Blepharophimosis-Impaired Intellectual Development Syndrome

Mendelian MONDO:0859139 Pathograph 4 Show in embeddings browser Neurodevelopmental disorder Syndromic intellectual disability BAF (SWI/SNF) complex-related disorder (BAFopathy) Chromatinopathy

Blepharophimosis-impaired intellectual development syndrome (BIS; OMIM 619293) is a rare neurodevelopmental disorder caused by de novo SMARCA2 variants that cluster OUTSIDE the helicase (ATPase) domains. SMARCA2 (BRM) is a catalytic ATPase subunit of the BAF (SWI/SNF) chromatin remodeling complex. Affected individuals have a recognizable facial gestalt — blepharophimosis, epicanthal folds, and a downturned nasal tip — together with developmental delay and a variable degree of intellectual disability. BIS is a distinct entity from Nicolaides-Baraitser syndrome (NCBRS, OMIM 601358, MONDO:0011053), the other SMARCA2-related disorder. Most NCBRS variants lie inside the helicase domains, and NCBRS is characterized clinically by sparse scalp hair, prominent interphalangeal joints, and frequent seizures — none of which is a defining feature of BIS. The separation is not only clinical: yeast growth-phenotype assays, blood-leukocyte transcriptomic profiles, and genome-wide DNA methylation (episignature) analysis each independently discriminate BIS from NCBRS. Because the great majority of the SMARCA2 clinical literature concerns NCBRS, cohort data from NCBRS series must not be imported into this entry.

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1
Inheritance
4
Pathophys.
6
Phenotypes
1
Hypotheses
3
Gaps
4
Pathograph
1
Genes
1
Medical Actions
3
Differentials
7
References
1
Deep Research
🏷

Classifications

Harrison's Chapter
GENETICS_ENVIRONMENT_DISEASE NEUROLOGIC
👪

Inheritance

1
Autosomal dominant inheritance HP:0000006
BIS results from heterozygous SMARCA2 variants that arose de novo in the reported probands. Inheritance is autosomal dominant; because every reported BIS variant has been de novo, sibling recurrence risk is low but not zero (germline mosaicism has not been excluded).
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:32694869 SUPPORT Human Clinical
"a novel recognizable syndrome named BIS associated with clustered de novo SMARCA2 variants outside the helicase domains"
The causal SMARCA2 variants are heterozygous and de novo, the pattern expected for a dominant disorder with reproductive fitness reduction.
◈

Mechanistic Hypotheses

1
BIS alleles perturb BAF inter-subunit interfaces, whereas NCBRS alleles impair ATPase catalysis
bis_interface_perturbation_vs_ncbrs_catalysis EMERGING
Evidence balance 3 partial
The leading explanatory model for why two allelic SMARCA2 disorders exist is that the two variant classes damage different properties of the same protein. NCBRS variants localize to ultra-conserved catalytic ATPase motifs and are proposed to impair ATPase activity while leaving complex assembly intact. BIS variants localize outside those motifs, and non-truncating mSWI/SNF neurodevelopmental variants in general concentrate at inter-subunit and nucleosome-engagement interfaces — suggesting that BIS is an assembly/engagement lesion rather than a catalytic one. Both classes act dominantly from heterozygous de novo variants. The argument against simple SMARCA2 haploinsufficiency deliberately does NOT rest on the BIS variant consequence class, which this entry does not assert (see genetic[].notes). It rests on two other observations: complete germline loss of mouse Brm yields a phenotypically normal animal through BRG1 compensation, so pure loss of SMARCA2 is buffered rather than pathogenic; and BIS individuals nevertheless carry a reproducible DNA methylation episignature — a positive, directional change in the chromatin output of the complex, not a silent dosage reduction.
Status is EMERGING, not CANONICAL, deliberately. The NCBRS arm rests on the founding paper's own stated inference ("likely do not impair SWI/SNF complex assembly but may be associated with disrupted ATPase activity"), not on a direct assembly assay. The BIS arm rests on variant position plus a pan-mSWI/SNF structural analysis that did not assay BIS alleles, plus a yeast growth assay that shows only that the two classes differ. No biochemical measurement of BAF assembly, subunit engagement, or nucleosome remodeling has been published for any BIS allele.
Show evidence (3 references)
PMID:22366787 PARTIAL Human Clinical
"These alterations likely do not impair SWI/SNF complex assembly but may be associated with disrupted ATPase activity."
The NCBRS arm of the hypothesis, stated by the authors as an inference ("likely", "may be") from variant position rather than from a direct assay — hence PARTIAL.
PMID:37500730 PARTIAL Computational
"Non-truncating NDD-associated protein variants predominantly disrupt the cBAF subcomplex and cluster in four key structural regions associated with high disease severity, including mSWI/SNF-nucleosome interfaces, the ATPase-core ARID-armadillo repeat (ARM) module insertion site, the Arp..."
The interface arm of the hypothesis: non-truncating mSWI/SNF NDD variants concentrate at structural interfaces. PARTIAL because this is an aggregate structural analysis across the complex, not a demonstration for BIS alleles.
PMID:32694869 PARTIAL In Vitro
"Yeast phenotype assays differentiated NCBRS from non-NCBRS SMARCA2 variants."
Functional support that the two allele classes are distinct, without identifying which property each one damages — the reason this hypothesis is EMERGING rather than CANONICAL.
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Discussions and Knowledge Gaps

