectual disability (97%), feeding problems (76%), hypotonia (88%) and characteristic facial features (93%)."

Quantifies the terminal clinical phenotype across the published literature.

PMID:33151654 SUPPORT Human Clinical

"ASXL3-related disorder is characterized by developmental delay or intellectual disability, typically in the moderate to severe range, with speech and language delay and/or absent speech."

The GeneReviews clinical summary of the terminal phenotype.

Absence of an ASXL3 DNA Methylation Episignature

A negative but mechanistically informative finding. Blood DNA methylation signatures are established for many chromatinopathies, and ASXL1-related Bohring-Opitz syndrome has a robust one. When that classifier was applied to ASXL3 patients their methylation profiles were control-like, and unlike ASXL1 and ASXL2 patients they showed no epigenetic age acceleration. This means (a) there is currently no validated episignature available to help classify ASXL3 variants of uncertain significance, and (b) ASXL3 dysfunction diverges mechanistically from ASXL1 despite paralogy - which is a molecular argument for keeping BRPS and BOS as separate entities.

Show evidence (2 references)

PMID:35361921 SUPPORT Human Clinical

"The DNAm profile of one individual with the ASXL2 variant was BOS-like, whereas the DNAm profiles of three individuals with ASXL3 variants were control-like."

Directly reports that ASXL3 patients lack the ASXL1/BOS methylation signature.

PMID:35361921 SUPPORT Human Clinical

"which showed acceleration in DNAm age in individuals with pathogenic ASXL1 variants, and the individual with the pathogenic ASXL2 variant, but not in individuals with ASXL3 variants."

The absence of epigenetic age acceleration in ASXL3 further separates it from ASXL1 and ASXL2.

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Pathograph

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Phenotypes

Digestive 2

Feeding difficulties VERY_FREQUENT Feeding difficulties HP:0011968

Onset: INFANTILE

Show evidence (3 references)

PMID:39833101 SUPPORT Human Clinical

"feeding difficulties (90.5%)"

90.5% in a 22-patient cohort supports the VERY_FREQUENT band.

PMID:23383720 SUPPORT Human Clinical

"including severe feeding difficulties, failure to thrive, and neurologic abnormalities with significant developmental delay"

The founding description places severe feeding difficulty at the centre of the phenotype.

PMID:42494517 SUPPORT Human Clinical

"Microcephaly, sleep apnea, hyperventilation, and feeding tube use had a statistically increased prevalence in the NMD and MCR1 groups."

Supports the genotype dependence of feeding-tube requirement.

Gastroesophageal reflux VERY_FREQUENT Gastroesophageal reflux HP:0002020

Show evidence (2 references)

PMID:39833101 SUPPORT Human Clinical

"gastroesophageal reflux disease (82.4%)"

82.4% supports the VERY_FREQUENT band in this cohort.

PMID:33151654 SUPPORT Human Clinical

"anti-reflux medication and/or fundoplication for those with gastroesophageal disease"

GeneReviews management guidance confirms gastroesophageal disease as a recognized manifestation requiring treatment.

Eye 2

Strabismus FREQUENT Strabismus HP:0000486

Show evidence (2 references)

PMID:33151654 SUPPORT Human Clinical

"Other findings may include poor postnatal growth, strabismus, seizures, sleep disturbance, and dental anomalies."

GeneReviews lists strabismus among the recognized clinical findings.

PMID:40552904 PARTIAL Human Clinical

"Dental and Ophthalmological follow-up for all"

The natural-history study recommends ophthalmological follow-up for all affected individuals. Marked PARTIAL because a surveillance recommendation is not itself evidence for the presence or frequency of strabismus; the FREQUENT band rests on the GeneReviews clinical-findings list and is not separately quantified in any cached source.

Hypertelorism OCCASIONAL Hypertelorism HP:0000316

Show evidence (1 reference)

PMID:28100473 PARTIAL Human Clinical

"hypertelorism and downslanting palpebral fissures"

Documents hypertelorism as part of the BRPS facial gestalt. Marked PARTIAL because the snippet supports the association only: the composite gestalt count does not decompose to this feature. The OCCASIONAL band reflects the lower per-feature frequency of hypertelorism in the HPO disease annotations for OMIM:615485, which is not itself a quoted reference.

Genitourinary 1

Renal anomalies Abnormality of the kidney HP:0000077

Deliberately annotated at low specificity and with no frequency band: the only source describes "an emerging renal phenotype" without naming the lesions or reporting a rate. A more specific HPO term should replace this once the phenotype is characterized.

Show evidence (1 reference)

PMID:40552904 PARTIAL Human Clinical

"an increased prevalence of antenatal and neonatal structural anomalies, an emerging renal phenotype"

The largest natural-history cohort reports an emerging renal phenotype. Marked PARTIAL because the finding is described only as "emerging", with no lesion-level detail or frequency.

Head and Neck 5

Highly arched eyebrows FREQUENT Highly arched eyebrow HP:0002553

Show evidence (2 references)

PMID:28100473 SUPPORT Human Clinical

"distinct face (arched eyebrows, prominent forehead, high-arched palate, hypertelorism and downslanting palpebral fissures), (9/12)"

9/12 (75%) for the composite facial gestalt including arched eyebrows supports the FREQUENT band.

PMID:39833101 SUPPORT Human Clinical

"higher frequency of arched eyebrows"

Supports the genotype-dependent enrichment of arched eyebrows in exon 11 variant carriers.

Downslanted palpebral fissures FREQUENT Downslanted palpebral fissures HP:0000494

Show evidence (2 references)

PMID:27901041 SUPPORT Human Clinical

"a characteristic craniofacial phenotype (long face, arched eyebrows with mild synophrys, downslanting palpebral fissures, prominent columella, small alae nasi, high, narrow palate and relatively little facial expression)"

Downslanting palpebral fissures are listed as part of the characteristic craniofacial phenotype in a six-patient European cohort.

PMID:28100473 SUPPORT Human Clinical

"hypertelorism and downslanting palpebral fissures), (9/12)"

Independently documents downslanting palpebral fissures in the facial gestalt at 9/12.

High palate FREQUENT High palate HP:0000218

Show evidence (2 references)

PMID:27901041 SUPPORT Human Clinical

"high, narrow palate and relatively little facial expression"

A high narrow palate is documented in the characteristic craniofacial phenotype.

PMID:28100473 SUPPORT Human Clinical

"arched eyebrows, prominent forehead, high-arched palate"

High-arched palate is listed in the DDD cohort facial description.

Prominent forehead OCCASIONAL Prominent forehead HP:0011220

Show evidence (1 reference)

PMID:28100473 PARTIAL Human Clinical

"distinct face (arched eyebrows, prominent forehead, high-arched palate, hypertelorism and downslanting palpebral fissures), (9/12)"

Prominent forehead is named within the composite facial gestalt scored 9/12. Marked PARTIAL because the 9/12 count is for the gestalt as a whole and does not decompose to this individual feature; the OCCASIONAL band follows the same reasoning applied to hypertelorism, which is drawn from this identical sentence and has a comparable per-feature frequency in the HPO disease annotations for OMIM:615485.

Microcephaly OCCASIONAL Microcephaly HP:0000252

Show evidence (3 references)

PMID:42494517 SUPPORT Human Clinical

"Microcephaly, sleep apnea, hyperventilation, and feeding tube use had a statistically increased prevalence in the NMD and MCR1 groups."

Establishes microcephaly as a genotype-dependent rather than universal feature.

PMID:24044690 SUPPORT Human Clinical

"truncating and frameshifting mutations in the ASXL3 gene are the cause of a newly recognized disorder characterized by severe global developmental delay, short stature, microcephaly, and craniofacial anomalies"

An early case establishing microcephaly within the ASXL3 phenotype spectrum.

PMID:27901041 PARTIAL Human Clinical

"The majority of key features characteristic for Bohring-Opitz syndrome were absent in our patients (eg, the typical posture of arms, intrauterine growth retardation, microcephaly, trigonocephaly"

Supports only the negative part of the claim: microcephaly was largely absent in this ASXL3 cohort, which is why the OCCASIONAL rather than FREQUENT band is used.

Musculoskeletal 3

Hypotonia VERY_FREQUENT Hypotonia HP:0001252

Show evidence (3 references)

PMID:38420660 SUPPORT Human Clinical

"hypotonia (88%)"

88% across the reviewed literature supports the VERY_FREQUENT band.

PMID:39833101 SUPPORT Human Clinical

"hypotonia (85.7%)"

An independent cohort reports a concordant 85.7% frequency.

PMID:33151654 SUPPORT Human Clinical

"Affected individuals may also have hypotonia that can transition to spasticity resulting in unusual posture with flexion contractions of the elbows, wrists, and fingers."

Documents the hypotonia-to-spasticity evolution described here.

Joint hypermobility FREQUENT Joint hypermobility HP:0001382

Show evidence (1 reference)

PMID:39833101 SUPPORT Human Clinical

"joint laxity (73.7%)"

73.7% falls squarely in the FREQUENT band (30-79%).

Joint contractures OCCASIONAL Joint contracture HP:0034392

Show evidence (1 reference)

PMID:33151654 SUPPORT Human Clinical

"spasticity resulting in unusual posture with flexion contractions of the elbows, wrists, and fingers"

GeneReviews documents the flexion contractures described here.

Nervous System 11

Global developmental delay VERY_FREQUENT Global developmental delay HP:0001263

Show evidence (1 reference)

PMID:38420660 SUPPORT Human Clinical

"Common phenotypic features comprised global developmental delay or intellectual disability (97%), feeding problems (76%), hypotonia (88%) and characteristic facial features (93%)."

97% across the reviewed literature supports the VERY_FREQUENT band (80-100%).

Intellectual disability VERY_FREQUENT Intellectual disability HP:0001249

Show evidence (3 references)

PMID:33151654 SUPPORT Human Clinical

"ASXL3-related disorder is characterized by developmental delay or intellectual disability, typically in the moderate to severe range"

The GeneReviews clinical characteristics statement on intellectual disability and its typical severity.

PMID:28100473 SUPPORT Human Clinical

"common emerging features include severe intellectual disability (11/12)"

11/12 (92%) in a systematically phenotyped DDD cohort supports the VERY_FREQUENT band.

PMID:42494517 SUPPORT Human Clinical

"Intellectual disability and global developmental delay were more severe in the NMD and MCR1 groups"

Supports the genotype-dependent severity gradient described here.

Absent or severely limited speech VERY_FREQUENT Absent speech HP:0001344

Show evidence (2 references)

PMID:28100473 SUPPORT Human Clinical

"poor/ absent speech (12/12)"

12/12 (100%) directly supports the VERY_FREQUENT band for absent or poor speech.

PMID:27901041 SUPPORT Human Clinical

"profound speech impairment"

An independent European cohort lists profound speech impairment among the concordant clinical features.

Delayed speech and language development VERY_FREQUENT Delayed speech and language development HP:0000750

Show evidence (1 reference)

PMID:33151654 SUPPORT Human Clinical

"with speech and language delay and/or absent speech"

GeneReviews names speech and language delay as a defining clinical characteristic.

Autistic features FREQUENT Autism HP:0000717

Show evidence (3 references)

PMID:39833101 SUPPORT Human Clinical

"autism spectrum disorder (75%)"

75% falls in the FREQUENT band (30-79%).

PMID:28100473 SUPPORT Human Clinical

"autistic traits (9/12)"

9/12 (75%) in an independent cohort is concordant with the FREQUENT band.

PMID:42494517 SUPPORT Human Clinical

"Although autistic features were observed across all groups, the no-NMD and MCR2 cohorts had a higher proportion of individuals with formal autism diagnoses."

Supports the genotype-dependent enrichment of formal autism diagnoses.

Sleep disturbance FREQUENT Sleep disturbance HP:0002360

Show evidence (2 references)

PMID:34086428 SUPPORT Human Clinical

"sleep impairment: 5 (71%)"

71% in a clinical series supports the FREQUENT band (30-79%).

PMID:33151654 SUPPORT Human Clinical

"Other findings may include poor postnatal growth, strabismus, seizures, sleep disturbance, and dental anomalies."

GeneReviews lists sleep disturbance among the recognized clinical findings.

Self-injurious behavior and aggression FREQUENT Self-injurious behavior HP:0100716

Show evidence (2 references)

PMID:34086428 SUPPORT Human Clinical

"self-injurious behavior: 3 (43%), aggression: 4 (57%)"

43% self-injury and 57% aggression both fall in the FREQUENT band.

PMID:28100473 SUPPORT Human Clinical

"Shared behavioural phenotypes include autistic traits, hand-flapping, rocking, aggressive behaviour and sleep disturbance."

Independently documents aggression as part of the shared behavioural phenotype.

Seizures FREQUENT Seizure HP:0001250

Onset: CHILDHOOD

Show evidence (3 references)

PMID:29367179 SUPPORT Human Clinical

"Seizures are reported in approximately a third of cases; however, the epileptology has not been thoroughly studied."

Approximately one third supports the FREQUENT band (30-79%), at its lower edge.

PMID:29367179 SUPPORT Human Clinical

"Bainbridge-Ropers syndrome is associated with childhood-onset generalized epilepsy with generalized tonic-clonic seizures and/or atypical absence seizures."

Characterizes the epilepsy syndrome and its childhood onset.

PMID:40552904 PARTIAL Human Clinical

"a lower-than-expected prevalence of seizures (compared to the existing literature)"

The largest natural-history cohort found fewer seizures than earlier reports, so the FREQUENT band should be read as an upper estimate subject to ascertainment bias.

Sleep apnea OCCASIONAL Sleep apnea HP:0010535

Show evidence (2 references)

PMID:42494517 SUPPORT Human Clinical

"Microcephaly, sleep apnea, hyperventilation, and feeding tube use had a statistically increased prevalence in the NMD and MCR1 groups."

Establishes sleep apnea as a documented, genotype-enriched feature.

PMID:33151654 SUPPORT Human Clinical

"standard treatment for epilepsy, joint contractures, sleep apnea, dental anomalies, strabismus and/or refractive error"

GeneReviews management guidance confirms sleep apnea as a recognized manifestation.

Attention deficit hyperactivity disorder FREQUENT Attention deficit hyperactivity disorder HP:0007018

Show evidence (1 reference)

PMID:34086428 SUPPORT Human Clinical

"attention-deficit/hyperactivity disorder: 3 (43%)"

43% in a clinical psychiatric series supports the FREQUENT band.

Dystonia Dystonia HP:0001332

Onset: INFANTILE

Based on a single detailed case report with a de novo ASXL3 nonsense variant, supported by a prior large-scale genomic association between ASXL3 variation and cerebral palsy. No frequency band is asserted.

Show evidence (2 references)

PMID:35863334 SUPPORT Human Clinical

"The patient presented with a mixture of infantile-onset limb/trunk dystonic postures and secondarily evolving distal spastic contractures"

Directly documents infantile-onset dystonic posturing in an individual with a de novo pathogenic ASXL3 variant.

PMID:35863334 SUPPORT Human Clinical

"indicates that dystonic features can be part of the clinical spectrum in Bainbridge-Ropers syndrome"

The authors' explicit conclusion that dystonia belongs to the BRPS clinical spectrum.

Respiratory 1

Hyperventilation OCCASIONAL Hyperventilation HP:0002883

Show evidence (2 references)

PMID:28955728 SUPPORT Human Clinical

"We describe a new case with a striking phenotype, namely hyperventilation-induced athetosis."

Directly documents the hyperventilation-athetosis phenotype in an ASXL3 patient.

PMID:42494517 SUPPORT Human Clinical

"Microcephaly, sleep apnea, hyperventilation, and feeding tube use had a statistically increased prevalence in the NMD and MCR1 groups."

Confirms hyperventilation as a recognized, genotype-enriched feature in a 204-individual analysis.

Growth 4

Failure to thrive Failure to thrive HP:0001508

Onset: INFANTILE

No frequency band is asserted: none of the cached sources reports a numeric frequency for failure to thrive specifically, as distinct from feeding difficulty. Per the frequency-evidence SOP, the band is omitted rather than inferred.

Show evidence (1 reference)

PMID:23383720 SUPPORT Human Clinical

"severe feeding difficulties, failure to thrive"

Failure to thrive is part of the founding phenotype description and of the disease name itself.

Poor postnatal growth Growth delay HP:0001510

No frequency band is asserted. Both cited sources are qualitative ("Other findings may include poor postnatal growth"; "a tendency for poor post-natal growth"); neither maps to a quantitative band. This applies the same frequency-evidence discipline used for Failure to thrive and Dental anomalies.

Show evidence (2 references)

PMID:33151654 SUPPORT Human Clinical

"Other findings may include poor postnatal growth, strabismus, seizures, sleep disturbance, and dental anomalies."

GeneReviews lists poor postnatal growth among the recognized clinical findings.

PMID:40552904 SUPPORT Human Clinical

"a tendency for poor post-natal growth (with novel reports of obesity later in childhood)"

The natural-history cohort documents poor postnatal growth and the later obesity trajectory.

Obesity Obesity HP:0001513

Onset: CHILDHOOD

No frequency band is asserted: the source describes "novel reports" of obesity without a count or rate, and ascertainment in a natural-history cohort is limited. Treat as an emerging observation.