3
What is the biochemical consequence of the BIS-class (non-helicase-domain) SMARCA2 variants, and is BIS a loss-of-function, gain-of-function, or dominant-negative disorder?
KNOWLEDGE GAP gap_bis_smarca2_variant_mechanism
Attached to
pathophysiology#Non-Helicase-Domain SMARCA2 Variants Perturb the BAF Chromatin Remodeling Complex
The BIS variant class is defined positionally (outside the helicase domains) and is known only to behave differently from NCBRS variants in a yeast growth assay. Whether these variants reduce ATPase-dependent remodeling, alter BAF complex assembly or genomic targeting, or perturb a non-catalytic regulatory function of SMARCA2 has not been established. Without this, the mechanism node in this entry can only be annotated as ABNORMAL rather than INCREASED/DECREASED, and no rational therapeutic target can be nominated.
Proposed experiments
Biochemical reconstitution of BIS-variant BAF complexes
exp_bis_baf_reconstitution
Reconstitute BAF complexes carrying BIS-class SMARCA2 variants and measure nucleosome remodeling and ATPase activity directly, in parallel with NCBRS-class variants and wild type.
Comparative BAF genomic occupancy in isogenic lines
exp_bis_baf_occupancy_chip
Perform ChIP-seq/CUT&RUN for BAF subunits in isogenic cell lines carrying BIS-class versus NCBRS-class SMARCA2 variants to test whether the BIS lesion alters genomic targeting rather than catalytic activity.
SMARCA2 allele-series modeling in human neural systems
exp_bis_allele_series_organoid
Model a SMARCA2 allele series (BIS variants, NCBRS variants, null) in human neural progenitors and cerebral organoids to test whether BIS variants phenocopy SMARCA2 knockout.
Show evidence (1 reference)
PMID:32694869 PARTIAL In Vitro
"Yeast phenotype assays differentiated NCBRS from non-NCBRS SMARCA2 variants."
Marks the current limit of functional knowledge: the only published functional discrimination of BIS-class SMARCA2 variants is a heterologous yeast growth phenotype, which establishes that they differ from NCBRS variants but not in which direction SMARCA2 function is altered. PARTIAL because it frames the gap rather than answering it.
What is the natural history of BIS, and are there condition-specific surveillance or management recommendations?
KNOWLEDGE GAP gap_bis_natural_history_and_management
BIS was delineated only in 2020 and has no GeneReviews chapter (searched: no GeneReviews article exists for BIS or for a SMARCA2 disorder other than the NCBRS chapter, PMID:26468571). Published data are cross-sectional dysmorphology and molecular analyses; there are no longitudinal outcome data, no reported adult outcomes, and no BIS-specific management or surveillance guideline. Management is therefore currently generic developmental-disability care, and this entry deliberately curates only genetic counseling rather than importing the NCBRS management plan.
Proposed experiments
Prospective BIS natural-history registry
exp_bis_natural_history_registry
Establish a prospective natural-history study or patient registry across the international BIS referral network, collecting uniform developmental, neurologic, ophthalmologic, and adult-outcome data.
Systematic ophthalmologic assessment of BIS blepharophimosis
exp_bis_ophthalmologic_assessment
Systematically assess visual axis obstruction, amblyopia risk, and surgical need in the blepharophimosis of BIS, to determine whether the eyelid surgery pathway used in other blepharophimosis syndromes applies here.
Show evidence (1 reference)
PMID:38884529 PARTIAL Human Clinical
"Blepharophimosis with intellectual disability (BIS) is a recently recognized disorder"
Supports the premise of the gap: BIS was only recently delineated, which is why no longitudinal natural-history data or condition-specific management guideline yet exists. PARTIAL because it establishes the recency, not the absence of guidelines per se.
Can any existing Smarca2 mouse model represent BIS, given that the germline Brm-null mouse develops normally through BRG1 compensation while BIS is caused by a heterozygous de novo allele clustered outside the helicase domains?
HUMAN MODEL MISMATCH mismatch_bis_smarca2_mouse_null
Attached to
pathophysiology#Non-Helicase-Domain SMARCA2 Variants Perturb the BAF Chromatin Remodeling Complex
The available Smarca2 animal model is a germline knockout, and it does not reproduce a disease phenotype: Brm-null mice develop normally, apparently because BRG1 (SMARCA4) is upregulated and substitutes functionally. This is a genuine model/human mismatch rather than merely absent evidence. It matters in two directions. First, it is one of the strongest arguments that BIS is not caused by SMARCA2 haploinsufficiency, since removing the gene entirely in mouse produces nothing resembling the human disorder. Second, it means no existing in vivo system can test the actual BIS lesion, because a null allele cannot model a dominant, position-specific allele: complete deletion cannot report on a lesion whose only directly evidenced property is its location within SMARCA2. Nor does the null mouse produce the positive human readout of the BIS lesion, the DNA methylation episignature; whether a null allele could generate that signature has never been tested, which is itself part of the mismatch. (This entry does not assert the BIS variant consequence class; see genetic[].notes.) Any mouse-derived negative result about SMARCA2 loss must therefore not be read as evidence about BIS.
Proposed experiments
BIS hotspot knock-in mouse
exp_bis_hotspot_knockin_mouse
Generate heterozygous knock-in mice carrying a recurrent BIS hotspot allele (for example the Arg525 or Arg937 substitutions) rather than a null allele, and assess craniofacial morphogenesis, neurodevelopmental behaviour, and the blood methylation profile against the human episignature.
Test BRG1 compensation in the presence of a BIS allele
exp_bis_brg1_compensation_test
Determine whether SMARCA4/BRG1 upregulation can compensate for a BIS-class SMARCA2 allele as it does for a null allele, or whether the mutant BRM protein blocks compensation by occupying the complex.
Show evidence (1 reference)
PMID:9843504 SUPPORT Model Organism
"BRM-/- mice develop normally, suggesting that an observed up-regulation of the BRG1 protein can functionally replace BRM in the SWI-SNF complexes of mutant cells."
Directly documents the mismatch: complete loss of mouse Brm gives a normal animal, so this model cannot represent a dominant human SMARCA2 missense disorder, and BRG1 compensation is the proposed reason.
⚙