Show evidence (1 reference)

PMID:40552904 PARTIAL Human Clinical

"a tendency for poor post-natal growth (with novel reports of obesity later in childhood)"

Documents obesity later in childhood as a novel association. Marked PARTIAL because "novel reports" is unquantified and this reverses the direction of the growth phenotype seen in infancy.

Intrauterine growth restriction FREQUENT Intrauterine growth retardation HP:0001511

Onset: ANTENATAL

Show evidence (1 reference)

PMID:39833101 SUPPORT Human Clinical

"The predominant prenatal finding was intrauterine growth restriction (35%)"

35% supports the FREQUENT band (30-79%) at its lower edge.

Other 2

Dental anomalies Dental crowding HP:0000678

No frequency band is asserted. GeneReviews lists dental anomalies only qualitatively ("Other findings may include ..."), the surveillance recommendation is not a frequency statement, and no cached source quantifies dental crowding specifically. Per the frequency-evidence SOP the band is omitted rather than inferred.

Show evidence (2 references)

PMID:33151654 SUPPORT Human Clinical

"sleep disturbance, and dental anomalies"

GeneReviews explicitly lists dental anomalies as a clinical finding. This supports the association only, not a frequency band.

PMID:33151654 PARTIAL Human Clinical

"Dental evaluation every six months after age three years or as clinically indicated."

A surveillance recommendation implying a recognized dental burden. Marked PARTIAL because a management recommendation is not direct evidence of the phenotype's presence or frequency.

Athetosis Athetosis HP:0002305

Single case report (n=1). No frequency band is asserted. Previously this feature was named only in the description of the hyperventilation phenotype and carried no ontology term of its own.

Show evidence (1 reference)

PMID:28955728 SUPPORT Human Clinical

"We describe a new case with a striking phenotype, namely hyperventilation-induced athetosis."

Directly documents hyperventilation-induced athetosis in an ASXL3 patient.

🧬

Genetic Associations

ASXL3 (Heterozygous protein-truncating (nonsense, frameshift, canonical splice-site) variants, clustered in the two large coding exons 11 and 12)

Gene: ASXL3 hgnc:29357 relationship_type: CAUSATIVE variant_origin: DE_NOVO

Show evidence (5 references)

PMID:23383720 SUPPORT Human Clinical

"Using genome-wide sequencing, we identified heterozygous, de novo truncating mutations in ASXL3, a transcriptional repressor related to ASXL1, in four unrelated probands."

The gene-discovery study establishing heterozygous de novo truncating ASXL3 variants as causal.

PMID:38420660 SUPPORT Human Clinical

"The majority of genetic variants were de novo truncating variants in exon 11 or 12 of the ASXL3 gene."

Confirms the variant class and exonic clustering across the published literature.

PMID:42494517 SUPPORT Human Clinical

"Phenotypes in 2 mutational clusters, mutational cluster region 1 (MCR1) (c.1095_2237, exon 11; n = 66) and mutational cluster region 2 (MCR2) (c.3043_4906, exon 12; n = 101), were also analyzed."

Defines the two mutational cluster regions by coordinate and exon.

+ 2 more references

💊

Medical Actions

Feeding therapy and gastrostomy tube placement

Action: gastrostomy Ontology label: Gastrostomy NCIT:C52006

The highest-yield intervention in infancy. Clinical feeding evaluation with a low threshold for referral, feeding therapy, and nasogastric then gastrostomy feeding where oral intake is inadequate. Many children later wean off tube feeding as feeding skills improve with age.

Target Phenotypes: Feeding difficulties HP:0011968

Show evidence (2 references)

PMID:33151654 SUPPORT Human Clinical

"Treatment of manifestations: Feeding therapy; gastrostomy tube placement for those with persistent feeding issues"

The GeneReviews management recommendation for the disorder's dominant infantile problem.

PMID:40552904 SUPPORT Human Clinical

"improvement trends in feeding, hypotonia, verbalisation, and motor skills over time"

Supports the expectation of improving feeding over time and therefore the possibility of later weaning from tube feeding.

Anti-reflux management

Action: Pharmacotherapy NCIT:C15986

Anti-reflux medication for gastroesophageal reflux disease, with fundoplication reserved for severe or refractory cases. Reflux control also reduces aspiration risk in a hypotonic child with dysphagia.

Target Phenotypes: Gastroesophageal reflux HP:0002020

Show evidence (1 reference)

PMID:33151654 SUPPORT Human Clinical

"anti-reflux medication and/or fundoplication for those with gastroesophageal disease"

The GeneReviews recommendation for gastroesophageal disease in this disorder.

Speech and language therapy with augmentative and alternative communication

Action: speech and language therapy Ontology label: Speech Language Therapy NCIT:C159273

Because most affected individuals are nonverbal or minimally verbal, speech and language therapy focused on augmentative and alternative communication is a core, lifelong intervention rather than an optional adjunct.

Target Phenotypes: Absent speech HP:0001344

Show evidence (2 references)

PMID:28100473 SUPPORT Human Clinical

"poor/ absent speech (12/12)"

Universal speech impairment in a phenotyped cohort establishes the need for communication-focused intervention.

PMID:33151654 SUPPORT Human Clinical

"standard treatment for epilepsy, joint contractures, sleep apnea, dental anomalies, strabismus and/or refractive error, and developmental delay / intellectual disability"

GeneReviews recommends standard developmental intervention, of which speech and language therapy is a component.

Physical therapy and rehabilitation

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

Physiotherapy for hypotonia, motor delay, joint laxity and contracture prevention, with durable medical equipment and orthotics as needed. Longitudinal data show motor skills improve over time, so rehabilitation goals should be progressive rather than purely maintenance.

Target Phenotypes: Hypotonia HP:0001252

Show evidence (1 reference)

PMID:40552904 SUPPORT Human Clinical

"improvement trends in feeding, hypotonia, verbalisation, and motor skills over time"

Documented improvement in hypotonia and motor skills supports an active rehabilitative approach.

Behavioral intervention for self-injury

Action: behavioral intervention Ontology label: Behavioral Counseling NCIT:C181743

Structured behaviour-analytic assessment and treatment, using functional analysis and differential reinforcement, is the best-evidenced non-pharmacological approach to self-injury in this disorder. Coexisting sleep disruption can confound assessment and should be addressed in parallel.

Target Phenotypes: Self-injurious behavior HP:0100716

Show evidence (2 references)

PMID:36249891 SUPPORT Human Clinical

"We targeted self-injury in a child with BRPS using a functional analysis and differential reinforcement, with several extensions to common procedures. Results present the first example of behavioral reduction for self-injury in BRPS."

The first published behavioural treatment demonstration in this disorder, supporting the approach while acknowledging n=1.

PMID:36249891 SUPPORT Human Clinical

"There are no published treatments for BRPS."

Confirms the absence of an established treatment evidence base at the time of publication, contextualizing the weight of this single case.

Pregabalin for severe challenging behavior

Action: Pharmacotherapy NCIT:C15986

Agent: pregabalin CHEBI:64356

Reported in a single adult with BRPS, severe intellectual disability, autism and epilepsy admitted for severe self- and hetero-aggression, in whom pregabalin produced rapid stabilization and allowed withdrawal of analgesics, neuroleptics, antidepressants and benzodiazepines, sustained at nine months. This is hypothesis-generating only.

Target Phenotypes: Self-injurious behavior HP:0100716

Show evidence (1 reference)

PMID:39698206 PARTIAL Human Clinical

"The introduction of Pregabalin leads to rapid stabilization of the clinical state, almost complete improvement in challenging behavior and gradual withdrawal of other treatments (class 2 analgesics, neuroleptics, antidepressants, and benzodiazepines)."

Supports the observation in a single patient. Marked PARTIAL because an uncontrolled n=1 report cannot establish efficacy.

Anti-seizure medication

Action: Pharmacotherapy NCIT:C15986

Standard neurologist-directed management of childhood-onset generalized epilepsy with generalized tonic-clonic and atypical absence seizures. Broad-spectrum agents are the rational choice given the generalized phenotype, but there are no BRPS-specific efficacy data. Confirm that paroxysmal events are epileptic on video-EEG before escalating, since breath-holding, hyperventilation and dystonic episodes in this disorder are non-epileptic.

Target Phenotypes: Seizure HP:0001250

Show evidence (2 references)

PMID:33151654 SUPPORT Human Clinical

"standard treatment for epilepsy, joint contractures, sleep apnea, dental anomalies, strabismus and/or refractive error"

GeneReviews recommends standard epilepsy treatment; no disorder-specific regimen is specified.

PMID:29367179 SUPPORT Human Clinical

"Bainbridge-Ropers syndrome is associated with childhood-onset generalized epilepsy with generalized tonic-clonic seizures and/or atypical absence seizures."

Defines the epilepsy syndrome that anti-seizure medication choice should target.

Preventive dental care

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

Six-monthly dental review from age three, with preventive measures. Dental anomalies are a recognized feature and oral health is difficult to maintain in a nonverbal child with behavioural challenges.

Target Phenotypes: Dental crowding HP:0000678

Show evidence (1 reference)

PMID:33151654 SUPPORT Human Clinical

"Dental evaluation every six months after age three years or as clinically indicated."

The GeneReviews surveillance recommendation for dental care.

Ophthalmological and renal surveillance

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

At least annual ophthalmology review for all, given the frequency of strabismus and refractive error. Baseline renal imaging after diagnosis is a newer recommendation arising from the emerging renal phenotype identified in the international natural history study.

Target Phenotypes: Strabismus HP:0000486 Abnormality of the kidney HP:0000077

Show evidence (2 references)

PMID:33151654 SUPPORT Human Clinical

"At least annual ophthalmology evaluation."

The GeneReviews ophthalmological surveillance recommendation.

PMID:40552904 SUPPORT Human Clinical

"Our recommendations include: baseline renal imaging after diagnosis, and Dental and Ophthalmological follow-up for all."

Adds baseline renal imaging to the surveillance plan on the basis of a newly recognized renal phenotype.

Genetic counseling

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

Counseling should cover the autosomal dominant, usually de novo, mode of inheritance; the low but non-zero sibling recurrence risk from parental germline or gonosomal mosaicism; the availability of prenatal and preimplantation genetic testing once a familial variant is known; and the option of ultra-deep parental sequencing to refine recurrence risk after an apparently de novo diagnosis.

Show evidence (3 references)

PMID:33151654 SUPPORT Human Clinical

"If the ASXL3 pathogenic variant identified in the proband is not identified in either parent, the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of parental germline mosaicism."

The GeneReviews recurrence-risk statement that counseling must convey.

PMID:33151654 SUPPORT Human Clinical

"Once the ASXL3 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible."

Establishes the reproductive options to be discussed.

PMID:39833101 SUPPORT Human Clinical

"We documented recurrence in nontwin siblings due to parental mosaicism."

Provides the concrete observed basis for the mosaicism recurrence-risk counselling point.

🔀

Differential Diagnoses

Conditions with similar clinical presentations that must be differentiated from Bainbridge-Ropers syndrome:

Bohring-Opitz syndrome MONDO:0011510

Overlapping Features THE critical differential and the origin of this entry's named-entity confusion risk. Bohring-Opitz syndrome is caused by de novo truncating variants in ASXL1, the closest paralog of ASXL3, and Bainbridge-Ropers syndrome was originally described in 2013 as a phenotype "with similarities to Bohring-Opitz syndrome". The two are now established as clinically and molecularly distinct entities and are curated separately in dismech. Any paper describing ASXL1 patients must not be used as evidence for ASXL3-related phenotypes.

Distinguishing Features

BOS is caused by ASXL1 (hgnc:18318); BRPS is caused by ASXL3 (hgnc:29357).
The BOS-defining features - characteristic arm posture, intrauterine growth retardation, microcephaly, trigonocephaly, facial nevus flammeus, exophthalmos - are largely absent in ASXL3 patients.
BOS has a validated blood DNA methylation episignature and epigenetic age acceleration; ASXL3 patients are control-like on both measures.
BRPS is dominated by profound speech impairment and severe muscular hypotonia with a long face and poor facial expressivity.

Show evidence (3 references)

PMID:27901041 SUPPORT Human Clinical

"The majority of key features characteristic for Bohring-Opitz syndrome were absent in our patients (eg, the typical posture of arms, intrauterine growth retardation, microcephaly, trigonocephaly, typical facial gestalt with nevus flammeus of the forehead and exophthalmos). Therefore we emphasize..."

The definitive clinical statement that BRPS is distinguishable from Bohring-Opitz syndrome, and the enumeration of the discriminating features.

PMID:23383720 PARTIAL Human Clinical

"Further, they showed less phenotypic overlap with patients who had de novo truncating mutations in ASXL1."

Even the founding paper, which framed BRPS as Bohring-Opitz-like, noted reduced phenotypic overlap with ASXL1 patients - an early signal of the eventual split.

PMID:35361921 SUPPORT Human Clinical

"the DNAm profiles of three individuals with ASXL3 variants were control-like"

Provides molecular (episignature) separation between the ASXL1 and ASXL3 disorders.

Shashi-Pena syndrome Not Yet Curated MONDO:0014963

Overlapping Features The third member of the ASXL disorder triad, caused by de novo truncating variants in ASXL2. It shares developmental delay, feeding difficulty, hypotonia and arched eyebrows with BRPS but is separated by macrocephaly and absence of growth retardation. Because all three ASXL disorders are routinely discussed together, papers on ASXL2 must not be cited as evidence for ASXL3 phenotypes.

Distinguishing Features

Shashi-Pena syndrome is caused by ASXL2; BRPS by ASXL3.
Macrocephaly and absence of growth retardation distinguish the ASXL2 condition from ASXL1- and ASXL3-related disorders.
ASXL2 truncating transcripts escape nonsense-mediated decay and are thought to act dominant-negatively, whereas ASXL3 NMD-class variants act by haploinsufficiency.
Glabellar nevus flammeus and prominent eyes are characteristic of Shashi-Pena syndrome and are not features of BRPS.

Show evidence (2 references)

PMID:27693232 SUPPORT Human Clinical

"Although overlapping features with Bohring-Opitz and Bainbridge-Ropers syndromes exist, features that distinguish the ASXL2-associated condition from ASXL1- and ASXL3-related disorders are macrocephaly, absence of growth retardation, and more variability in the degree of intellectual disabilities."

States explicitly which features separate the ASXL2 disorder from the ASXL1 and ASXL3 disorders.

PMID:33751773 SUPPORT Human Clinical

"Over the past decade, pathogenic variants in all members of the ASXL family of genes, ASXL1, ASXL2, and ASXL3, have been found to lead to clinically distinct but overlapping syndromes."

A direct statement that the three ASXL syndromes are clinically distinct despite overlap, supporting the keep-split decision.

Angelman syndrome MONDO:0007113

Overlapping Features ASXL3 variants are recovered in cohorts of individuals with an Angelman-like presentation, because absent speech, seizures, and a happy or excitable demeanour overlap. Molecular testing separates them.

Distinguishing Features

Angelman syndrome arises from loss of maternal UBE3A function (deletion, UPD, imprinting defect, or variant), not from ASXL3.
BRPS lacks the characteristic Angelman EEG pattern and the ataxic gait with jerky limb movements.
Angelman syndrome methylation and UBE3A testing are diagnostic and will be normal in BRPS.

Show evidence (1 reference)

PMID:33751773 PARTIAL Human Clinical

"This will assist in diagnosis of these overlapping conditions and allow clinicians to more comprehensively counsel affected families."

Supports the general point that the ASXL disorders present as overlapping neurodevelopmental conditions requiring careful diagnostic discrimination; it does not itself name Angelman syndrome, so this is marked PARTIAL.

Other Mendelian chromatinopathies with syndromic intellectual disability Not Yet Curated MONDO:0000508

Overlapping Features Because the developmental delay and dysmorphism of BRPS are nonspecific, the practical differential is broad and includes the other Mendelian disorders of the epigenetic machinery presenting with intellectual disability, limited speech, and behavioural difficulty. Discrimination is molecular rather than clinical.

Distinguishing Features

Each chromatinopathy is separated by its causal gene; only ASXL3 variants establish BRPS.
Several other chromatinopathies have validated blood DNA methylation episignatures that can classify variants, whereas ASXL3 currently does not.

Show evidence (1 reference)

PMID:35361921 SUPPORT Human Clinical

"Our previous work has shown that syndromic conditions caused by pathogenic variants in epigenetic regulatory genes show consistent patterns of genome-wide DNA methylation (DNAm) alterations, i.e., DNAm signatures in peripheral blood."

Supports the framing of BRPS within the broader class of epigenetic regulatory gene disorders and the episignature-based approach to distinguishing them.