Pathophysiology

4
Non-Helicase-Domain SMARCA2 Variants Perturb the BAF Chromatin Remodeling Complex
SMARCA2 (BRM) encodes a catalytic ATPase subunit of the BAF (SWI/SNF) chromatin remodeling complex, which uses ATP hydrolysis to reposition nucleosomes and thereby control transcription. BIS-causing variants cluster outside the helicase (ATPase) domains, a positionally distinct class from the helicase-domain variants that cause Nicolaides-Baraitser syndrome. Yeast growth-phenotype assays separate the two variant classes functionally, indicating that BIS variants do not simply reproduce the NCBRS lesion. The precise biochemical consequence of the BIS variant class (for example, altered subunit assembly, altered targeting, or altered non-catalytic regulatory function rather than loss of ATPase activity) has not been resolved.
chromatin remodeling GO:0006338 ⚠ ABNORMAL
ATP-dependent chromatin remodeler activity GO:0140658 ⚠ ABNORMAL
BAF (SWI/SNF) complex GO:0016514
Downstream
Altered Transcriptional and DNA Methylation Programs Perturbation of BAF-mediated nucleosome remodeling changes the transcriptional output and the genome-wide DNA methylation landscape of patient cells, producing the BIS-specific transcriptomic and episignature profiles measurable in blood leukocytes.
BAF Subunit Switching in Neural Development A SMARCA2 lesion is carried into the neural-progenitor BAF (npBAF) complexes in which BRM is an ATPase, so the remodeling defect is expressed in the compartment whose BAF composition is developmentally regulated.
Show evidence (5 references)
PMID:38884529 SUPPORT Human Clinical
"SMARCA2, that encodes the catalytic subunit of the superfamily II helicase group of the BRG1 and BRM-associated factors (BAF) forming the BAF complex, a chromatin remodeling complex involved in transcriptional regulation"
Establishes SMARCA2 as the catalytic ATPase subunit of the BAF chromatin remodeling complex and its role in transcriptional regulation, supporting the GO chromatin-remodeling, remodeler-activity, and SWI/SNF-complex annotations on this node.
PMID:32694869 SUPPORT In Vitro
"Yeast phenotype assays differentiated NCBRS from non-NCBRS SMARCA2 variants."
Functional (yeast) evidence that BIS-class SMARCA2 variants behave differently from NCBRS-class variants, supporting the claim that the BIS lesion is mechanistically distinct rather than a milder NCBRS.
PMID:37500730 SUPPORT Computational
"whereas mutations within the SMARCA2 helicase cause NCBRS, SMARCA2 mutations outside of this domain are"
Independent confirmation, from a pan-mSWI/SNF structural and variant-landscape analysis by a different group, that the SMARCA2 positional dichotomy (helicase-domain versus non-helicase-domain) maps onto the NCBRS/BIS disease split. COMPUTATIONAL because this paper is a structural and variant-aggregation analysis, not a wet-lab assay of BIS alleles.
+ 2 more references
Altered Transcriptional and DNA Methylation Programs
Cells from individuals with BIS carry a reproducible, disease-specific transcriptomic profile and a genome-wide DNA methylation episignature that is detectable in peripheral blood leukocytes and that distinguishes BIS from NCBRS. Notably, the BIS episignature is shared with class II Helsmoortel-Van der Aa syndrome (truncating ADNP variants), consistent with known molecular interaction between ADNP and the BAF complex and with the overlapping narrow-palpebral-fissure craniofacial phenotype of the two conditions. This is the first reported instance of a phenotype-specific rather than gene-specific episignature.
regulation of transcription by RNA polymerase II GO:0006357 ⚠ ABNORMAL
Downstream
Abnormal Craniofacial and Neurodevelopmental Patterning The shared BIS/HVDAS episignature tracks with a shared craniofacial phenotype (narrowing of the palpebral fissures), linking the altered chromatin/transcriptional program to the recognizable facial gestalt and the neurodevelopmental outcome.
Show evidence (3 references)
PMID:38884529 SUPPORT Human Clinical
"This represents first evidence of a sensitive phenotype-specific episignature biomarker shared across distinct genetic conditions that also exhibit unique gene-specific episignatures."
Characterizes the BIS methylation program as a phenotype-specific episignature shared with another genetic condition, which is the substantive claim of this node.
PMID:38884529 SUPPORT Human Clinical
"Due to molecular interactions between ADNP and BAF complex"
Supports the mechanistic rationale for why a SMARCA2/BAF disorder and an ADNP disorder converge on the same methylation program.
PMID:38751117 PARTIAL Human Clinical
"common episignatures affecting homologous residues in highly conserved paralogous proteins (SMARCA2 M856V and SMARCA4 M866V)"
Supports the narrower, directly quoted claim that a specific SMARCA2 missense allele and its structurally homologous SMARCA4 counterpart converge on a common DNA methylation program — reinforcing that SMARCA2 missense variants produce reproducible, residue-level epigenomic consequences. PARTIAL and deliberately scoped: this abstract does NOT state that its SMARCA2 M856V case has BIS. p.Met856Val is listed as a BIS allele in the Sarli et al. variant table, but that table is in the paywalled full text and is not quotable here, so the BIS attribution is flagged as inference rather than asserted.
BAF Subunit Switching in Neural Development
The route from a BAF-complex lesion to a neurodevelopmental phenotype runs through the developmentally regulated subunit composition of neural BAF complexes. SMARCA2 (Brm) is one of the two ATPases found in the neural-progenitor BAF (npBAF) complex, and an obligatory switch in the accessory subunits of these complexes accompanies — and is required for — the transition from proliferating neural progenitors to postmitotic neurons. A SMARCA2 lesion therefore acts on a complex whose correct composition and activity are rate-limiting for neuronal differentiation.
neural progenitor cell CL:0011020
neuron differentiation GO:0030182 ⚠ ABNORMAL
npBAF complex GO:0071564
Downstream
Abnormal Craniofacial and Neurodevelopmental Patterning Disruption of BAF activity in the neural progenitor compartment, where correct complex composition is required for the progenitor-to-neuron transition, is the proposed route to the developmental delay and intellectual disability arm of the BIS phenotype. This edge covers the neurodevelopmental arm only; no mechanism has been proposed linking SMARCA2 to periocular or midfacial morphogenesis.
Show evidence (2 references)
PMID:17640523 PARTIAL In Vitro
"are quantitatively associated with the SWI2/SNF2-like ATPases, Brg and Brm."
Places Brm (SMARCA2) in the neural progenitor BAF complex, which is the premise of this node. PARTIAL because it establishes SMARCA2's presence in npBAF, not the effect of a BIS allele. IN_VITRO because the subunit composition was determined by proteomic analysis of neural stem/progenitor cell complexes.
PMID:17640523 PARTIAL In Vitro
"Preventing the subunit switch impairs neuronal differentiation, indicating that this molecular event is essential for the transition from neural stem/progenitors to postmitotic neurons."
Establishes that correct BAF subunit composition is required for neuronal differentiation, which is why a BAF-subunit lesion can produce a neurodevelopmental disorder. PARTIAL: the perturbation tested was the subunit switch itself, not a SMARCA2 disease variant.
Abnormal Craniofacial and Neurodevelopmental Patterning
The downstream clinical expression of the altered BAF-dependent transcriptional program is a recognizable, reproducible combination of periocular and midfacial dysmorphism (blepharophimosis, epicanthal folds, downturned nasal tip) with global developmental delay and intellectual disability of variable severity. The specific developmental programs and cell populations that translate BAF dysfunction into this particular facial gestalt have not been identified.
nervous system development GO:0007399 ⚠ ABNORMAL
Show evidence (1 reference)
PMID:32694869 SUPPORT Human Clinical
"14 showed a recognizable phenotype with recurrent features including epicanthal folds, blepharophimosis, and downturned nasal tip along with variable degree of intellectual disability"
States the organism-level output of the mechanism: a recognizable facial gestalt combined with variable intellectual disability.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Blepharophimosis-Impaired Intellectual Development Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

6
Head and Neck 1
Epicanthus Epicanthus HP:0000286
Show evidence (1 reference)
PMID:32694869 SUPPORT Human Clinical
"recurrent features including epicanthal folds, blepharophimosis, and downturned nasal tip"
Epicanthal folds are explicitly listed as a recurrent BIS feature.
Nervous System 2
Intellectual disability VERY_FREQUENT Intellectual disability HP:0001249
Frequency band basis: intellectual disability is part of the definitional description of BIS in both published series. The HPO annotation of OMIM:619293 records intellectual disability in 14/14 of the Cappuccio cohort, but that count comes from the paper's full-text table rather than the quotable abstract and is recorded here only as provenance.
Show evidence (2 references)
PMID:32694869 SUPPORT Human Clinical
"along with variable degree of intellectual disability"
States both the presence of intellectual disability and that its degree varies between affected individuals.
PMID:38884529 SUPPORT Human Clinical
"presents with distinct facial features of blepharophimosis, developmental delay, and intellectual disability"
Independent confirmation that intellectual disability is a defining feature.
Global developmental delay VERY_FREQUENT Global developmental delay HP:0001263
Frequency band basis: developmental delay is named in the definitional description of BIS. The HPO annotation of OMIM:619293 records global developmental delay in 14/14 of the Cappuccio cohort; that count is from the paper's full-text table, not the quotable abstract, and is given here as provenance only.
Show evidence (1 reference)
PMID:38884529 SUPPORT Human Clinical
"presents with distinct facial features of blepharophimosis, developmental delay, and intellectual disability"
Developmental delay is named as a defining presenting feature of BIS.
Other 3
Blepharophimosis VERY_FREQUENT Blepharophimosis HP:0000581
Frequency band basis: blepharophimosis is definitional for the entity — both the founding delineation and the subsequent series describe BIS as presenting with blepharophimosis, and it is listed among the recurrent features of the recognizable phenotype. The HPO annotation of OMIM:619293 records blepharophimosis in 14/14 of the Cappuccio cohort, but that count is taken from the paper's full-text table (the article is not open access), so it cannot be quoted as a snippet here and is recorded only as provenance.
Show evidence (2 references)
PMID:32694869 SUPPORT Human Clinical
"recurrent features including epicanthal folds, blepharophimosis, and downturned nasal tip"
Blepharophimosis is named as one of the three recurrent facial features of the recognizable BIS phenotype.
PMID:38884529 SUPPORT Human Clinical
"presents with distinct facial features of blepharophimosis, developmental delay, and intellectual disability"
Independent statement that blepharophimosis is part of the defining presentation of BIS.
Abnormal nasal tip morphology Abnormal nasal tip morphology HP:0000436
Term-binding note: HPO was searched for a "downturned nasal tip" term (both via OAK and the HPO term-search API); no such term or synonym exists. HP:0000437 Depressed nasal tip is a different concept (decreased distance from nasal tip to nasal base), so the more general HP:0000436 was chosen rather than a semantically wrong specific term.
Show evidence (1 reference)
PMID:32694869 SUPPORT Human Clinical
"recurrent features including epicanthal folds, blepharophimosis, and downturned nasal tip"
A downturned nasal tip is explicitly listed as a recurrent feature of the recognizable BIS phenotype.
Narrow palpebral fissure Narrow palpebral fissure HP:0045025
Near-duplicate relationship with the Blepharophimosis entry above, recorded explicitly so downstream consumers do not double-count. HP:0000581 Blepharophimosis and HP:0045025 Narrow palpebral fissure are siblings under HP:0200007 Abnormal size of the palpebral fissures, and their definitions differ only in scope: HP:0045025 is reduction in the vertical eyelid distance alone, whereas HP:0000581 adds the short (horizontally reduced) fissure and the "fixed" qualifier. Both are retained here deliberately, for two reasons. First, the HPO annotation of OMIM:619293 itself carries both terms at different counts, blepharophimosis 14/14 and narrow palpebral fissure 10/14, both sourced to PMID:32694869 (checked against the HPO annotation API on 2026-08-01), so collapsing them would discard a distinction the source annotation makes. Second, HP:0045025 is the term that carries the BIS-versus-HVDAS shared-craniofacial-feature evidence from PMID:38884529, which is the observation that motivated the shared-episignature study; that argument is about the shared narrowing specifically, not about the full BIS facial gestalt. A consumer computing feature counts should treat HP:0045025 here as subsumed by HP:0000581 rather than as an additional independent feature.
Show evidence (1 reference)
PMID:38884529 SUPPORT Human Clinical
"an overlapping craniofacial phenotype with narrowing of the palpebral fissures in a subset of patients with HVDAS and BIS"
Directly documents narrowing of the palpebral fissures in patients with BIS.
🧬