{ }

Source YAML

click to show

name: Bainbridge-Ropers syndrome
creation_date: "2026-07-31T00:00:00Z"
category: Mendelian
description: >-
  Bainbridge-Ropers syndrome (BRPS), increasingly called ASXL3-related
  disorder, is a rare autosomal dominant neurodevelopmental syndrome caused by
  heterozygous, predominantly de novo protein-truncating variants in ASXL3
  clustered in exons 11 and 12. It is a chromatinopathy: ASXL3 is the
  non-catalytic scaffolding subunit that partners the deubiquitinase BAP1 in
  the Polycomb repressive deubiquitinase (PR-DUB) complex, and its loss raises
  H2A lysine 119 monoubiquitination and broadly dysregulates transcription
  during neural development. The core clinical picture is moderate-to-severe
  intellectual disability with absent or profoundly limited speech, infantile
  hypotonia, severe feeding difficulties with failure to thrive,
  gastroesophageal reflux, autistic features, and a recognizable but
  nonspecific craniofacial gestalt. BRPS was originally described as a
  "Bohring-Opitz-like" phenotype, but it is now established as a clinically
  distinct entity from ASXL1-related Bohring-Opitz syndrome and
  ASXL2-related Shashi-Pena syndrome.
synonyms:
- Bainbridge-Ropers syndrome
- BRPS
- ASXL3-related disorder
- ASXL3 deficiency syndrome
- severe feeding difficulties-failure to thrive-microcephaly due to ASXL3 deficiency syndrome
disease_term:
  preferred_term: Bainbridge-Ropers syndrome
  term:
    id: MONDO:0014205
    label: severe feeding difficulties-failure to thrive-microcephaly due to ASXL3 deficiency syndrome
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0014205
      label: severe feeding difficulties-failure to thrive-microcephaly due to ASXL3 deficiency syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      Primary MONDO identifier for Bainbridge-Ropers syndrome; MONDO:0014205
      xrefs OMIM:615485 and Orphanet:352577 and carries the RO:0004003 gene
      relation to HGNC:29357 (ASXL3), confirming the entity anchor.
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
parents:
- hereditary disease
- multiple congenital anomalies/dysmorphic syndrome-intellectual disability

review_notes: >-
  NAMED-ENTITY-CONFUSION / LUMP-VS-SPLIT REASONING. The ASXL family is a
  documented confusion class and this entry sits at its centre. ASXL1 causes
  Bohring-Opitz syndrome (BOS, MONDO:0011510, curated separately at
  kb/disorders/Bohring-Opitz_syndrome.yaml); ASXL2 causes Shashi-Pena syndrome
  (SHAPNS, MONDO:0014963); ASXL3 causes Bainbridge-Ropers syndrome (BRPS,
  MONDO:0014205, this entry). The three are paralogous PR-DUB scaffolds with
  overlapping core features (developmental delay, hypotonia, feeding
  difficulty, dysmorphism), and BRPS was literally introduced in 2013 as a
  phenotype "with similarities to Bohring-Opitz syndrome" (PMID:23383720), so
  the older literature and many secondary sources conflate them.
  DECISION: KEEP SPLIT. Three independent lines of evidence support treating
  BRPS as a distinct disease entity rather than lumping it with BOS or SHAPNS.
  (1) Gene/ontology anchor: MONDO:0014205 asserts RO:0004003 to HGNC:29357
  (ASXL3) and xrefs OMIM:615485, distinct from ASXL1/BOS (OMIM 605039) and
  ASXL2/SHAPNS (OMIM 617190). (2) Clinical discrimination: Kuechler et al.
  demonstrated that the defining BOS features (the characteristic arm posture,
  IUGR, microcephaly, trigonocephaly, nevus flammeus, exophthalmos) are
  largely absent in ASXL3 patients and concluded BRPS is "a clinically
  distinct intellectual disability syndrome with a recognizable phenotype
  distinguishable from that of Bohring-Opitz syndrome" (PMID:27901041);
  SHAPNS is separated by macrocephaly and absence of growth retardation
  (PMID:27693232). (3) Molecular discrimination: the ASXL1/BOS blood DNA
  methylation episignature does not classify ASXL3 patients, whose profiles
  are control-like, and ASXL3 patients show no epigenetic age acceleration
  (PMID:35361921) - a mechanistic dissociation despite paralogy.
  CURATION GUARDRAIL: every citation in this entry was checked for which ASXL
  paralog it reports. Papers cited here for BRPS-specific claims name ASXL3
  explicitly. ASXL1 and ASXL2 papers appear ONLY in the
  differential_diagnoses section and in explicitly comparative statements;
  no ASXL1/ASXL2 finding is used to support an ASXL3 phenotype or mechanism.

progression:
- phase: Prenatal and neonatal presentation
  age_range: Prenatal period to the neonatal period
  notes: >-
    Intrauterine growth restriction is the commonest prenatal finding, and
    antenatal/neonatal structural anomalies are more frequent than previously
    appreciated. Presentation at birth is usually with hypotonia and feeding
    difficulty rather than a recognizable dysmorphic gestalt.
  evidence:
  - reference: PMID:39833101
    reference_title: Comprehensive Clinical and Genetic Characterization of a Spanish Cohort of 22 Patients With Bainbridge-Ropers Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The predominant prenatal finding was intrauterine growth restriction
      (35%) followed, after birth, by feeding difficulties (90.5%), hypotonia
      (85.7%), and gastroesophageal reflux disease (82.4%).
    explanation: >-
      The largest single-country cohort documents the prenatal-to-neonatal
      sequence of IUGR followed by feeding difficulty and hypotonia.
  - reference: PMID:40552904
    reference_title: "An International ASXL3 Natural History Study: Deep Phenotypic Analyses Including Detailed Reports of a Milder Phenotype, Novel Associations, and Clinical Recommendations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Findings include: an increased prevalence of antenatal and neonatal
      structural anomalies, an emerging renal phenotype, a tendency for poor
      post-natal growth (with novel reports of obesity later in childhood),
      and a lower-than-expected prevalence of seizures (compared to the
      existing literature).
    explanation: >-
      The international natural-history cohort documents increased antenatal
      and neonatal structural anomalies at this phase.
- phase: Infancy - feeding failure and hypotonia
  age_range: Birth through infancy
  notes: >-
    Severe feeding difficulty dominates infancy, frequently requiring
    nasogastric then gastrostomy feeding, with failure to thrive, marked
    central hypotonia, and gastroesophageal reflux. This is the phase that
    typically triggers referral and molecular testing.
  evidence:
  - reference: PMID:23383720
    reference_title: De novo truncating mutations in ASXL3 are associated with a novel clinical phenotype with similarities to Bohring-Opitz syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We found that these probands shared similar phenotypes, including severe
      feeding difficulties, failure to thrive, and neurologic abnormalities
      with significant developmental delay.
    explanation: >-
      The founding description establishes severe infantile feeding difficulty
      and failure to thrive as the presenting phenotype.
  - reference: PMID:33151654
    reference_title: ASXL3-Related Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment of manifestations: Feeding therapy; gastrostomy tube placement
      for those with persistent feeding issues
    explanation: >-
      GeneReviews indicates that feeding difficulty in this phase is often
      severe enough to require gastrostomy.
- phase: Childhood - neurodevelopmental and behavioral phase
  age_range: Early childhood through adolescence
  notes: >-
    Once feeding stabilizes, the picture is dominated by moderate-to-severe
    intellectual disability with absent or minimal speech, autistic features,
    sleep disturbance, self-injury and aggression, and in a minority
    childhood-onset generalized epilepsy. Tone may evolve from central
    hypotonia toward limb hypertonia and flexion contractures.
  evidence:
  - reference: PMID:33151654
    reference_title: ASXL3-Related Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected individuals may also have hypotonia that can transition to
      spasticity resulting in unusual posture with flexion contractions of the
      elbows, wrists, and fingers.
    explanation: >-
      GeneReviews documents the evolution of tone from hypotonia toward
      spasticity and contractures over childhood.
  - reference: PMID:29367179
    reference_title: Childhood-onset generalized epilepsy in Bainbridge-Ropers syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All three had childhood-onset generalized epilepsy with generalized
      tonic-clonic seizures, with one also having atypical absence seizures.
    explanation: >-
      Where epilepsy occurs, its onset is in childhood with a generalized
      phenotype.
- phase: Later childhood and adulthood - gradual functional gains on a static substrate
  age_range: Later childhood through adulthood
  notes: >-
    The underlying developmental lesion is static, not degenerative. Deep
    phenotyping shows measurable improvement over time in feeding, tone,
    verbalisation and motor skills, and many children wean off tube feeding,
    though near-universal intellectual disability and communication impairment
    persist and most individuals require lifelong support. Poor postnatal
    growth may give way to obesity later in childhood.
  evidence:
  - reference: PMID:40552904
    reference_title: "An International ASXL3 Natural History Study: Deep Phenotypic Analyses Including Detailed Reports of a Milder Phenotype, Novel Associations, and Clinical Recommendations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report significant phenotypic variability, but improvement trends in
      feeding, hypotonia, verbalisation, and motor skills over time.
    explanation: >-
      Longitudinal natural-history data support gradual functional gains
      rather than regression, an important counselling point.

clinical_burden:
  burden_level: HIGH
  rationale: >-
    Near-universal moderate-to-severe intellectual disability with absent or
    minimal speech, lifelong dependence for most activities of daily living,
    high rates of tube feeding in infancy, and a substantial neurobehavioral
    burden (self-injury, aggression, sleep disturbance) requiring
    multidisciplinary and often psychiatric care.
  evidence:
  - reference: PMID:28100473
    reference_title: "Delineating the phenotypic spectrum of Bainbridge-Ropers syndrome: 12 new patients with de novo, heterozygous, loss-of-function mutations in ASXL3 and review of published literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      common emerging features include severe intellectual disability (11/12),
      poor/ absent speech (12/12), autistic traits (9/12)
    explanation: >-
      Near-universal severe intellectual disability and absent speech in a
      systematically phenotyped cohort underpin the high burden rating.
  - reference: PMID:34086428
    reference_title: Comorbid Psychiatric Aspects of Bainbridge-Ropers Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All 7 patients (100%) had multiple DSM-5 diagnoses.
    explanation: >-
      Every individual in this clinical series carried multiple psychiatric
      diagnoses, indicating substantial additional care burden.

inheritance:
- name: Autosomal dominant, typically de novo
  description: >-
    BRPS is inherited in an autosomal dominant manner and is typically caused
    by a de novo heterozygous protein-truncating ASXL3 variant. Transmission
    from a mildly affected or mosaic parent is documented but uncommon, and
    sibling recurrence attributable to parental gonadal or gonosomal mosaicism
    has been reported, so recurrence risk after an apparently de novo event is
    low but not negligible.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:33151654
    reference_title: ASXL3-Related Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ASXL3-related disorder is an autosomal dominant disorder typically
      caused by a de novo pathogenic variant.
    explanation: >-
      GeneReviews states the mode of inheritance and the predominance of
      de novo variants.
  - reference: PMID:33151654
    reference_title: ASXL3-Related Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Rarely, individuals diagnosed with ASXL3-related disorder have the
      disorder as the result of a pathogenic variant inherited from a parent.
    explanation: >-
      Supports the documented but uncommon inherited route.
  - reference: PMID:39833101
    reference_title: Comprehensive Clinical and Genetic Characterization of a Spanish Cohort of 22 Patients With Bainbridge-Ropers Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We documented recurrence in nontwin siblings due to parental mosaicism.
    explanation: >-
      Directly documents sibling recurrence via parental mosaicism, the basis
      for the non-negligible recurrence-risk counselling point.

pathophysiology:
- name: ASXL3 Haploinsufficiency from Protein-Truncating Variants
  biological_scale: MOLECULAR
  description: >-
    A heterozygous nonsense, frameshift, or canonical splice-site variant,
    almost always falling in the two large coding exons 11 and 12, is the
    initiating lesion. For variants predicted to trigger nonsense-mediated
    decay the mutant transcript is degraded and total ASXL3 message and
    protein fall, producing true haploinsufficiency. A second class of
    truncating variants escapes decay and yields a truncated protein, and the
    two classes are associated with measurably different clinical severity,
    which argues that reduced dosage is the dominant but not the only
    mechanism.
  mechanism_confidence: ESTABLISHED
  gene:
    preferred_term: ASXL3
    term:
      id: hgnc:29357
      label: ASXL3
  biological_processes:
  - preferred_term: nonsense-mediated decay of the mutant ASXL3 transcript
    term:
      id: GO:0000184
      label: nuclear-transcribed mRNA catabolic process, nonsense-mediated decay
    modifier: INCREASED
  cell_types:
  - preferred_term: patient dermal fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  downstream:
  - target: Impaired PR-DUB Deubiquitinase Complex Function
    causal_link_type: DIRECT
    description: >-
      Reduced ASXL3 protein limits assembly of the ASXL3-BAP1 PR-DUB complex,
      of which ASXL3 is an obligate scaffolding subunit.
    evidence:
    - reference: PMID:26647312
      reference_title: De novo dominant ASXL3 mutations alter H2A deubiquitination and transcription in Bainbridge-Ropers syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We found that ASXL3 interacts with BAP1, a hydrolase that removes
        mono-ubiquitin from histone H2A lysine 119 (H2AK119Ub1) as a component
        of the Polycomb repressive deubiquitination (PR-DUB) complex.
      explanation: >-
        Establishes that ASXL3 is a constituent of PR-DUB, so that reduced
        ASXL3 dosage directly compromises the complex.
  evidence:
  - reference: PMID:23383720
    reference_title: De novo truncating mutations in ASXL3 are associated with a novel clinical phenotype with similarities to Bohring-Opitz syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Using genome-wide sequencing, we identified heterozygous, de novo
      truncating mutations in ASXL3, a transcriptional repressor related to
      ASXL1, in four unrelated probands.
    explanation: >-
      Establishes heterozygous de novo truncating ASXL3 variants as the
      initiating molecular lesion.
  - reference: PMID:26647312
    reference_title: De novo dominant ASXL3 mutations alter H2A deubiquitination and transcription in Bainbridge-Ropers syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      ASXL3 mRNA transcripts from the mutated allele are prone to
      nonsense-mediated decay, and expression of ASXL3 is reduced.
    explanation: >-
      Patient fibroblasts directly demonstrate NMD of the mutant allele and
      reduced ASXL3 expression, the molecular definition of
      haploinsufficiency.
  - reference: PMID:38420660
    reference_title: "ASXL3-related disorder: Molecular phenotyping and comprehensive review providing insights into disease mechanism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The majority of genetic variants were de novo truncating variants in
      exon 11 or 12 of the ASXL3 gene.
    explanation: >-
      A systematic review confirms the exon 11/12 clustering of the causal
      truncating variants.
  - reference: PMID:42494517
    reference_title: Broadening the inherited ASXL3 spectrum and unveiling molecular mechanisms through detailed genotypic-phenotypic analyses.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Statistical comparisons were made between individuals with variants
      leading to no protein product
    explanation: >-
      Establishes the two-class analysis dividing individuals into a
      nonsense-mediated-decay group (n = 87, no protein product) and a
      no-NMD protein-truncating group (n = 117). Marked PARTIAL because this
      shows the two classes are separable and were compared, but does not by
      itself prove that the no-NMD truncated protein acts by a distinct
      (e.g. dominant-negative) molecular mechanism.

- name: Impaired PR-DUB Deubiquitinase Complex Function
  biological_scale: MOLECULAR
  description: >-
    ASXL3 is a non-catalytic scaffolding subunit of the Polycomb repressive
    deubiquitinase (PR-DUB) complex, binding the ubiquitin C-terminal
    hydrolase BAP1 through its DEUBAD module. BAP1 has little activity on
    nucleosomes on its own and depends on an ASXL partner, so reduced ASXL3
    dosage limits assembly of functional ASXL3-BAP1 PR-DUB and blunts its
    catalytic output. The ASXL paralogs are epigenetic scaffolds more
    generally, also engaging EZH2, nuclear receptors and other partners.
  mechanism_confidence: ESTABLISHED
  protein_complexes:
  - preferred_term: ASXL3-BAP1 PR-DUB complex
    term:
      id: GO:0035517
      label: PR-DUB complex
  molecular_functions:
  - preferred_term: histone H2A deubiquitinase activity of the PR-DUB complex
    term:
      id: GO:0140950
      label: histone H2A deubiquitinase activity
    modifier: DECREASED
  downstream:
  - target: Elevated H2A Lysine 119 Monoubiquitination
    causal_link_type: DIRECT
    description: >-
      Loss of PR-DUB catalytic output leaves the repressive H2AK119
      monoubiquitin mark abnormally elevated.
    evidence:
    - reference: PMID:26647312
      reference_title: De novo dominant ASXL3 mutations alter H2A deubiquitination and transcription in Bainbridge-Ropers syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        A significant increase in H2AK119Ub1 was observed in ASXL3 patient
        fibroblasts, highlighting an important functional role for ASXL3 in
        PR-DUB mediated deubiquitination.
      explanation: >-
        Directly measures the increase in H2AK119Ub1 that follows loss of
        ASXL3-dependent PR-DUB activity.
  evidence:
  - reference: PMID:26647312
    reference_title: De novo dominant ASXL3 mutations alter H2A deubiquitination and transcription in Bainbridge-Ropers syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We found that ASXL3 interacts with BAP1, a hydrolase that removes
      mono-ubiquitin from histone H2A lysine 119 (H2AK119Ub1) as a component
      of the Polycomb repressive deubiquitination (PR-DUB) complex.
    explanation: >-
      Directly establishes the ASXL3-BAP1 PR-DUB interaction that this node
      describes.
  - reference: PMID:25835095
    reference_title: "Functional proteomics of the epigenetic regulators ASXL1, ASXL2 and ASXL3: a convergence of proteomics and epigenetics for translational medicine."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      ASXL1, ASXL2 and ASXL3 are epigenetic scaffolds for BAP1, EZH2, NCOA1,
      nuclear receptors and WTIP.
    explanation: >-
      A functional-proteomics review supports the scaffolding role of ASXL3
      for BAP1 and additional chromatin and nuclear-receptor partners.
  - reference: PMID:32132929
    reference_title: Modeling Bainbridge-Ropers Syndrome in Xenopus laevis Embryos.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      ASXL3 protein is a component of the polycomb deubiquitinase complex that
      removes mono-ubiquitin from Histone H2A.
    explanation: >-
      Independently confirms ASXL3 membership in the H2A-directed Polycomb
      deubiquitinase complex.