Genetic Associations

1
SMARCA2
Gene: SMARCA2 hgnc:11098
Show evidence (3 references)
PMID:32694869 SUPPORT Human Clinical
"In contrast to most NCBRS variants, all SMARCA2 variants associated with BIS are localized outside the helicase domains."
Defines the BIS-specific SMARCA2 variant class and the positional contrast with the NCBRS variant class.
PMID:32694869 SUPPORT Human Clinical
"By next-generation sequencing, we identified candidate variants in SMARCA2 in 20 individuals from 18 families with a syndromic neurodevelopmental disorder not consistent with NCBRS."
Establishes SMARCA2 as the ascertained locus in a cohort explicitly selected for NOT having the NCBRS phenotype.
PMID:38884529 SUPPORT Human Clinical
"BIS is caused by pathogenic variants in SMARCA2"
Independent confirmation of SMARCA2 as the BIS disease gene.
💊

Medical Actions

1
Genetic counseling
Category: Counseling / Informational Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240
Counseling for an autosomal dominant condition in which all reported causal SMARCA2 variants have arisen de novo. Recurrence risk for siblings of a proband is correspondingly low, with the standard caveat that parental germline mosaicism cannot be excluded. Counseling should also cover the distinction from Nicolaides-Baraitser syndrome, since families may encounter NCBRS material when researching "SMARCA2".
Show evidence (1 reference)
PMID:32694869 PARTIAL Human Clinical
"clustered de novo SMARCA2 variants outside the helicase domains"
Supports the de novo occurrence that determines the recurrence-risk content of counseling. PARTIAL because the cited paper reports the genetics, not a counseling recommendation; no BIS-specific management guideline exists.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Blepharophimosis-Impaired Intellectual Development Syndrome:

Nicolaides-Baraitser syndrome Not Yet Curated MONDO:0011053
Overlapping Features NCBRS is the other, far better known, SMARCA2-related disorder (OMIM 601358). It is allelic to BIS but is a separate clinical and molecular entity. This is the single most important named-entity distinction for this file: the large majority of published SMARCA2 clinical literature describes NCBRS, and NCBRS cohort data must NOT be attributed to BIS.
Distinguishing Features
  • Variant position - NCBRS variants lie predominantly INSIDE the SMARCA2 helicase (ATPase) domains, whereas all reported BIS variants lie OUTSIDE them. Position within the gene is the primary molecular discriminator.
  • Ascertainment - the BIS cohort was deliberately assembled from individuals with a syndromic neurodevelopmental disorder judged NOT consistent with NCBRS, so the two entities were separated clinically before they were separated molecularly.
  • Facial gestalt - BIS is defined by blepharophimosis, epicanthal folds, and a downturned nasal tip; NCBRS is defined by sparse scalp hair and prominent interphalangeal joints.
  • Functional assay - yeast growth-phenotype assays differentiate NCBRS-causing from non-NCBRS SMARCA2 variants.
  • Episignature and transcriptome - blood-leukocyte transcriptomic and DNA methylation signatures differentiate NCBRS from BIS.
  • Seizure burden - epilepsy is a prominent feature of NCBRS but is not part of the BIS definition; no seizure frequency is curated in this entry because importing the NCBRS epilepsy burden would materially misstate the BIS phenotype.
  • Proposed molecular lesion differs in kind, not degree - the NCBRS variants sit in ultra-conserved catalytic ATPase motifs and are proposed to disrupt ATPase activity while leaving SWI/SNF assembly intact; the BIS variants sit outside those motifs, so the two allele classes are not a severity gradient of one lesion.
Show evidence (5 references)
PMID:32694869 SUPPORT Human Clinical
"phenotypically and molecularly distinct from NCBRS"
The founding report's own conclusion is that BIS is a distinct entity from NCBRS on both clinical and molecular grounds.
PMID:32694869 SUPPORT Human Clinical
"Nontruncating variants in SMARCA2, encoding a catalytic subunit of SWI/SNF chromatin remodeling complex, cause Nicolaides-Baraitser syndrome (NCBRS), a condition with intellectual disability and multiple congenital anomalies."
Identifies NCBRS as the pre-existing SMARCA2 disorder from which BIS had to be distinguished.
PMID:38884529 SUPPORT Human Clinical
"Blepharophimosis with intellectual disability (BIS) is a recently recognized disorder distinct from Nicolaides-Baraister syndrome"
Independent restatement that BIS is a distinct disorder from NCBRS. (The cited abstract spells the eponym "Nicolaides-Baraister"; the snippet is reproduced verbatim.)
+ 2 more references
Helsmoortel-Van der Aa syndrome (ADNP syndrome), class II MONDO:0014379
Overlapping Features HVDAS is caused by variants in ADNP; the class II subgroup is caused by truncating ADNP variants. A subset of individuals with HVDAS shares the narrow-palpebral-fissure craniofacial phenotype with BIS, and class II HVDAS shares the BIS DNA methylation episignature. HVDAS is therefore both a clinical and an epigenetic mimic of BIS. MONDO additionally carries a dedicated entity for this overlap, MONDO:0979360 (ADNP-related blepharophimosis-intellectual disability syndrome).
Distinguishing Features
  • Causal gene - HVDAS is caused by ADNP variants (specifically truncating variants for class II), not SMARCA2; sequencing resolves the two unambiguously.
  • Episignature does NOT discriminate - the shared episignature is phenotype-specific rather than gene-specific, so methylation testing alone cannot separate BIS from class II HVDAS and must be interpreted with the sequencing result.
  • Mechanistic basis of the overlap - ADNP interacts molecularly with the BAF complex of which SMARCA2 is the catalytic subunit, which is the proposed explanation for the convergent methylation profile.
Show evidence (2 references)
PMID:38884529 SUPPORT Human Clinical
"A distinct episignature was shared by 15 individuals with BIS-causing SMARCA2 pathogenic variants and 12 individuals with class II HVDAS caused by truncating pathogenic ADNP variants."
Establishes the shared episignature between BIS and class II HVDAS, which is what makes HVDAS a genuine epigenetic differential for BIS.
PMID:38884529 SUPPORT Human Clinical
"Individuals bearing variants within the bipartite nuclear localization (BNL) signal domain of ADNP present with the neurodevelopmental disorder known as Helsmoortel-Van Der Aa Syndrome (HVDAS)."
Identifies ADNP as the causal gene of HVDAS, the discriminating feature.
SMARCA2-variant carriers with a nonspecific dysmorphic phenotype
Overlapping Features Not every individual with a rare SMARCA2 variant has BIS or NCBRS. In the founding cohort, six of twenty SMARCA2-variant carriers had only nonspecific dysmorphic features and could not be assigned to either syndrome even after functional, transcriptomic, and methylation analysis. Their variants remained unclassified. This group is a reminder that a rare SMARCA2 variant is not by itself a BIS diagnosis.
Distinguishing Features
  • Absence of the recognizable BIS facial gestalt (blepharophimosis plus epicanthal folds plus downturned nasal tip).
  • Failure to match the BIS transcriptomic or DNA methylation signature.
  • Variant remains of uncertain significance after multimodal stratification.
Show evidence (1 reference)
PMID:32694869 SUPPORT Human Clinical
"In the remaining six individuals with nonspecific dysmorphic features, clinical and molecular data did not permit variant reclassification."
Directly documents the unclassifiable subgroup and the limits of current SMARCA2 variant interpretation.
{ }

Source YAML

click to show 
name: Blepharophimosis-Impaired Intellectual Development Syndrome
creation_date: '2026-08-01T00:00:00Z'
category: Mendelian
synonyms:
- BIS
- Blepharophimosis intellectual disability syndrome
- Blepharophimosis with intellectual disability
- SMARCA2-related blepharophimosis-intellectual disability syndrome
description: >
  Blepharophimosis-impaired intellectual development syndrome (BIS; OMIM 619293)
  is a rare neurodevelopmental disorder caused by de novo SMARCA2 variants that
  cluster OUTSIDE the helicase (ATPase) domains. SMARCA2 (BRM) is a catalytic
  ATPase subunit of the BAF (SWI/SNF) chromatin remodeling complex. Affected
  individuals have a recognizable facial gestalt — blepharophimosis, epicanthal
  folds, and a downturned nasal tip — together with developmental delay and a
  variable degree of intellectual disability.