- name: Elevated H2A Lysine 119 Monoubiquitination
  biological_scale: MOLECULAR
  description: >-
    Loss of PR-DUB output leaves H2AK119 monoubiquitination abnormally high.
    This mark is the repressive output of Polycomb repressive complex 1, and
    its dynamic removal by PR-DUB is required for normal derepression of
    developmental target genes. BRPS was the first single-gene disorder
    attributed to a defect in H2AK119Ub1 deubiquitination, making this the
    defining chromatin lesion of the syndrome.
  mechanism_confidence: ESTABLISHED
  biological_processes:
  - preferred_term: PR-DUB-mediated histone H2A deubiquitination
    term:
      id: GO:0016579
      label: protein deubiquitination
    modifier: DECREASED
  - preferred_term: chromatin organization at Polycomb target loci
    term:
      id: GO:0006325
      label: chromatin organization
    modifier: ABNORMAL
  cell_types:
  - preferred_term: patient dermal fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  downstream:
  - target: Absence of an ASXL3 DNA Methylation Episignature
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The chromatin lesion does not propagate into a detectable peripheral
      blood DNA methylation signature: ASXL3 patients profile as control-like
      on the ASXL1/Bohring-Opitz classifier. The steps that would connect an
      elevated H2AK119Ub1 mark to a blood DNAm readout are unknown, and this
      edge asserts the absence of a detectable downstream signature rather
      than a positive effect.
    evidence:
    - reference: PMID:35361921
      reference_title: "DNA methylation signature associated with Bohring-Opitz syndrome: a new tool for functional classification of variants in ASXL genes."
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        the DNAm profiles of three individuals with ASXL3 variants were
        control-like
      explanation: >-
        The only measurement linking the ASXL3 chromatin lesion to a blood
        methylation readout, and it is negative. Marked PARTIAL because it
        rests on three individuals tested with a classifier built for a
        different paralog, so absence of a detectable signature is not
        established as absence of a signature.
  - target: Genome-Wide Transcriptional Dysregulation
    causal_link_type: DIRECT
    description: >-
      The altered chromatin state produces widespread bidirectional changes in
      gene expression in patient-derived cells.
    evidence:
    - reference: PMID:26647312
      reference_title: De novo dominant ASXL3 mutations alter H2A deubiquitination and transcription in Bainbridge-Ropers syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Transcriptomes of ASXL3 patient and control fibroblasts were compared
        to investigate the impact of chromatin changes on transcriptional
        regulation.
      explanation: >-
        The study design explicitly tests, and the results establish, the
        chromatin-to-transcription link asserted by this edge.
  evidence:
  - reference: PMID:26647312
    reference_title: De novo dominant ASXL3 mutations alter H2A deubiquitination and transcription in Bainbridge-Ropers syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      A significant increase in H2AK119Ub1 was observed in ASXL3 patient
      fibroblasts, highlighting an important functional role for ASXL3 in
      PR-DUB mediated deubiquitination.
    explanation: >-
      Directly measures the elevated H2AK119Ub1 mark in patient-derived cells.
  - reference: PMID:26647312
    reference_title: De novo dominant ASXL3 mutations alter H2A deubiquitination and transcription in Bainbridge-Ropers syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This is the first single gene disorder linked to defects in
      deubiquitination of H2AK119Ub1
    explanation: >-
      Establishes the H2AK119Ub1 deubiquitination defect as the defining
      molecular lesion of this disorder.

- name: Genome-Wide Transcriptional Dysregulation
  biological_scale: MOLECULAR
  description: >-
    The aberrant chromatin state translates into widespread transcriptional
    change. Patient fibroblast transcriptomes show hundreds of differentially
    expressed genes split almost evenly between up- and downregulated, which
    is more consistent with loss of a chromatin scaffold that tunes both
    repression and activation than with loss of a pure repressor. The affected
    genes are enriched for transcriptional regulation, development, and
    proliferation.
  mechanism_confidence: ESTABLISHED
  biological_processes:
  - preferred_term: dysregulated transcription of developmental target genes
    term:
      id: GO:0006355
      label: regulation of DNA-templated transcription
    modifier: ABNORMAL
  cell_types:
  - preferred_term: patient dermal fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  downstream:
  - target: Disrupted Neural Cell Fate Specification
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Transcriptional dysregulation during early neural patterning is inferred
      to derail cell-fate specification. The specific intermediate target
      genes in human neural tissue are not known, and the direct evidence is
      model-organism only.
    intermediate_mechanisms:
    - Derepression of Polycomb target genes at neural patterning loci
    - Altered dosage of hindbrain, primary neuron, and neural crest fate determinants
    evidence:
    - reference: PMID:32132929
      reference_title: Modeling Bainbridge-Ropers Syndrome in Xenopus laevis Embryos.
      supports: PARTIAL
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Dynamic chromatin modifications play important roles in the
        specification of cell fates during early neural patterning and
        development.
      explanation: >-
        Supports the general chromatin-to-cell-fate link. Marked PARTIAL
        because the intermediates between the human transcriptional signature
        and a human neural cell-fate defect are not established.
  evidence:
  - reference: PMID:26647312
    reference_title: De novo dominant ASXL3 mutations alter H2A deubiquitination and transcription in Bainbridge-Ropers syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Out of 564 significantly differentially expressed genes (DEGs) in ASXL3
      patient fibroblasts, 52% were upregulated and 48% downregulated. DEGs
      were enriched in molecular processes impacting transcriptional
      regulation, development and proliferation, consistent with the features
      of BRS.
    explanation: >-
      Quantifies the transcriptional consequence and its near-symmetric
      up/down distribution in patient cells.

- name: Disrupted Neural Cell Fate Specification
  biological_scale: CELLULAR
  description: >-
    The developmental consequence of ASXL3 loss falls on early neural
    patterning. In a vertebrate embryo model, ASXL3 depletion severely
    perturbs specification of neural cell fates, with reduced expression of
    hindbrain, primary neuron, and neural crest markers, while spinal-cord
    identity is relatively spared. This positions ASXL3 as a chromatin
    regulator required during the earliest steps of nervous system induction
    and anteroposterior patterning, which is when the human phenotype is
    determined.
  mechanism_confidence: PROVISIONAL
  biological_processes:
  - preferred_term: neural cell fate commitment
    term:
      id: GO:0045165
      label: cell fate commitment
    modifier: ABNORMAL
  - preferred_term: nervous system development
    term:
      id: GO:0007399
      label: nervous system development
    modifier: ABNORMAL
  - preferred_term: neuron differentiation
    term:
      id: GO:0030182
      label: neuron differentiation
    modifier: DECREASED
  cell_types:
  - preferred_term: developing neuron
    term:
      id: CL:0000540
      label: neuron
  downstream:
  - target: Neurodevelopmental and Multisystem Clinical Phenotype
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Disrupted early neural specification is inferred to produce the clinical
      neurodevelopmental phenotype. Because most affected individuals have
      structurally normal brain imaging, the intervening steps between a
      patterning defect and the clinical picture are unresolved.
    evidence:
    - reference: PMID:32132929
      reference_title: Modeling Bainbridge-Ropers Syndrome in Xenopus laevis Embryos.
      supports: PARTIAL
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We have found that ASXL3 protein knockdown during early embryo
        development highly perturbs neural cell fate specification, potentially
        resembling the Bainbridge-Ropers syndrome phenotype in humans.
      explanation: >-
        The authors themselves qualify the link as "potentially resembling"
        the human phenotype, which is why this edge is PARTIAL and indirect.
  notes: >-
    Evidence for this node is model-organism only (Xenopus laevis morpholino
    knockdown). No human neuropathological or human-neural-progenitor study
    has confirmed the specific cell-fate defect, and most affected individuals
    have normal brain MRI. See the HUMAN_MODEL_MISMATCH discussion item.
  evidence:
  - reference: PMID:32132929
    reference_title: Modeling Bainbridge-Ropers Syndrome in Xenopus laevis Embryos.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We have found that ASXL3 protein knockdown during early embryo
      development highly perturbs neural cell fate specification, potentially
      resembling the Bainbridge-Ropers syndrome phenotype in humans.
    explanation: >-
      Directly demonstrates that ASXL3 depletion disrupts early neural cell
      fate specification in a vertebrate embryo.
  - reference: PMID:32132929
    reference_title: Modeling Bainbridge-Ropers Syndrome in Xenopus laevis Embryos.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Dynamic chromatin modifications play important roles in the
      specification of cell fates during early neural patterning and
      development.
    explanation: >-
      Provides the mechanistic rationale linking the chromatin lesion to a
      cell-fate specification defect.

- name: Neurodevelopmental and Multisystem Clinical Phenotype
  biological_scale: ORGANISM
  description: >-
    The terminal node: a static (non-degenerative) neurodevelopmental
    phenotype comprising moderate-to-severe intellectual disability, absent or
    profoundly limited speech, autistic features, central hypotonia evolving
    toward limb hypertonia, severe infantile feeding difficulty with failure
    to thrive, gastroesophageal reflux, and a nonspecific craniofacial
    gestalt, with generalized epilepsy in a minority.
  mechanism_confidence: ESTABLISHED
  evidence:
  - reference: PMID:38420660
    reference_title: "ASXL3-related disorder: Molecular phenotyping and comprehensive review providing insights into disease mechanism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Common phenotypic features comprised global developmental delay or
      intellectual disability (97%), feeding problems (76%), hypotonia (88%)
      and characteristic facial features (93%).
    explanation: >-
      Quantifies the terminal clinical phenotype across the published
      literature.
  - reference: PMID:33151654
    reference_title: ASXL3-Related Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ASXL3-related disorder is characterized by developmental delay or
      intellectual disability, typically in the moderate to severe range, with
      speech and language delay and/or absent speech.
    explanation: >-
      The GeneReviews clinical summary of the terminal phenotype.

- name: Absence of an ASXL3 DNA Methylation Episignature
  biological_scale: MOLECULAR
  description: >-
    A negative but mechanistically informative finding. Blood DNA methylation
    signatures are established for many chromatinopathies, and ASXL1-related
    Bohring-Opitz syndrome has a robust one. When that classifier was applied
    to ASXL3 patients their methylation profiles were control-like, and unlike
    ASXL1 and ASXL2 patients they showed no epigenetic age acceleration. This
    means (a) there is currently no validated episignature available to help
    classify ASXL3 variants of uncertain significance, and (b) ASXL3
    dysfunction diverges mechanistically from ASXL1 despite paralogy - which
    is a molecular argument for keeping BRPS and BOS as separate entities.
  mechanism_confidence: PROVISIONAL
  role: BIOMARKER
  notes: >-
    Based on only three ASXL3 individuals; an adequately powered BRPS-specific
    episignature study has not been done. Do not read the negative result as
    proof that no ASXL3 signature exists.
  evidence:
  - reference: PMID:35361921
    reference_title: "DNA methylation signature associated with Bohring-Opitz syndrome: a new tool for functional classification of variants in ASXL genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The DNAm profile of one individual with the ASXL2 variant was BOS-like,
      whereas the DNAm profiles of three individuals with ASXL3 variants were
      control-like.
    explanation: >-
      Directly reports that ASXL3 patients lack the ASXL1/BOS methylation
      signature.
  - reference: PMID:35361921
    reference_title: "DNA methylation signature associated with Bohring-Opitz syndrome: a new tool for functional classification of variants in ASXL genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      which showed acceleration in DNAm age in individuals with pathogenic
      ASXL1 variants, and the individual with the pathogenic ASXL2 variant,
      but not in individuals with ASXL3 variants.
    explanation: >-
      The absence of epigenetic age acceleration in ASXL3 further separates it
      from ASXL1 and ASXL2.

phenotypes:
- name: Global developmental delay
  category: Neurologic
  description: >-
    Delay across all developmental domains is essentially universal and is
    usually the finding that prompts genetic testing.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:38420660
    reference_title: "ASXL3-related disorder: Molecular phenotyping and comprehensive review providing insights into disease mechanism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Common phenotypic features comprised global developmental delay or
      intellectual disability (97%), feeding problems (76%), hypotonia (88%)
      and characteristic facial features (93%).
    explanation: >-
      97% across the reviewed literature supports the VERY_FREQUENT band
      (80-100%).

- name: Intellectual disability
  category: Neurologic
  description: >-
    Intellectual disability, typically in the moderate to severe range.
    Severity is greater in individuals whose variants are predicted to undergo
    nonsense-mediated decay and in those with exon 11 (MCR1) variants.
  frequency: VERY_FREQUENT
  severity: SEVERE
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:33151654
    reference_title: ASXL3-Related Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ASXL3-related disorder is characterized by developmental delay or
      intellectual disability, typically in the moderate to severe range
    explanation: >-
      The GeneReviews clinical characteristics statement on intellectual
      disability and its typical severity.
  - reference: PMID:28100473
    reference_title: "Delineating the phenotypic spectrum of Bainbridge-Ropers syndrome: 12 new patients with de novo, heterozygous, loss-of-function mutations in ASXL3 and review of published literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      common emerging features include severe intellectual disability (11/12)
    explanation: >-
      11/12 (92%) in a systematically phenotyped DDD cohort supports the
      VERY_FREQUENT band.
  - reference: PMID:42494517
    reference_title: Broadening the inherited ASXL3 spectrum and unveiling molecular mechanisms through detailed genotypic-phenotypic analyses.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Intellectual disability and global developmental delay were more severe
      in the NMD and MCR1 groups
    explanation: >-
      Supports the genotype-dependent severity gradient described here.

- name: Absent or severely limited speech
  category: Neurologic
  description: >-
    Speech and language impairment is the most consistent feature of the
    syndrome. Most affected individuals are nonverbal or have only a handful
    of words, and augmentative and alternative communication is a core need.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Absent speech
    term:
      id: HP:0001344
      label: Absent speech
  evidence:
  - reference: PMID:28100473
    reference_title: "Delineating the phenotypic spectrum of Bainbridge-Ropers syndrome: 12 new patients with de novo, heterozygous, loss-of-function mutations in ASXL3 and review of published literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      poor/ absent speech (12/12)
    explanation: >-
      12/12 (100%) directly supports the VERY_FREQUENT band for absent or
      poor speech.
  - reference: PMID:27901041
    reference_title: "Bainbridge-Ropers syndrome caused by loss-of-function variants in ASXL3: a recognizable condition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      profound speech impairment
    explanation: >-
      An independent European cohort lists profound speech impairment among
      the concordant clinical features.

- name: Delayed speech and language development
  category: Neurologic
  description: >-
    Where speech does develop it is markedly delayed and limited, and speech
    and language delay is one of the two GeneReviews-defining developmental
    features.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:33151654
    reference_title: ASXL3-Related Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      with speech and language delay and/or absent speech
    explanation: >-
      GeneReviews names speech and language delay as a defining clinical
      characteristic.

- name: Hypotonia
  category: Neurologic
  description: >-
    Central hypotonia, often severe and evident from infancy, contributing to
    feeding failure and motor delay. In many individuals truncal hypotonia
    later coexists with, or gives way to, increased limb tone and flexion
    contractures of the elbows, wrists, and fingers.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:38420660
    reference_title: "ASXL3-related disorder: Molecular phenotyping and comprehensive review providing insights into disease mechanism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hypotonia (88%)
    explanation: >-
      88% across the reviewed literature supports the VERY_FREQUENT band.
  - reference: PMID:39833101
    reference_title: Comprehensive Clinical and Genetic Characterization of a Spanish Cohort of 22 Patients With Bainbridge-Ropers Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hypotonia (85.7%)
    explanation: >-
      An independent cohort reports a concordant 85.7% frequency.
  - reference: PMID:33151654
    reference_title: ASXL3-Related Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected individuals may also have hypotonia that can transition to
      spasticity resulting in unusual posture with flexion contractions of the
      elbows, wrists, and fingers.
    explanation: >-
      Documents the hypotonia-to-spasticity evolution described here.

- name: Feeding difficulties
  category: Gastrointestinal
  description: >-
    Severe feeding difficulty is one of the two features that named the
    disorder. It presents in early infancy, frequently necessitates
    nasogastric and then gastrostomy feeding, and drives failure to thrive.
    Feeding tube use is more frequent in the nonsense-mediated-decay and exon
    11 variant groups.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
    onset:
      onset_category: INFANTILE
  evidence:
  - reference: PMID:39833101
    reference_title: Comprehensive Clinical and Genetic Characterization of a Spanish Cohort of 22 Patients With Bainbridge-Ropers Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      feeding difficulties (90.5%)
    explanation: >-
      90.5% in a 22-patient cohort supports the VERY_FREQUENT band.
  - reference: PMID:23383720
    reference_title: De novo truncating mutations in ASXL3 are associated with a novel clinical phenotype with similarities to Bohring-Opitz syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      including severe feeding difficulties, failure to thrive, and neurologic
      abnormalities with significant developmental delay
    explanation: >-
      The founding description places severe feeding difficulty at the centre
      of the phenotype.
  - reference: PMID:42494517
    reference_title: Broadening the inherited ASXL3 spectrum and unveiling molecular mechanisms through detailed genotypic-phenotypic analyses.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Microcephaly, sleep apnea, hyperventilation, and feeding tube use had a
      statistically increased prevalence in the NMD and MCR1 groups.
    explanation: >-
      Supports the genotype dependence of feeding-tube requirement.

- name: Failure to thrive
  category: Growth
  description: >-
    Failure to thrive in infancy, secondary to the severe feeding difficulty,
    is one of the two features that named the disorder and appears in the
    Orphanet/MONDO disease label itself.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
    onset:
      onset_category: INFANTILE
  notes: >-
    No frequency band is asserted: none of the cached sources reports a
    numeric frequency for failure to thrive specifically, as distinct from
    feeding difficulty. Per the frequency-evidence SOP, the band is omitted
    rather than inferred.
  evidence:
  - reference: PMID:23383720
    reference_title: De novo truncating mutations in ASXL3 are associated with a novel clinical phenotype with similarities to Bohring-Opitz syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      severe feeding difficulties, failure to thrive
    explanation: >-
      Failure to thrive is part of the founding phenotype description and of
      the disease name itself.

- name: Poor postnatal growth
  category: Growth
  description: >-
    Poor weight gain and growth failure follow from the feeding difficulty.
    Deep phenotyping notes that poor early growth may be followed by obesity
    later in childhood, modelled separately as Obesity.
  phenotype_term:
    preferred_term: Growth delay
    term:
      id: HP:0001510
      label: Growth delay
  notes: >-
    No frequency band is asserted. Both cited sources are qualitative
    ("Other findings may include poor postnatal growth"; "a tendency for poor
    post-natal growth"); neither maps to a quantitative band. This applies the
    same frequency-evidence discipline used for Failure to thrive and Dental
    anomalies.
  evidence:
  - reference: PMID:33151654
    reference_title: ASXL3-Related Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other findings may include poor postnatal growth, strabismus, seizures,
      sleep disturbance, and dental anomalies.
    explanation: >-
      GeneReviews lists poor postnatal growth among the recognized clinical
      findings.
  - reference: PMID:40552904
    reference_title: "An International ASXL3 Natural History Study: Deep Phenotypic Analyses Including Detailed Reports of a Milder Phenotype, Novel Associations, and Clinical Recommendations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a tendency for poor post-natal growth (with novel reports of obesity
      later in childhood)
    explanation: >-
      The natural-history cohort documents poor postnatal growth and the later
      obesity trajectory.

- name: Obesity
  category: Growth
  description: >-
    Obesity in later childhood is a newly reported trajectory in the
    international natural history study, and is the late-phase counterpart of
    the poor early postnatal growth that dominates infancy.
  phenotype_term:
    preferred_term: Obesity
    term:
      id: HP:0001513
      label: Obesity
    onset:
      onset_category: CHILDHOOD
  notes: >-
    No frequency band is asserted: the source describes "novel reports" of
    obesity without a count or rate, and ascertainment in a natural-history
    cohort is limited. Treat as an emerging observation.
  evidence:
  - reference: PMID:40552904
    reference_title: "An International ASXL3 Natural History Study: Deep Phenotypic Analyses Including Detailed Reports of a Milder Phenotype, Novel Associations, and Clinical Recommendations."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a tendency for poor post-natal growth (with novel reports of obesity
      later in childhood)
    explanation: >-
      Documents obesity later in childhood as a novel association. Marked
      PARTIAL because "novel reports" is unquantified and this reverses the
      direction of the growth phenotype seen in infancy.

- name: Gastroesophageal reflux
  category: Gastrointestinal
  description: >-
    Gastroesophageal reflux disease is common, compounds the feeding
    difficulty and aspiration risk, and may require anti-reflux medication or
    fundoplication.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Gastroesophageal reflux
    term:
      id: HP:0002020
      label: Gastroesophageal reflux
  evidence:
  - reference: PMID:39833101
    reference_title: Comprehensive Clinical and Genetic Characterization of a Spanish Cohort of 22 Patients With Bainbridge-Ropers Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      gastroesophageal reflux disease (82.4%)
    explanation: >-
      82.4% supports the VERY_FREQUENT band in this cohort.
  - reference: PMID:33151654
    reference_title: ASXL3-Related Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      anti-reflux medication and/or fundoplication for those with
      gastroesophageal disease
    explanation: >-
      GeneReviews management guidance confirms gastroesophageal disease as a
      recognized manifestation requiring treatment.

- name: Autistic features
  category: Behavioral
  description: >-
    Autistic traits are very common and a formal autism spectrum disorder
    diagnosis is frequent. Autism diagnoses are proportionally more common in
    the no-nonsense-mediated-decay and exon 12 (MCR2) genotype groups.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Autism
    term:
      id: HP:0000717
      label: Autism
  evidence:
  - reference: PMID:39833101
    reference_title: Comprehensive Clinical and Genetic Characterization of a Spanish Cohort of 22 Patients With Bainbridge-Ropers Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      autism spectrum disorder (75%)
    explanation: >-
      75% falls in the FREQUENT band (30-79%).
  - reference: PMID:28100473
    reference_title: "Delineating the phenotypic spectrum of Bainbridge-Ropers syndrome: 12 new patients with de novo, heterozygous, loss-of-function mutations in ASXL3 and review of published literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      autistic traits (9/12)
    explanation: >-
      9/12 (75%) in an independent cohort is concordant with the FREQUENT
      band.
  - reference: PMID:42494517
    reference_title: Broadening the inherited ASXL3 spectrum and unveiling molecular mechanisms through detailed genotypic-phenotypic analyses.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although autistic features were observed across all groups, the no-NMD
      and MCR2 cohorts had a higher proportion of individuals with formal
      autism diagnoses.
    explanation: >-
      Supports the genotype-dependent enrichment of formal autism diagnoses.

- name: Sleep disturbance
  category: Neurologic
  description: >-
    Disrupted sleep is a common and clinically significant problem, listed in
    GeneReviews and reported in the majority of individuals in clinical
    psychiatric series. It complicates behavioral assessment and management.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Sleep disturbance
    term:
      id: HP:0002360
      label: Sleep disturbance
  evidence:
  - reference: PMID:34086428
    reference_title: Comorbid Psychiatric Aspects of Bainbridge-Ropers Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      sleep impairment: 5 (71%)
    explanation: >-
      71% in a clinical series supports the FREQUENT band (30-79%).
  - reference: PMID:33151654
    reference_title: ASXL3-Related Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other findings may include poor postnatal growth, strabismus, seizures,
      sleep disturbance, and dental anomalies.
    explanation: >-
      GeneReviews lists sleep disturbance among the recognized clinical
      findings.

- name: Self-injurious behavior and aggression
  category: Behavioral
  description: >-
    Self-injury and aggression are a major source of morbidity and can be
    severe enough to require inpatient psychiatric admission. They are
    amenable to structured behavioral intervention.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Self-injurious behavior
    term:
      id: HP:0100716
      label: Self-injurious behavior
  evidence:
  - reference: PMID:34086428
    reference_title: Comorbid Psychiatric Aspects of Bainbridge-Ropers Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      self-injurious behavior: 3 (43%), aggression: 4 (57%)
    explanation: >-
      43% self-injury and 57% aggression both fall in the FREQUENT band.
  - reference: PMID:28100473
    reference_title: "Delineating the phenotypic spectrum of Bainbridge-Ropers syndrome: 12 new patients with de novo, heterozygous, loss-of-function mutations in ASXL3 and review of published literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Shared behavioural phenotypes include autistic traits, hand-flapping,
      rocking, aggressive behaviour and sleep disturbance.
    explanation: >-
      Independently documents aggression as part of the shared behavioural
      phenotype.

- name: Seizures
  category: Neurologic
  description: >-
    A minority of individuals develop childhood-onset generalized epilepsy,
    typically with generalized tonic-clonic and sometimes atypical absence
    seizures, and EEG features of generalized epilepsy. Most affected
    individuals have normal brain MRI. Non-epileptic breath-holding and
    dystonic episodes are an important mimic, so video-EEG is needed before
    escalating anti-seizure medication.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
    onset:
      onset_category: CHILDHOOD
  evidence:
  - reference: PMID:29367179
    reference_title: Childhood-onset generalized epilepsy in Bainbridge-Ropers syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seizures are reported in approximately a third of cases; however, the
      epileptology has not been thoroughly studied.
    explanation: >-
      Approximately one third supports the FREQUENT band (30-79%), at its
      lower edge.
  - reference: PMID:29367179
    reference_title: Childhood-onset generalized epilepsy in Bainbridge-Ropers syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bainbridge-Ropers syndrome is associated with childhood-onset
      generalized epilepsy with generalized tonic-clonic seizures and/or
      atypical absence seizures.
    explanation: >-
      Characterizes the epilepsy syndrome and its childhood onset.
  - reference: PMID:40552904
    reference_title: "An International ASXL3 Natural History Study: Deep Phenotypic Analyses Including Detailed Reports of a Milder Phenotype, Novel Associations, and Clinical Recommendations."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a lower-than-expected prevalence of seizures (compared to the existing
      literature)
    explanation: >-
      The largest natural-history cohort found fewer seizures than earlier
      reports, so the FREQUENT band should be read as an upper estimate
      subject to ascertainment bias.

- name: Strabismus
  category: Ophthalmologic
  description: >-
    Strabismus is the commonest ophthalmological finding and is one of the
    reasons annual ophthalmology review is recommended for all affected
    individuals.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: PMID:33151654
    reference_title: ASXL3-Related Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other findings may include poor postnatal growth, strabismus, seizures,
      sleep disturbance, and dental anomalies.
    explanation: >-
      GeneReviews lists strabismus among the recognized clinical findings.
  - reference: PMID:40552904
    reference_title: "An International ASXL3 Natural History Study: Deep Phenotypic Analyses Including Detailed Reports of a Milder Phenotype, Novel Associations, and Clinical Recommendations."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dental and Ophthalmological follow-up for all
    explanation: >-
      The natural-history study recommends ophthalmological follow-up for all
      affected individuals. Marked PARTIAL because a surveillance
      recommendation is not itself evidence for the presence or frequency of
      strabismus; the FREQUENT band rests on the GeneReviews clinical-findings
      list and is not separately quantified in any cached source.

- name: Dental anomalies
  category: Dental
  description: >-
    Dental anomalies including crowding are recognized manifestations, and
    six-monthly dental review from age three is recommended.
  phenotype_term:
    preferred_term: Dental crowding
    term:
      id: HP:0000678
      label: Dental crowding
  notes: >-
    No frequency band is asserted. GeneReviews lists dental anomalies only
    qualitatively ("Other findings may include ..."), the surveillance
    recommendation is not a frequency statement, and no cached source
    quantifies dental crowding specifically. Per the frequency-evidence SOP
    the band is omitted rather than inferred.
  evidence:
  - reference: PMID:33151654
    reference_title: ASXL3-Related Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      sleep disturbance, and dental anomalies
    explanation: >-
      GeneReviews explicitly lists dental anomalies as a clinical finding.
      This supports the association only, not a frequency band.
  - reference: PMID:33151654
    reference_title: ASXL3-Related Disorder.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dental evaluation every six months after age three years or as
      clinically indicated.
    explanation: >-
      A surveillance recommendation implying a recognized dental burden.
      Marked PARTIAL because a management recommendation is not direct
      evidence of the phenotype's presence or frequency.

- name: Highly arched eyebrows
  category: Craniofacial
  description: >-
    Arched eyebrows, often with mild synophrys, are part of the recognizable
    but nonspecific craniofacial gestalt. They are reported more frequently in
    individuals with exon 11 (5' MCR) variants.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Highly arched eyebrow
    term:
      id: HP:0002553
      label: Highly arched eyebrow
  evidence:
  - reference: PMID:28100473
    reference_title: "Delineating the phenotypic spectrum of Bainbridge-Ropers syndrome: 12 new patients with de novo, heterozygous, loss-of-function mutations in ASXL3 and review of published literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      distinct face (arched eyebrows, prominent forehead, high-arched palate,
      hypertelorism and downslanting palpebral fissures), (9/12)
    explanation: >-
      9/12 (75%) for the composite facial gestalt including arched eyebrows
      supports the FREQUENT band.
  - reference: PMID:39833101
    reference_title: Comprehensive Clinical and Genetic Characterization of a Spanish Cohort of 22 Patients With Bainbridge-Ropers Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      higher frequency of arched eyebrows
    explanation: >-
      Supports the genotype-dependent enrichment of arched eyebrows in exon 11
      variant carriers.

- name: Downslanted palpebral fissures
  category: Craniofacial
  description: >-
    Downslanting palpebral fissures are a consistent component of the BRPS
    facial gestalt across independent cohorts.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Downslanted palpebral fissures
    term:
      id: HP:0000494
      label: Downslanted palpebral fissures
  evidence:
  - reference: PMID:27901041
    reference_title: "Bainbridge-Ropers syndrome caused by loss-of-function variants in ASXL3: a recognizable condition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a characteristic craniofacial phenotype (long face, arched eyebrows with
      mild synophrys, downslanting palpebral fissures, prominent columella,
      small alae nasi, high, narrow palate and relatively little facial
      expression)
    explanation: >-
      Downslanting palpebral fissures are listed as part of the characteristic
      craniofacial phenotype in a six-patient European cohort.
  - reference: PMID:28100473
    reference_title: "Delineating the phenotypic spectrum of Bainbridge-Ropers syndrome: 12 new patients with de novo, heterozygous, loss-of-function mutations in ASXL3 and review of published literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hypertelorism and downslanting palpebral fissures), (9/12)
    explanation: >-
      Independently documents downslanting palpebral fissures in the facial
      gestalt at 9/12.

- name: High palate
  category: Craniofacial
  description: >-
    A high, narrow, or high-arched palate is a recurrent oral finding and
    contributes to the feeding difficulty.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: High palate
    term:
      id: HP:0000218
      label: High palate
  evidence:
  - reference: PMID:27901041
    reference_title: "Bainbridge-Ropers syndrome caused by loss-of-function variants in ASXL3: a recognizable condition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      high, narrow palate and relatively little facial expression
    explanation: >-
      A high narrow palate is documented in the characteristic craniofacial
      phenotype.
  - reference: PMID:28100473
    reference_title: "Delineating the phenotypic spectrum of Bainbridge-Ropers syndrome: 12 new patients with de novo, heterozygous, loss-of-function mutations in ASXL3 and review of published literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      arched eyebrows, prominent forehead, high-arched palate
    explanation: >-
      High-arched palate is listed in the DDD cohort facial description.

- name: Prominent forehead
  category: Craniofacial
  description: >-
    A prominent forehead is part of the described facial gestalt, though the
    dysmorphic features overall are nonspecific and molecular testing rather
    than gestalt recognition establishes the diagnosis.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Prominent forehead
    term:
      id: HP:0011220
      label: Prominent forehead
  evidence:
  - reference: PMID:28100473
    reference_title: "Delineating the phenotypic spectrum of Bainbridge-Ropers syndrome: 12 new patients with de novo, heterozygous, loss-of-function mutations in ASXL3 and review of published literature."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      distinct face (arched eyebrows, prominent forehead, high-arched palate,
      hypertelorism and downslanting palpebral fissures), (9/12)
    explanation: >-
      Prominent forehead is named within the composite facial gestalt scored
      9/12. Marked PARTIAL because the 9/12 count is for the gestalt as a
      whole and does not decompose to this individual feature; the OCCASIONAL
      band follows the same reasoning applied to hypertelorism, which is drawn
      from this identical sentence and has a comparable per-feature frequency
      in the HPO disease annotations for OMIM:615485.

- name: Hypertelorism
  category: Craniofacial
  description: >-
    Widely spaced eyes are reported as part of the facial gestalt in
    systematically phenotyped cohorts.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: PMID:28100473
    reference_title: "Delineating the phenotypic spectrum of Bainbridge-Ropers syndrome: 12 new patients with de novo, heterozygous, loss-of-function mutations in ASXL3 and review of published literature."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hypertelorism and downslanting palpebral fissures
    explanation: >-
      Documents hypertelorism as part of the BRPS facial gestalt. Marked
      PARTIAL because the snippet supports the association only: the composite
      gestalt count does not decompose to this feature. The OCCASIONAL band
      reflects the lower per-feature frequency of hypertelorism in the HPO
      disease annotations for OMIM:615485, which is not itself a quoted
      reference.