  BIS is a distinct entity from Nicolaides-Baraitser syndrome (NCBRS,
  OMIM 601358, MONDO:0011053), the other SMARCA2-related disorder. Most NCBRS
  variants lie inside the helicase domains, and NCBRS is characterized clinically
  by sparse scalp hair, prominent interphalangeal joints, and frequent seizures —
  none of which is a defining feature of BIS. The separation is not only clinical:
  yeast growth-phenotype assays, blood-leukocyte transcriptomic profiles, and
  genome-wide DNA methylation (episignature) analysis each independently
  discriminate BIS from NCBRS. Because the great majority of the SMARCA2
  clinical literature concerns NCBRS, cohort data from NCBRS series must not be
  imported into this entry.
disease_term:
  preferred_term: blepharophimosis-impaired intellectual development syndrome
  term:
    id: MONDO:0859139
    label: blepharophimosis-impaired intellectual development syndrome
parents:
- Neurodevelopmental disorder
- Syndromic intellectual disability
- BAF (SWI/SNF) complex-related disorder (BAFopathy)
- Chromatinopathy
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:32694869
      reference_title: "De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides-Baraitser syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We identified a novel recognizable syndrome named BIS associated with clustered de novo SMARCA2 variants outside the helicase domains"
      explanation: >
        BIS is a de novo single-gene (Mendelian) disorder, placing it in the
        genetics-and-disease chapter.
  - classification_value: NEUROLOGIC
    evidence:
    - reference: PMID:38884529
      reference_title: "Blepharophimosis with intellectual disability and Helsmoortel-Van Der Aa Syndrome share episignature and phenotype."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "presents with distinct facial features of blepharophimosis, developmental delay, and intellectual disability"
      explanation: >
        Developmental delay and intellectual disability are core, defining
        manifestations, making this a neurodevelopmental (neurologic) disorder.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Ultra-rare and only recently delineated (2020). The founding report described
    14 individuals meeting the BIS phenotype out of 20 SMARCA2-variant carriers
    ascertained from 18 families; a later episignature study analysed 15
    individuals with BIS-causing SMARCA2 variants, drawn from a partly
    overlapping international referral network. The two counts are therefore NOT
    additive and no denominator-based population estimate exists. No
    population-based incidence or prevalence figure has been published.
  evidence:
  - reference: PMID:32694869
    reference_title: "De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of 20 individuals, 14 showed a recognizable phenotype with recurrent features including epicanthal folds, blepharophimosis, and downturned nasal tip along with variable degree of intellectual disability (or blepharophimosis intellectual disability syndrome [BIS])."
    explanation: >
      Documents the size of the founding BIS case series (14 individuals) at
      disease delineation, supporting a cases-in-literature measure rather than
      a population rate.
  - reference: PMID:38884529
    reference_title: "Blepharophimosis with intellectual disability and Helsmoortel-Van Der Aa Syndrome share episignature and phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A distinct episignature was shared by 15 individuals with BIS-causing SMARCA2 pathogenic variants"
    explanation: >
      The largest subsequent BIS series comprised 15 individuals, confirming that
      the total reported population remains in the tens.
inheritance:
- name: Autosomal dominant inheritance
  description: >
    BIS results from heterozygous SMARCA2 variants that arose de novo in the
    reported probands. Inheritance is autosomal dominant; because
    every reported BIS variant has been de novo, sibling recurrence risk is low
    but not zero (germline mosaicism has not been excluded).
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:32694869
    reference_title: "De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a novel recognizable syndrome named BIS associated with clustered de novo SMARCA2 variants outside the helicase domains"
    explanation: >
      The causal SMARCA2 variants are heterozygous and de novo, the pattern
      expected for a dominant disorder with reproductive fitness reduction.
genetic:
- name: SMARCA2
  notes: >
    De novo SMARCA2 variants that cluster OUTSIDE the helicase (ATPase) domains
    cause BIS. Variant location within SMARCA2 is the discriminating genotype
    feature: most Nicolaides-Baraitser syndrome variants fall INSIDE the helicase
    domains, whereas all BIS variants reported in the founding cohort fall
    outside them.

    Deliberate under-assertion: the specific variant consequence class for BIS
    (missense versus in-frame versus truncating) is NOT asserted here. The
    quotable abstract applies the word "nontruncating" to the NCBRS variant class,
    not explicitly to the BIS variant class, and the per-variant table lives in
    the paywalled full text. Positional clustering outside the helicase domains
    is the only variant property this entry claims, because it is the only one
    directly stated for BIS.