- name: Microcephaly
  category: Craniofacial
  description: >-
    Microcephaly is present in a minority of affected individuals. It is not a
    universal feature despite appearing in the Orphanet/MONDO disease label,
    and it is significantly enriched in the nonsense-mediated-decay and exon
    11 (MCR1) genotype groups. Its relative infrequency is one of the features
    separating BRPS from ASXL1-related Bohring-Opitz syndrome.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:42494517
    reference_title: Broadening the inherited ASXL3 spectrum and unveiling molecular mechanisms through detailed genotypic-phenotypic analyses.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Microcephaly, sleep apnea, hyperventilation, and feeding tube use had a
      statistically increased prevalence in the NMD and MCR1 groups.
    explanation: >-
      Establishes microcephaly as a genotype-dependent rather than universal
      feature.
  - reference: PMID:24044690
    reference_title: De novo frameshift mutation in ASXL3 in a patient with global developmental delay, microcephaly, and craniofacial anomalies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      truncating and frameshifting mutations in the ASXL3 gene are the cause
      of a newly recognized disorder characterized by severe global
      developmental delay, short stature, microcephaly, and craniofacial
      anomalies
    explanation: >-
      An early case establishing microcephaly within the ASXL3 phenotype
      spectrum.
  - reference: PMID:27901041
    reference_title: "Bainbridge-Ropers syndrome caused by loss-of-function variants in ASXL3: a recognizable condition."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The majority of key features characteristic for Bohring-Opitz syndrome
      were absent in our patients (eg, the typical posture of arms,
      intrauterine growth retardation, microcephaly, trigonocephaly
    explanation: >-
      Supports only the negative part of the claim: microcephaly was largely
      absent in this ASXL3 cohort, which is why the OCCASIONAL rather than
      FREQUENT band is used.

- name: Joint hypermobility
  category: Musculoskeletal
  description: >-
    Joint laxity is common and, together with hypotonia, contributes to motor
    delay, gait abnormality, and orthopaedic complications such as scoliosis
    and contractures.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Joint hypermobility
    term:
      id: HP:0001382
      label: Joint hypermobility
  evidence:
  - reference: PMID:39833101
    reference_title: Comprehensive Clinical and Genetic Characterization of a Spanish Cohort of 22 Patients With Bainbridge-Ropers Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      joint laxity (73.7%)
    explanation: >-
      73.7% falls squarely in the FREQUENT band (30-79%).

- name: Intrauterine growth restriction
  category: Growth
  description: >-
    Intrauterine growth restriction is the predominant prenatal finding,
    present in about a third of pregnancies in a systematically ascertained
    cohort. Note that IUGR is far more characteristic of ASXL1-related
    Bohring-Opitz syndrome, where it is a near-defining feature.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Intrauterine growth retardation
    term:
      id: HP:0001511
      label: Intrauterine growth retardation
    onset:
      onset_category: ANTENATAL
  evidence:
  - reference: PMID:39833101
    reference_title: Comprehensive Clinical and Genetic Characterization of a Spanish Cohort of 22 Patients With Bainbridge-Ropers Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The predominant prenatal finding was intrauterine growth restriction
      (35%)
    explanation: >-
      35% supports the FREQUENT band (30-79%) at its lower edge.

- name: Hyperventilation
  category: Neurologic
  description: >-
    Episodic hyperventilation, sometimes with hyperventilation-induced
    athetoid movements (modelled separately as Athetosis), is a distinctive
    but uncommon manifestation. It is
    non-epileptic and ceases with sleep, and it must be distinguished from
    seizures to avoid unnecessary anti-seizure medication. Hyperventilation is
    enriched in the nonsense-mediated-decay and exon 11 genotype groups.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Hyperventilation
    term:
      id: HP:0002883
      label: Hyperventilation
  evidence:
  - reference: PMID:28955728
    reference_title: Hyperventilation-athetosis in ASXL3 deficiency (Bainbridge-Ropers) syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a new case with a striking phenotype, namely
      hyperventilation-induced athetosis.
    explanation: >-
      Directly documents the hyperventilation-athetosis phenotype in an ASXL3
      patient.
  - reference: PMID:42494517
    reference_title: Broadening the inherited ASXL3 spectrum and unveiling molecular mechanisms through detailed genotypic-phenotypic analyses.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Microcephaly, sleep apnea, hyperventilation, and feeding tube use had a
      statistically increased prevalence in the NMD and MCR1 groups.
    explanation: >-
      Confirms hyperventilation as a recognized, genotype-enriched feature in
      a 204-individual analysis.

- name: Sleep apnea
  category: Respiratory
  description: >-
    Obstructive and central sleep apnea occur and warrant polysomnography and
    ENT or sleep-specialist input. Sleep apnea is enriched in the
    nonsense-mediated-decay and exon 11 genotype groups.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Sleep apnea
    term:
      id: HP:0010535
      label: Sleep apnea
  evidence:
  - reference: PMID:42494517
    reference_title: Broadening the inherited ASXL3 spectrum and unveiling molecular mechanisms through detailed genotypic-phenotypic analyses.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Microcephaly, sleep apnea, hyperventilation, and feeding tube use had a
      statistically increased prevalence in the NMD and MCR1 groups.
    explanation: >-
      Establishes sleep apnea as a documented, genotype-enriched feature.
  - reference: PMID:33151654
    reference_title: ASXL3-Related Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      standard treatment for epilepsy, joint contractures, sleep apnea, dental
      anomalies, strabismus and/or refractive error
    explanation: >-
      GeneReviews management guidance confirms sleep apnea as a recognized
      manifestation.

- name: Attention deficit hyperactivity disorder
  category: Behavioral
  description: >-
    ADHD is a documented psychiatric comorbidity in clinically ascertained
    series and contributes to the multidisciplinary management burden.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Attention deficit hyperactivity disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
  evidence:
  - reference: PMID:34086428
    reference_title: Comorbid Psychiatric Aspects of Bainbridge-Ropers Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      attention-deficit/hyperactivity disorder: 3 (43%)
    explanation: >-
      43% in a clinical psychiatric series supports the FREQUENT band.

- name: Renal anomalies
  category: Renal
  description: >-
    An emerging renal phenotype was identified in the international natural
    history study and is the basis for the recommendation of baseline renal
    imaging after diagnosis. The specific renal lesions and their frequency
    are not yet characterized.
  phenotype_term:
    preferred_term: Abnormality of the kidney
    term:
      id: HP:0000077
      label: Abnormality of the kidney
  notes: >-
    Deliberately annotated at low specificity and with no frequency band: the
    only source describes "an emerging renal phenotype" without naming the
    lesions or reporting a rate. A more specific HPO term should replace this
    once the phenotype is characterized.
  evidence:
  - reference: PMID:40552904
    reference_title: "An International ASXL3 Natural History Study: Deep Phenotypic Analyses Including Detailed Reports of a Milder Phenotype, Novel Associations, and Clinical Recommendations."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      an increased prevalence of antenatal and neonatal structural anomalies,
      an emerging renal phenotype
    explanation: >-
      The largest natural-history cohort reports an emerging renal phenotype.
      Marked PARTIAL because the finding is described only as "emerging",
      with no lesion-level detail or frequency.

- name: Dystonia
  category: Neurologic
  description: >-
    Infantile-onset limb and trunk dystonic posturing, with secondarily
    evolving distal spastic contractures, is a documented part of the ASXL3
    clinical spectrum and can bring affected individuals to attention as
    dystonic cerebral palsy. This is the movement-disorder counterpart of the
    hypotonia-to-spasticity evolution described in GeneReviews.
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
    onset:
      onset_category: INFANTILE
  notes: >-
    Based on a single detailed case report with a de novo ASXL3 nonsense
    variant, supported by a prior large-scale genomic association between
    ASXL3 variation and cerebral palsy. No frequency band is asserted.
  evidence:
  - reference: PMID:35863334
    reference_title: ASXL3 De Novo Variant-Related Neurodevelopmental Disorder Presenting as Dystonic Cerebral Palsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient presented with a mixture of infantile-onset limb/trunk
      dystonic postures and secondarily evolving distal spastic contractures
    explanation: >-
      Directly documents infantile-onset dystonic posturing in an individual
      with a de novo pathogenic ASXL3 variant.
  - reference: PMID:35863334
    reference_title: ASXL3 De Novo Variant-Related Neurodevelopmental Disorder Presenting as Dystonic Cerebral Palsy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      indicates that dystonic features can be part of the clinical spectrum in
      Bainbridge-Ropers syndrome
    explanation: >-
      The authors' explicit conclusion that dystonia belongs to the BRPS
      clinical spectrum.

- name: Athetosis
  category: Neurologic
  description: >-
    Athetoid movements of the upper extremities, induced by hyperventilation,
    have been described in ASXL3 deficiency and were interpreted as evidence
    of a link between respiratory and motor control pathways in this disorder.
  phenotype_term:
    preferred_term: Athetosis
    term:
      id: HP:0002305
      label: Athetosis
  notes: >-
    Single case report (n=1). No frequency band is asserted. Previously this
    feature was named only in the description of the hyperventilation
    phenotype and carried no ontology term of its own.
  evidence:
  - reference: PMID:28955728
    reference_title: Hyperventilation-athetosis in ASXL3 deficiency (Bainbridge-Ropers) syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a new case with a striking phenotype, namely
      hyperventilation-induced athetosis.
    explanation: >-
      Directly documents hyperventilation-induced athetosis in an ASXL3
      patient.

- name: Joint contractures
  category: Musculoskeletal
  description: >-
    Flexion contractures of the elbows, wrists and fingers develop as central
    hypotonia gives way to increased limb tone, and require orthopaedic and
    physiotherapy management.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Joint contracture
    term:
      id: HP:0034392
      label: Joint contracture
  evidence:
  - reference: PMID:33151654
    reference_title: ASXL3-Related Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      spasticity resulting in unusual posture with flexion contractions of the
      elbows, wrists, and fingers
    explanation: >-
      GeneReviews documents the flexion contractures described here.

genetic:
- name: ASXL3
  gene_term:
    preferred_term: ASXL3
    term:
      id: hgnc:29357
      label: ASXL3
  association: >-
    Heterozygous protein-truncating (nonsense, frameshift, canonical
    splice-site) variants, clustered in the two large coding exons 11 and 12
  relationship_type: CAUSATIVE
  variant_origin: DE_NOVO
  notes: >-
    ASXL3 (18q12.1) is the sole established cause of Bainbridge-Ropers
    syndrome and is severely constrained against loss of function. Two
    mutational cluster regions are recognized, MCR1 in exon 11 and MCR2 in
    exon 12, and they are associated with different phenotypic profiles.
    Missense variants are not established as a cause of the autosomal dominant
    disorder. PENETRANCE AND EXPRESSIVITY: penetrance is not established. The
    de novo truncating variants that define the classical phenotype are
    treated as fully penetrant in practice, but the inherited-variant series
    documents substantial intrafamilial and possible interfamilial variability
    and describes mildly affected or apparently unaffected transmitting
    parents. The authors themselves decline to separate genuinely reduced
    penetrance from uncertainty about the pathogenicity of those inherited
    variants, so no penetrance figure is asserted here; see the
    brps_penetrance_expressivity discussion. Systematic review lists
    penetrance data as an explicit knowledge gap. GENE-IDENTITY GUARD: this
    entry's causal gene is ASXL3 (hgnc:29357), NOT the paralogs ASXL1
    (Bohring-Opitz syndrome) or ASXL2 (Shashi-Pena syndrome); every citation
    below was checked to name ASXL3.
  evidence:
  - reference: PMID:23383720
    reference_title: De novo truncating mutations in ASXL3 are associated with a novel clinical phenotype with similarities to Bohring-Opitz syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Using genome-wide sequencing, we identified heterozygous, de novo
      truncating mutations in ASXL3, a transcriptional repressor related to
      ASXL1, in four unrelated probands.
    explanation: >-
      The gene-discovery study establishing heterozygous de novo truncating
      ASXL3 variants as causal.
  - reference: PMID:38420660
    reference_title: "ASXL3-related disorder: Molecular phenotyping and comprehensive review providing insights into disease mechanism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The majority of genetic variants were de novo truncating variants in
      exon 11 or 12 of the ASXL3 gene.
    explanation: >-
      Confirms the variant class and exonic clustering across the published
      literature.
  - reference: PMID:42494517
    reference_title: Broadening the inherited ASXL3 spectrum and unveiling molecular mechanisms through detailed genotypic-phenotypic analyses.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Phenotypes in 2 mutational clusters, mutational cluster region 1 (MCR1)
      (c.1095_2237, exon 11; n = 66) and mutational cluster region 2 (MCR2)
      (c.3043_4906, exon 12; n = 101), were also analyzed.
    explanation: >-
      Defines the two mutational cluster regions by coordinate and exon.
  - reference: PMID:39833101
    reference_title: Comprehensive Clinical and Genetic Characterization of a Spanish Cohort of 22 Patients With Bainbridge-Ropers Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individuals with variants in the 3' mutational cluster region (MCR) of
      exon 12 exhibited more perinatal feeding problems, and those with
      variants in the 5' MCR of exon 11 displayed lower percentiles in height
      and occipitofrontal circumference, as well as higher frequency of arched
      eyebrows.
    explanation: >-
      Provides the genotype-phenotype correlation between mutational cluster
      region and clinical profile.
  - reference: PMID:32132929
    reference_title: Modeling Bainbridge-Ropers Syndrome in Xenopus laevis Embryos.
    supports: PARTIAL
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Human genomic studies also identified missense ASXL3 variants associated
      with autism spectrum disorder, but lacking more severe Bainbridge-Ropers
      syndromic features.
    explanation: >-
      Supports the statement that missense variants do not produce the full
      BRPS phenotype, though the disease contribution of missense variants
      remains an acknowledged open question.

diagnosis:
- name: ASXL3 molecular genetic testing
  description: >-
    The diagnosis is molecular. There are no consensus clinical diagnostic
    criteria, no biochemical marker, and no validated methylation
    episignature, so identification of a heterozygous pathogenic ASXL3 variant
    is required. In practice trio exome or genome sequencing is the workhorse;
    an intellectual disability multigene panel is an alternative, and
    chromosomal microarray remains standard first-line for undiagnosed
    developmental delay although it rarely identifies ASXL3 variants.
  presence: >-
    Identification of a heterozygous pathogenic or likely pathogenic ASXL3
    variant in a proband with suggestive clinical features establishes the
    diagnosis.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:33151654
    reference_title: ASXL3-Related Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of ASXL3-related disorder is established in a proband by
      identification of a heterozygous pathogenic variant in ASXL3 by
      molecular genetic testing.
    explanation: >-
      GeneReviews states the diagnostic criterion directly.
  - reference: PMID:28100473
    reference_title: "Delineating the phenotypic spectrum of Bainbridge-Ropers syndrome: 12 new patients with de novo, heterozygous, loss-of-function mutations in ASXL3 and review of published literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Trio-based exome sequencing was performed on all 12 patients included in
      this study, which found a de novo truncating mutation in ASXL3.
    explanation: >-
      Documents trio exome sequencing as the practical diagnostic route.

- name: Electroencephalography
  description: >-
    EEG is the most informative functional test when paroxysmal events occur.
    It distinguishes true generalized epilepsy from the non-epileptic
    breath-holding, hyperventilation and dystonic episodes that also occur in
    this disorder, and therefore prevents over-treatment with anti-seizure
    medication.
  presence: >-
    Generalized spike-wave, photoparoxysmal response, and occipital
    intermittent rhythmic epileptiform activity support a generalized epilepsy
    diagnosis; absence of an ictal correlate during a clinical episode
    indicates a non-epileptic event.
  diagnosis_term:
    preferred_term: electroencephalography
    term:
      id: NCIT:C38054
      label: Electroencephalography
  evidence:
  - reference: PMID:29367179
    reference_title: Childhood-onset generalized epilepsy in Bainbridge-Ropers syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      EEG typically showed features consistent with generalized epilepsy
      including generalized spike-wave, photoparoxysmal response, and
      occipital intermittent rhythmic epileptiform activity.
    explanation: >-
      Describes the characteristic EEG findings that support the diagnosis of
      the associated epilepsy syndrome.

differential_diagnoses:
- name: Bohring-Opitz syndrome
  description: >-
    THE critical differential and the origin of this entry's named-entity
    confusion risk. Bohring-Opitz syndrome is caused by de novo truncating
    variants in ASXL1, the closest paralog of ASXL3, and Bainbridge-Ropers
    syndrome was originally described in 2013 as a phenotype "with
    similarities to Bohring-Opitz syndrome". The two are now established as
    clinically and molecularly distinct entities and are curated separately in
    dismech. Any paper describing ASXL1 patients must not be used as evidence
    for ASXL3-related phenotypes.
  disease_term:
    preferred_term: Bohring-Opitz syndrome
    term:
      id: MONDO:0011510
      label: Bohring-Opitz syndrome
  distinguishing_features:
  - BOS is caused by ASXL1 (hgnc:18318); BRPS is caused by ASXL3 (hgnc:29357).
  - The BOS-defining features - characteristic arm posture, intrauterine growth retardation, microcephaly, trigonocephaly, facial nevus flammeus, exophthalmos - are largely absent in ASXL3 patients.
  - BOS has a validated blood DNA methylation episignature and epigenetic age acceleration; ASXL3 patients are control-like on both measures.
  - BRPS is dominated by profound speech impairment and severe muscular hypotonia with a long face and poor facial expressivity.
  evidence:
  - reference: PMID:27901041
    reference_title: "Bainbridge-Ropers syndrome caused by loss-of-function variants in ASXL3: a recognizable condition."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The majority of key features characteristic for Bohring-Opitz syndrome
      were absent in our patients (eg, the typical posture of arms,
      intrauterine growth retardation, microcephaly, trigonocephaly, typical
      facial gestalt with nevus flammeus of the forehead and exophthalmos).
      Therefore we emphasize that BRPS syndrome, caused by ASXL3
      loss-of-function variants, is a clinically distinct intellectual
      disability syndrome with a recognizable phenotype distinguishable from
      that of Bohring-Opitz syndrome.
    explanation: >-
      The definitive clinical statement that BRPS is distinguishable from
      Bohring-Opitz syndrome, and the enumeration of the discriminating
      features.
  - reference: PMID:23383720
    reference_title: De novo truncating mutations in ASXL3 are associated with a novel clinical phenotype with similarities to Bohring-Opitz syndrome.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Further, they showed less phenotypic overlap with patients who had de
      novo truncating mutations in ASXL1.
    explanation: >-
      Even the founding paper, which framed BRPS as Bohring-Opitz-like, noted
      reduced phenotypic overlap with ASXL1 patients - an early signal of the
      eventual split.
  - reference: PMID:35361921
    reference_title: "DNA methylation signature associated with Bohring-Opitz syndrome: a new tool for functional classification of variants in ASXL genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the DNAm profiles of three individuals with ASXL3 variants were
      control-like
    explanation: >-
      Provides molecular (episignature) separation between the ASXL1 and ASXL3
      disorders.

- name: Shashi-Pena syndrome
  description: >-
    The third member of the ASXL disorder triad, caused by de novo truncating
    variants in ASXL2. It shares developmental delay, feeding difficulty,
    hypotonia and arched eyebrows with BRPS but is separated by macrocephaly
    and absence of growth retardation. Because all three ASXL disorders are
    routinely discussed together, papers on ASXL2 must not be cited as
    evidence for ASXL3 phenotypes.
  disease_term:
    preferred_term: Shashi-Pena syndrome
    term:
      id: MONDO:0014963
      label: Shashi-Pena syndrome
  distinguishing_features:
  - Shashi-Pena syndrome is caused by ASXL2; BRPS by ASXL3.
  - Macrocephaly and absence of growth retardation distinguish the ASXL2 condition from ASXL1- and ASXL3-related disorders.
  - ASXL2 truncating transcripts escape nonsense-mediated decay and are thought to act dominant-negatively, whereas ASXL3 NMD-class variants act by haploinsufficiency.
  - Glabellar nevus flammeus and prominent eyes are characteristic of Shashi-Pena syndrome and are not features of BRPS.
  evidence:
  - reference: PMID:27693232
    reference_title: De Novo Truncating Variants in ASXL2 Are Associated with a Unique and Recognizable Clinical Phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although overlapping features with Bohring-Opitz and Bainbridge-Ropers
      syndromes exist, features that distinguish the ASXL2-associated
      condition from ASXL1- and ASXL3-related disorders are macrocephaly,
      absence of growth retardation, and more variability in the degree of
      intellectual disabilities.
    explanation: >-
      States explicitly which features separate the ASXL2 disorder from the
      ASXL1 and ASXL3 disorders.
  - reference: PMID:33751773
    reference_title: "Understanding the phenotypic spectrum of ASXL-related disease: Ten cases and a review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Over the past decade, pathogenic variants in all members of the ASXL
      family of genes, ASXL1, ASXL2, and ASXL3, have been found to lead to
      clinically distinct but overlapping syndromes.
    explanation: >-
      A direct statement that the three ASXL syndromes are clinically distinct
      despite overlap, supporting the keep-split decision.

- name: Angelman syndrome
  description: >-
    ASXL3 variants are recovered in cohorts of individuals with an
    Angelman-like presentation, because absent speech, seizures, and a happy
    or excitable demeanour overlap. Molecular testing separates them.
  disease_term:
    preferred_term: Angelman syndrome
    term:
      id: MONDO:0007113
      label: Angelman syndrome
  distinguishing_features:
  - Angelman syndrome arises from loss of maternal UBE3A function (deletion, UPD, imprinting defect, or variant), not from ASXL3.
  - BRPS lacks the characteristic Angelman EEG pattern and the ataxic gait with jerky limb movements.
  - Angelman syndrome methylation and UBE3A testing are diagnostic and will be normal in BRPS.
  evidence:
  - reference: PMID:33751773
    reference_title: "Understanding the phenotypic spectrum of ASXL-related disease: Ten cases and a review of the literature."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This will assist in diagnosis of these overlapping conditions and allow
      clinicians to more comprehensively counsel affected families.
    explanation: >-
      Supports the general point that the ASXL disorders present as
      overlapping neurodevelopmental conditions requiring careful diagnostic
      discrimination; it does not itself name Angelman syndrome, so this is
      marked PARTIAL.

- name: Other Mendelian chromatinopathies with syndromic intellectual disability
  description: >-
    Because the developmental delay and dysmorphism of BRPS are nonspecific,
    the practical differential is broad and includes the other Mendelian
    disorders of the epigenetic machinery presenting with intellectual
    disability, limited speech, and behavioural difficulty. Discrimination is
    molecular rather than clinical.
  disease_term:
    preferred_term: syndromic intellectual disability
    term:
      id: MONDO:0000508
      label: syndromic intellectual disability
  distinguishing_features:
  - Each chromatinopathy is separated by its causal gene; only ASXL3 variants establish BRPS.
  - Several other chromatinopathies have validated blood DNA methylation episignatures that can classify variants, whereas ASXL3 currently does not.
  evidence:
  - reference: PMID:35361921
    reference_title: "DNA methylation signature associated with Bohring-Opitz syndrome: a new tool for functional classification of variants in ASXL genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our previous work has shown that syndromic conditions caused by
      pathogenic variants in epigenetic regulatory genes show consistent
      patterns of genome-wide DNA methylation (DNAm) alterations, i.e., DNAm
      signatures in peripheral blood.
    explanation: >-
      Supports the framing of BRPS within the broader class of epigenetic
      regulatory gene disorders and the episignature-based approach to
      distinguishing them.

treatments:
- name: Feeding therapy and gastrostomy tube placement
  description: >-
    The highest-yield intervention in infancy. Clinical feeding evaluation
    with a low threshold for referral, feeding therapy, and nasogastric then
    gastrostomy feeding where oral intake is inadequate. Many children later
    wean off tube feeding as feeding skills improve with age.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: gastrostomy
    term:
      id: NCIT:C52006
      label: Gastrostomy
  target_phenotypes:
  - preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:33151654
    reference_title: ASXL3-Related Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment of manifestations: Feeding therapy; gastrostomy tube placement
      for those with persistent feeding issues
    explanation: >-
      The GeneReviews management recommendation for the disorder's dominant
      infantile problem.
  - reference: PMID:40552904
    reference_title: "An International ASXL3 Natural History Study: Deep Phenotypic Analyses Including Detailed Reports of a Milder Phenotype, Novel Associations, and Clinical Recommendations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      improvement trends in feeding, hypotonia, verbalisation, and motor
      skills over time
    explanation: >-
      Supports the expectation of improving feeding over time and therefore
      the possibility of later weaning from tube feeding.

- name: Anti-reflux management
  description: >-
    Anti-reflux medication for gastroesophageal reflux disease, with
    fundoplication reserved for severe or refractory cases. Reflux control
    also reduces aspiration risk in a hypotonic child with dysphagia.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_phenotypes:
  - preferred_term: Gastroesophageal reflux
    term:
      id: HP:0002020
      label: Gastroesophageal reflux
  evidence:
  - reference: PMID:33151654
    reference_title: ASXL3-Related Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      anti-reflux medication and/or fundoplication for those with
      gastroesophageal disease
    explanation: >-
      The GeneReviews recommendation for gastroesophageal disease in this
      disorder.

- name: Speech and language therapy with augmentative and alternative communication
  description: >-
    Because most affected individuals are nonverbal or minimally verbal,
    speech and language therapy focused on augmentative and alternative
    communication is a core, lifelong intervention rather than an optional
    adjunct.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: speech and language therapy
    term:
      id: NCIT:C159273
      label: Speech Language Therapy
  target_phenotypes:
  - preferred_term: Absent speech
    term:
      id: HP:0001344
      label: Absent speech
  evidence:
  - reference: PMID:28100473
    reference_title: "Delineating the phenotypic spectrum of Bainbridge-Ropers syndrome: 12 new patients with de novo, heterozygous, loss-of-function mutations in ASXL3 and review of published literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      poor/ absent speech (12/12)
    explanation: >-
      Universal speech impairment in a phenotyped cohort establishes the need
      for communication-focused intervention.
  - reference: PMID:33151654
    reference_title: ASXL3-Related Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      standard treatment for epilepsy, joint contractures, sleep apnea, dental
      anomalies, strabismus and/or refractive error, and developmental delay /
      intellectual disability
    explanation: >-
      GeneReviews recommends standard developmental intervention, of which
      speech and language therapy is a component.

- name: Physical therapy and rehabilitation
  description: >-
    Physiotherapy for hypotonia, motor delay, joint laxity and contracture
    prevention, with durable medical equipment and orthotics as needed.
    Longitudinal data show motor skills improve over time, so rehabilitation
    goals should be progressive rather than purely maintenance.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  target_phenotypes:
  - preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:40552904
    reference_title: "An International ASXL3 Natural History Study: Deep Phenotypic Analyses Including Detailed Reports of a Milder Phenotype, Novel Associations, and Clinical Recommendations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      improvement trends in feeding, hypotonia, verbalisation, and motor
      skills over time
    explanation: >-
      Documented improvement in hypotonia and motor skills supports an active
      rehabilitative approach.

- name: Behavioral intervention for self-injury
  description: >-
    Structured behaviour-analytic assessment and treatment, using functional
    analysis and differential reinforcement, is the best-evidenced
    non-pharmacological approach to self-injury in this disorder. Coexisting
    sleep disruption can confound assessment and should be addressed in
    parallel.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: behavioral intervention
    term:
      id: NCIT:C181743
      label: Behavioral Counseling
  target_phenotypes:
  - preferred_term: Self-injurious behavior
    term:
      id: HP:0100716
      label: Self-injurious behavior
  notes: >-
    Evidence is a single-case experimental design (n=1). Treat as a
    demonstration of feasibility, not as a population-level efficacy estimate.
  evidence:
  - reference: PMID:36249891
    reference_title: "Treatment of Self-Injury in Bainbridge-Ropers Syndrome: Replication and Extensions of Behavioral Assessments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We targeted self-injury in a child with BRPS using a functional analysis
      and differential reinforcement, with several extensions to common
      procedures. Results present the first example of behavioral reduction
      for self-injury in BRPS.
    explanation: >-
      The first published behavioural treatment demonstration in this
      disorder, supporting the approach while acknowledging n=1.
  - reference: PMID:36249891
    reference_title: "Treatment of Self-Injury in Bainbridge-Ropers Syndrome: Replication and Extensions of Behavioral Assessments."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There are no published treatments for BRPS.
    explanation: >-
      Confirms the absence of an established treatment evidence base at the
      time of publication, contextualizing the weight of this single case.

- name: Pregabalin for severe challenging behavior
  description: >-
    Reported in a single adult with BRPS, severe intellectual disability,
    autism and epilepsy admitted for severe self- and hetero-aggression, in
    whom pregabalin produced rapid stabilization and allowed withdrawal of
    analgesics, neuroleptics, antidepressants and benzodiazepines, sustained
    at nine months. This is hypothesis-generating only.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: pregabalin
      term:
        id: CHEBI:64356
        label: pregabalin
  target_phenotypes:
  - preferred_term: Self-injurious behavior
    term:
      id: HP:0100716
      label: Self-injurious behavior
  notes: >-
    Single case report (n=1), uncontrolled, with concurrent withdrawal of
    several other psychotropics. There is no BRPS-specific controlled evidence
    for any psychotropic agent.
  evidence:
  - reference: PMID:39698206
    reference_title: "Pregabalin treatment in a 30-year-old patient with Bainbridge-Ropers syndrome: a case-report."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The introduction of Pregabalin leads to rapid stabilization of the
      clinical state, almost complete improvement in challenging behavior and
      gradual withdrawal of other treatments (class 2 analgesics,
      neuroleptics, antidepressants, and benzodiazepines).
    explanation: >-
      Supports the observation in a single patient. Marked PARTIAL because an
      uncontrolled n=1 report cannot establish efficacy.

- name: Anti-seizure medication
  description: >-
    Standard neurologist-directed management of childhood-onset generalized
    epilepsy with generalized tonic-clonic and atypical absence seizures.
    Broad-spectrum agents are the rational choice given the generalized
    phenotype, but there are no BRPS-specific efficacy data. Confirm that
    paroxysmal events are epileptic on video-EEG before escalating, since
    breath-holding, hyperventilation and dystonic episodes in this disorder
    are non-epileptic.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:33151654
    reference_title: ASXL3-Related Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      standard treatment for epilepsy, joint contractures, sleep apnea, dental
      anomalies, strabismus and/or refractive error
    explanation: >-
      GeneReviews recommends standard epilepsy treatment; no disorder-specific
      regimen is specified.
  - reference: PMID:29367179
    reference_title: Childhood-onset generalized epilepsy in Bainbridge-Ropers syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bainbridge-Ropers syndrome is associated with childhood-onset
      generalized epilepsy with generalized tonic-clonic seizures and/or
      atypical absence seizures.
    explanation: >-
      Defines the epilepsy syndrome that anti-seizure medication choice should
      target.

- name: Preventive dental care
  description: >-
    Six-monthly dental review from age three, with preventive measures.
    Dental anomalies are a recognized feature and oral health is
    difficult to maintain in a nonverbal child with behavioural challenges.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Dental crowding
    term:
      id: HP:0000678
      label: Dental crowding
  evidence:
  - reference: PMID:33151654
    reference_title: ASXL3-Related Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dental evaluation every six months after age three years or as
      clinically indicated.
    explanation: >-
      The GeneReviews surveillance recommendation for dental care.

- name: Ophthalmological and renal surveillance
  description: >-
    At least annual ophthalmology review for all, given the frequency of
    strabismus and refractive error. Baseline renal imaging after diagnosis is
    a newer recommendation arising from the emerging renal phenotype
    identified in the international natural history study.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  - preferred_term: Abnormality of the kidney
    term:
      id: HP:0000077
      label: Abnormality of the kidney
  evidence:
  - reference: PMID:33151654
    reference_title: ASXL3-Related Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At least annual ophthalmology evaluation.
    explanation: >-
      The GeneReviews ophthalmological surveillance recommendation.
  - reference: PMID:40552904
    reference_title: "An International ASXL3 Natural History Study: Deep Phenotypic Analyses Including Detailed Reports of a Milder Phenotype, Novel Associations, and Clinical Recommendations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our recommendations include: baseline renal imaging after diagnosis, and
      Dental and Ophthalmological follow-up for all.
    explanation: >-
      Adds baseline renal imaging to the surveillance plan on the basis of a
      newly recognized renal phenotype.

- name: Genetic counseling
  description: >-
    Counseling should cover the autosomal dominant, usually de novo, mode of
    inheritance; the low but non-zero sibling recurrence risk from parental
    germline or gonosomal mosaicism; the availability of prenatal and
    preimplantation genetic testing once a familial variant is known; and the
    option of ultra-deep parental sequencing to refine recurrence risk after
    an apparently de novo diagnosis.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:33151654
    reference_title: ASXL3-Related Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      If the ASXL3 pathogenic variant identified in the proband is not
      identified in either parent, the risk to sibs is presumed to be low but
      greater than that of the general population because of the possibility
      of parental germline mosaicism.
    explanation: >-
      The GeneReviews recurrence-risk statement that counseling must convey.
  - reference: PMID:33151654
    reference_title: ASXL3-Related Disorder.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Once the ASXL3 pathogenic variant has been identified in an affected
      family member, prenatal testing for a pregnancy at increased risk and
      preimplantation genetic testing are possible.
    explanation: >-
      Establishes the reproductive options to be discussed.
  - reference: PMID:39833101
    reference_title: Comprehensive Clinical and Genetic Characterization of a Spanish Cohort of 22 Patients With Bainbridge-Ropers Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We documented recurrence in nontwin siblings due to parental mosaicism.
    explanation: >-
      Provides the concrete observed basis for the mosaicism recurrence-risk
      counselling point.

discussions:
- discussion_id: brps_human_model_mismatch_neural_fate
  kind: HUMAN_MODEL_MISMATCH
  attaches_to:
  - pathophysiology#Disrupted Neural Cell Fate Specification
  status: OPEN
  prompt: >-
    Does the severe early neural cell-fate specification defect seen on ASXL3
    knockdown in Xenopus laevis embryos actually occur in human ASXL3
    haploinsufficiency, given that most affected individuals have structurally
    normal brain MRI?
  rationale: >-
    The strongest mechanistic link between the ASXL3 chromatin lesion and the
    neurodevelopmental phenotype comes from a morpholino knockdown in a frog
    embryo, which produces open neural plates and loss of hindbrain, primary
    neuron and neural crest markers - a far more dramatic patterning failure
    than anything seen in human patients, in whom GeneReviews notes that most
    individuals with seizures still have normal brain MRI. Two features of the
    model may explain the gap and limit translation: morpholino knockdown
    approaches a near-null state whereas human disease is heterozygous
    haploinsufficiency, and the human transcriptomic evidence comes from
    dermal fibroblasts rather than neural tissue. The translational validity of
    the cell-fate mechanism, not its existence in the model, is the open
    question.
  evidence:
  - reference: PMID:32132929
    reference_title: Modeling Bainbridge-Ropers Syndrome in Xenopus laevis Embryos.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In this study, we utilize the frog, Xenopus laevis as a simpler and more
      accessible vertebrate neurodevelopmental model system to understand the
      embryological cause of Bainbridge-Ropers syndrome.
    explanation: >-
      Identifies the model system whose translational validity to human
      heterozygous ASXL3 disease is the subject of this mismatch item.
  proposed_experiments:
  - experiment_id: brps_exp_ipsc_cortical_patterning
    name: Cortical differentiation of ASXL3 heterozygous iPSC and organoid models
    description: >-
      Differentiate ASXL3 patient-derived and isogenic heterozygous-null iPSC
      lines into cortical neurons and cerebral organoids, then assay regional
      patterning, cortical layer identity, and genome-wide H2AK119Ub1
      distribution. This tests whether a human heterozygous gene dose is
      sufficient to produce a measurable neural cell-fate defect, which the
      near-null frog knockdown cannot address.
    decision_criterion: >-
      A reproducible shift in layer-marker proportions or regional identity in
      heterozygous versus isogenic control lines, accompanied by redistributed
      H2AK119Ub1 at developmental loci, would support translation of the frog
      cell-fate mechanism to human heterozygous dosage.
  - experiment_id: brps_exp_quantitative_mri
    name: Quantitative volumetric and cortical-thickness MRI in an ASXL3 cohort
    description: >-
      Perform quantitative volumetric and cortical-thickness MRI in a
      phenotyped ASXL3 cohort against matched controls, to test whether subtle
      structural differences exist below the threshold at which routine
      clinical radiology reports an abnormality.
    decision_criterion: >-
      Statistically significant reduction in cortical thickness or
      upper-layer-associated volume relative to matched controls would
      reconcile the model finding with the clinical observation of
      "normal" MRI.
  - experiment_id: brps_exp_heterozygous_vertebrate_model
    name: Dose-controlled heterozygous vertebrate model of Asxl3 loss
    description: >-
      Generate and phenotype a heterozygous (rather than morpholino
      knockdown-null) vertebrate model to test whether the early neural
      patterning defect is dose-dependent and whether it attenuates at a gene
      dosage comparable to human disease.
    decision_criterion: >-
      Persistence of a measurable patterning phenotype at heterozygous dosage
      would support translational relevance; complete rescue at heterozygous
      dosage would indicate the knockdown phenotype is a null-specific
      artefact.

- discussion_id: brps_missing_episignature
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Absence of an ASXL3 DNA Methylation Episignature
  status: OPEN
  prompt: >-
    Is there a genuine ASXL3-specific DNA methylation episignature that a
    dedicated, adequately powered study would detect, or does ASXL3
    haploinsufficiency truly leave no peripheral blood methylation footprint?
  rationale: >-
    The only relevant data come from applying an ASXL1/Bohring-Opitz classifier
    to three ASXL3 individuals, whose profiles were control-like. That is a
    negative result from a classifier built for a different gene on a very
    small sample, not evidence of absence. The question matters clinically
    because without an episignature there is no functional assay to
    reclassify ASXL3 variants of uncertain significance, which is precisely
    where the missense-variant question is unresolved.
  evidence:
  - reference: PMID:35361921
    reference_title: "DNA methylation signature associated with Bohring-Opitz syndrome: a new tool for functional classification of variants in ASXL genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the DNAm profiles of three individuals with ASXL3 variants were
      control-like
    explanation: >-
      The sole empirical basis for the current belief that ASXL3 has no
      episignature - three individuals tested with a classifier built for a
      different gene - which is why this remains an open gap rather than a
      settled negative.
  proposed_experiments:
  - experiment_id: brps_exp_dedicated_episignature
    name: Adequately powered ASXL3-specific blood DNA methylation study
    description: >-
      Profile genome-wide blood DNA methylation in a cohort of 25 or more
      individuals with confirmed pathogenic ASXL3 variants against
      sex- and age-matched controls, powered to derive a signature de novo
      rather than by cross-classification with an ASXL1-derived model.
    decision_criterion: >-
      Identification of a reproducible set of differentially methylated
      positions that classifies held-out ASXL3 cases would establish an
      ASXL3 episignature; failure at this sample size would substantially
      strengthen the negative result.
  - experiment_id: brps_exp_episignature_by_variant_class
    name: Episignature stratification by NMD class and mutational cluster region
    description: >-
      Stratify any candidate methylation signature by nonsense-mediated-decay
      versus no-NMD variant class and by MCR1 (exon 11) versus MCR2 (exon 12)
      location, to test whether the two proposed mechanistic classes leave
      different epigenomic footprints.
    decision_criterion: >-
      Divergent methylation profiles between the NMD and no-NMD groups would
      provide molecular support for two distinct disease mechanisms rather
      than a single haploinsufficiency mechanism.
  - experiment_id: brps_exp_episignature_vus_classification
    name: Clinical validation of an ASXL3 episignature for variant classification
    description: >-
      Test any derived signature against ASXL3 missense variants and variants
      of uncertain significance to establish whether it has clinical utility
      for reclassification.
    decision_criterion: >-
      Concordant classification of known pathogenic and known benign control
      variants would qualify the assay for clinical variant interpretation.

- discussion_id: brps_penetrance_expressivity
  kind: KNOWLEDGE_GAP
  attaches_to:
  - genetic#ASXL3
  status: OPEN
  prompt: >-
    Is ASXL3-related disorder fully penetrant, and if not, is the apparent
    nonpenetrance in inherited-variant families genuine reduced penetrance or
    misclassification of variant pathogenicity?
  rationale: >-
    Almost the entire published cohort consists of de novo protein-truncating
    variants ascertained through severely affected probands, so penetrance has
    never been estimated against an unbiased denominator and a reader would
    reasonably but wrongly infer complete penetrance. The inherited-variant
    series reports substantial intrafamilial and possible interfamilial
    variability, with transmitting parents who are mildly affected or
    apparently unaffected. Critically, the authors decline to attribute this to
    reduced penetrance, offering instead the competing explanation that the
    inherited variants may not be pathogenic - an ambiguity that cannot be
    resolved without a functional assay, which is precisely what the absent
    episignature denies. Systematic review lists penetrance among the explicit
    unresolved gaps. This matters directly for counselling families in whom an
    ASXL3 variant is inherited rather than de novo.
  evidence:
  - reference: PMID:42494517
    reference_title: Broadening the inherited ASXL3 spectrum and unveiling molecular mechanisms through detailed genotypic-phenotypic analyses.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      substantial intrafamilial phenotypic variability, as well as the
      possibility of interfamilial phenotypic variability
    explanation: >-
      Establishes variable expressivity across and within families carrying
      inherited ASXL3 variants.
  - reference: PMID:42494517
    reference_title: Broadening the inherited ASXL3 spectrum and unveiling molecular mechanisms through detailed genotypic-phenotypic analyses.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The family reports emphasize the possibility of additional, yet
      currently unidentified, factors influencing phenotypic expression or,
      alternatively, may reflect uncertainty about the pathogenicity of
      inherited ASXL3 variants.
    explanation: >-
      The authors explicitly refuse to separate reduced penetrance or modifier
      effects from pathogenicity uncertainty, which is why this is curated as
      an open gap rather than as a penetrance estimate.
  - reference: PMID:38420660
    reference_title: "ASXL3-related disorder: Molecular phenotyping and comprehensive review providing insights into disease mechanism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Several gaps in our knowledge of this disorder were identified, namely,
      underlying pathophysiology and disease mechanism, disease contribution
      of missense variants, relevance of variant location, prevalence and
      penetrance data.
    explanation: >-
      A systematic review names penetrance data as an explicit, unresolved
      knowledge gap.
  proposed_experiments:
  - experiment_id: brps_exp_biobank_penetrance
    name: Unselected-cohort penetrance estimation for ASXL3 truncating variants
    description: >-
      Ascertain ASXL3 protein-truncating variants in large unselected
      population biobanks with linked phenotype data, rather than through
      clinically referred probands, and measure the proportion of carriers
      meeting neurodevelopmental diagnostic criteria.
    decision_criterion: >-
      A carrier frequency substantially exceeding the expected disease
      prevalence, with a meaningful fraction of carriers lacking a
      neurodevelopmental diagnosis, would establish reduced penetrance for at
      least some variant classes.
  - experiment_id: brps_exp_family_deep_phenotyping
    name: Deep phenotyping and mosaicism testing of transmitting parents
    description: >-
      Systematically deep-phenotype apparently unaffected transmitting parents
      in inherited ASXL3 families and apply ultra-deep sequencing of multiple
      tissues to distinguish true germline heterozygosity with reduced
      penetrance from low-level parental mosaicism.
    decision_criterion: >-
      Demonstration of constitutional heterozygosity in a rigorously
      phenotyped unaffected parent would establish genuine nonpenetrance;
      detection of mosaicism would instead explain the mild parental phenotype
      without invoking reduced penetrance.

- discussion_id: brps_missense_contribution
  kind: KNOWLEDGE_GAP
  attaches_to:
  - genetic#ASXL3
  status: OPEN
  prompt: >-
    Do ASXL3 missense variants contribute to disease, and if so to which
    phenotype - autism spectrum disorder without syndromic features, a
    recessive congenital heart phenotype, or nothing at all?
  rationale: >-
    Every established BRPS variant is protein-truncating. Missense ASXL3
    variants have been reported in autism cohorts without the severe syndromic
    features, and biallelic missense variants have been reported in a small
    number of individuals with congenital heart defects, but neither
    association is established. Systematic reviews list the disease
    contribution of missense variants as an explicit unresolved gap. Without
    an episignature or another functional assay there is currently no way to
    resolve individual missense variants of uncertain significance.
  evidence:
  - reference: PMID:38420660
    reference_title: "ASXL3-related disorder: Molecular phenotyping and comprehensive review providing insights into disease mechanism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Several gaps in our knowledge of this disorder were identified, namely,
      underlying pathophysiology and disease mechanism, disease contribution
      of missense variants, relevance of variant location, prevalence and
      penetrance data.
    explanation: >-
      A systematic review names the disease contribution of missense variants
      as an explicit, unresolved knowledge gap.
  proposed_experiments:
  - experiment_id: brps_exp_deubad_deep_mutational_scan
    name: Deep mutational scanning of the ASXL3 DEUBAD domain
    description: >-
      Perform saturation mutagenesis of the ASXL3 DEUBAD (BAP1-binding)
      domain and measure BAP1 binding and PR-DUB H2A deubiquitinase activity
      for each substitution, generating a functional score for every possible
      missense change in the domain.
    decision_criterion: >-
      A bimodal functional score distribution separating known pathogenic
      truncating-equivalent losses from tolerated substitutions would provide
      a calibrated assay for missense variant interpretation.
  - experiment_id: brps_exp_missense_burden
    name: Rare ASXL3 missense burden analysis in neurodevelopmental cohorts
    description: >-
      Conduct a case-control burden analysis of rare ASXL3 missense variants
      in large autism and neurodevelopmental-disorder cohorts against
      population reference data.
    decision_criterion: >-
      Significant excess of rare missense variants in cases after correction
      would support a genuine, phenotypically milder missense contribution
      distinct from the truncating BRPS phenotype.
  - experiment_id: brps_exp_biallelic_missense_chd
    name: Segregation and functional follow-up of biallelic missense congenital heart defect families
    description: >-
      Re-examine segregation and perform functional assays in the reported
      families with biallelic ASXL3 missense variants and congenital heart
      defects, to determine whether this represents a genuinely distinct
      recessive allelic disorder or an incidental finding.
    decision_criterion: >-
      Consistent biallelic segregation with a shared functional deficit
      across independent families would support a distinct recessive
      ASXL3-related cardiac phenotype.

prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: ULTRA_RARE
  notes: >-
    No population-based prevalence estimate exists. More than 200 individuals
    have been reported in the literature, and the largest single analyses
    aggregate 204 individuals from the literature and natural history study.
    The prevalence_class is assigned qualitatively on the basis of published
    case counts, not from a denominator-based epidemiological study; treat any
    numeric estimate for this disorder with suspicion.
  evidence:
  - reference: PMID:42494517
    reference_title: Broadening the inherited ASXL3 spectrum and unveiling molecular mechanisms through detailed genotypic-phenotypic analyses.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we conducted a detailed genotype-phenotype review of 204 individuals
      from the literature, including the International ASXL3 Natural History
      Study
    explanation: >-
      Establishes the order of magnitude of reported cases (about 200
      worldwide), which supports an ultra-rare qualitative classification but
      is not a prevalence measurement.
  - reference: PMID:38420660
    reference_title: "ASXL3-related disorder: Molecular phenotyping and comprehensive review providing insights into disease mechanism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Several gaps in our knowledge of this disorder were identified, namely,
      underlying pathophysiology and disease mechanism, disease contribution
      of missense variants, relevance of variant location, prevalence and
      penetrance data.
    explanation: >-
      A systematic review explicitly names prevalence data as a knowledge gap,
      supporting the decision not to assert a numeric rate.

notes: >-
  Deep research provenance: this entry was curated after a
  `just research-disorder claude_code Bainbridge-Ropers_Syndrome` run
  (report at research/Bainbridge-Ropers_Syndrome-deep-research-claude_code.md).
  The deep-research report was treated as a lead generator only; every PMID
  cited here was independently fetched with `just fetch-reference` and every
  snippet copied from the cached abstract.
  Deliberately NOT curated: (1) the 2026 bioRxiv preprint describing an
  ASXL3-DIO3-thyroid hormone-parvalbumin interneuron axis and an AAV
  split-intein gene replacement rescue in mice and non-human primates. This
  is the most interesting mechanistic and therapeutic development in the
  field, but it is an unrefereed preprint and could not be fetched into
  references_cache with the standard tooling, so it is omitted rather than
  cited weakly. It should be added once peer-reviewed. (2) Somatic ASXL3
  mutations in tumours, which have no established driver role and are not
  part of this constitutional disorder. (3) The provisional biallelic-missense
  congenital heart defect phenotype, which is captured as a knowledge gap
  rather than as an asserted allelic disorder.

references:
- reference: PMID:33151654
  title: ASXL3-Related Disorder.
  tags:
  - GeneReviews
- reference: PMID:23383720
  title: De novo truncating mutations in ASXL3 are associated with a novel clinical phenotype with similarities to Bohring-Opitz syndrome.
- reference: PMID:26647312
  title: De novo dominant ASXL3 mutations alter H2A deubiquitination and transcription in Bainbridge-Ropers syndrome.
- reference: PMID:27901041
  title: "Bainbridge-Ropers syndrome caused by loss-of-function variants in ASXL3: a recognizable condition."
- reference: PMID:28100473
  title: "Delineating the phenotypic spectrum of Bainbridge-Ropers syndrome: 12 new patients with de novo, heterozygous, loss-of-function mutations in ASXL3 and review of published literature."
- reference: PMID:39833101
  title: Comprehensive Clinical and Genetic Characterization of a Spanish Cohort of 22 Patients With Bainbridge-Ropers Syndrome.
- reference: PMID:38420660
  title: "ASXL3-related disorder: Molecular phenotyping and comprehensive review providing insights into disease mechanism."
- reference: PMID:42494517
  title: Broadening the inherited ASXL3 spectrum and unveiling molecular mechanisms through detailed genotypic-phenotypic analyses.
- reference: PMID:40552904
  title: "An International ASXL3 Natural History Study: Deep Phenotypic Analyses Including Detailed Reports of a Milder Phenotype, Novel Associations, and Clinical Recommendations."
- reference: PMID:35361921
  title: "DNA methylation signature associated with Bohring-Opitz syndrome: a new tool for functional classification of variants in ASXL genes."
- reference: PMID:32132929
  title: Modeling Bainbridge-Ropers Syndrome in Xenopus laevis Embryos.
- reference: PMID:29367179
  title: Childhood-onset generalized epilepsy in Bainbridge-Ropers syndrome.
- reference: PMID:34086428
  title: Comorbid Psychiatric Aspects of Bainbridge-Ropers Syndrome.
- reference: PMID:36249891
  title: "Treatment of Self-Injury in Bainbridge-Ropers Syndrome: Replication and Extensions of Behavioral Assessments."
- reference: PMID:39698206
  title: "Pregabalin treatment in a 30-year-old patient with Bainbridge-Ropers syndrome: a case-report."
- reference: PMID:28955728
  title: Hyperventilation-athetosis in ASXL3 deficiency (Bainbridge-Ropers) syndrome.
- reference: PMID:24044690
  title: De novo frameshift mutation in ASXL3 in a patient with global developmental delay, microcephaly, and craniofacial anomalies.
- reference: PMID:25835095
  title: "Functional proteomics of the epigenetic regulators ASXL1, ASXL2 and ASXL3: a convergence of proteomics and epigenetics for translational medicine."
- reference: PMID:27693232
  title: De Novo Truncating Variants in ASXL2 Are Associated with a Unique and Recognizable Clinical Phenotype.
- reference: PMID:33751773
  title: "Understanding the phenotypic spectrum of ASXL-related disease: Ten cases and a review of the literature."
- reference: PMID:35863334
  title: ASXL3 De Novo Variant-Related Neurodevelopmental Disorder Presenting as Dystonic Cerebral Palsy.

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