    Domain-boundary nuance (important for anyone auditing this entry for internal
    consistency): "outside the helicase domains" is the founding paper's
    FUNCTIONAL partition — the ultra-conserved catalytic ATPase motifs — and not
    UniProt's annotation boundary. UniProt P51531 annotates a Helicase
    ATP-binding domain spanning residues 736-901 (feature table checked
    2026-08-01), and two reported BIS alleles, p.(Met856Val) and p.(Leu766Val),
    fall INSIDE that span; p.(Leu766Val) is in fact the allele Sarli et al.
    label "BIS_atypical". This entry therefore reports the positional claim as
    the authors frame it and does NOT assert that every BIS residue lies outside
    UniProt's annotated DExx domain. This matters concretely here because the
    PMID:38751117 evidence item cited on the episignature pathophysiology node
    is about SMARCA2 M856V. The per-variant residue list comes from the Sarli
    et al. 2024 Table 1, which lives in full text that is not in this
    repository's reference cache, so it is recorded as provenance rather than
    quoted as a snippet.
  gene_term:
    preferred_term: SMARCA2
    term:
      id: hgnc:11098
      label: SMARCA2
  evidence:
  - reference: PMID:32694869
    reference_title: "De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast to most NCBRS variants, all SMARCA2 variants associated with BIS are localized outside the helicase domains."
    explanation: >
      Defines the BIS-specific SMARCA2 variant class and the positional contrast
      with the NCBRS variant class.
  - reference: PMID:32694869
    reference_title: "De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By next-generation sequencing, we identified candidate variants in SMARCA2 in 20 individuals from 18 families with a syndromic neurodevelopmental disorder not consistent with NCBRS."
    explanation: >
      Establishes SMARCA2 as the ascertained locus in a cohort explicitly
      selected for NOT having the NCBRS phenotype.
  - reference: PMID:38884529
    reference_title: "Blepharophimosis with intellectual disability and Helsmoortel-Van Der Aa Syndrome share episignature and phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "BIS is caused by pathogenic variants in SMARCA2"
    explanation: Independent confirmation of SMARCA2 as the BIS disease gene.
diagnosis:
- name: Molecular genetic testing for a de novo non-helicase-domain SMARCA2 variant
  description: >
    The diagnosis is established by identification of a heterozygous de novo
    SMARCA2 variant lying outside the helicase domains, in an
    individual with the BIS facial gestalt (blepharophimosis, epicanthal folds,
    downturned nasal tip) and developmental delay/intellectual disability. In the
    founding cohort the variants were found by next-generation (exome/genome)
    sequencing. Variant position within SMARCA2 is itself diagnostically
    informative because it separates BIS from Nicolaides-Baraitser syndrome.
  evidence:
  - reference: PMID:32694869
    reference_title: "De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By next-generation sequencing, we identified candidate variants in SMARCA2 in 20 individuals from 18 families"
    explanation: >
      Next-generation sequencing was the route by which the causal SMARCA2
      variants were identified in the founding BIS cohort.
- name: DNA methylation episignature testing
  description: >
    Genome-wide DNA methylation profiling of blood leukocytes yields a
    reproducible BIS episignature that separates BIS from Nicolaides-Baraitser
    syndrome and from SMARCA2-variant carriers with nonspecific phenotypes, and
    can therefore be used to resolve SMARCA2 variants of uncertain significance.
    Note an important interpretive caveat: the BIS episignature is NOT unique to
    SMARCA2 — it is shared with class II Helsmoortel-Van der Aa syndrome caused
    by truncating ADNP variants, so a positive episignature must be read together
    with the sequencing result.
  evidence:
  - reference: PMID:32694869
    reference_title: "De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Transcriptomic and DNA methylation signatures differentiated NCBRS from BIS and those with nonspecific phenotype."
    explanation: >
      Establishes that methylation (and transcriptomic) profiling discriminates
      BIS from NCBRS and from unclassified SMARCA2-variant carriers.
  - reference: PMID:38884529
    reference_title: "Blepharophimosis with intellectual disability and Helsmoortel-Van Der Aa Syndrome share episignature and phenotype."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "A distinct episignature was shared by 15 individuals with BIS-causing SMARCA2 pathogenic variants and 12 individuals with class II HVDAS caused by truncating pathogenic ADNP variants."
    explanation: >
      Supports the caveat rather than the assay's specificity: the BIS
      episignature is reproducible across 15 BIS individuals but is shared with
      ADNP-related class II HVDAS, so it is phenotype-specific rather than
      gene-specific. Recorded as PARTIAL because it qualifies, rather than
      simply endorses, the diagnostic claim.
- name: Yeast functional assay for SMARCA2 variant stratification
  description: >
    Heterologous expression of SMARCA2 variants in yeast produced growth
    phenotypes that separated NCBRS-causing from non-NCBRS SMARCA2 variants,
    providing an orthogonal functional readout used to stratify variant
    interpretation. This is a research assay, not a clinical test.
  evidence:
  - reference: PMID:32694869
    reference_title: "De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Yeast phenotype assays differentiated NCBRS from non-NCBRS SMARCA2 variants."
    explanation: >
      Documents the yeast assay and exactly what it discriminates. Classified
      IN_VITRO because the readout is a heterologous yeast growth assay, not a
      human clinical observation.
pathophysiology:
- name: Non-Helicase-Domain SMARCA2 Variants Perturb the BAF Chromatin Remodeling Complex
  biological_scale: MOLECULAR
  description: >
    SMARCA2 (BRM) encodes a catalytic ATPase subunit of the BAF (SWI/SNF)
    chromatin remodeling complex, which uses ATP hydrolysis to reposition
    nucleosomes and thereby control transcription. BIS-causing variants
    cluster outside the helicase (ATPase) domains, a
    positionally distinct class from the helicase-domain variants that cause
    Nicolaides-Baraitser syndrome. Yeast growth-phenotype assays separate the two
    variant classes functionally, indicating that BIS variants do not simply
    reproduce the NCBRS lesion. The precise biochemical consequence of the BIS
    variant class (for example, altered subunit assembly, altered targeting, or
    altered non-catalytic regulatory function rather than loss of ATPase
    activity) has not been resolved.
  biological_processes:
  - preferred_term: chromatin remodeling
    term:
      id: GO:0006338
      label: chromatin remodeling
    modifier: ABNORMAL
  molecular_functions:
  - preferred_term: ATP-dependent chromatin remodeler activity
    term:
      id: GO:0140658
      label: ATP-dependent chromatin remodeler activity
    modifier: ABNORMAL
  cellular_components:
  - preferred_term: BAF (SWI/SNF) complex
    term:
      id: GO:0016514
      label: SWI/SNF complex
  downstream:
  - target: Altered Transcriptional and DNA Methylation Programs
    description: >-
      Perturbation of BAF-mediated nucleosome remodeling changes the
      transcriptional output and the genome-wide DNA methylation landscape of
      patient cells, producing the BIS-specific transcriptomic and episignature
      profiles measurable in blood leukocytes.
    evidence:
    - reference: PMID:32694869
      reference_title: "De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides-Baraitser syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Transcriptomic and DNA methylation signatures differentiated NCBRS from BIS and those with nonspecific phenotype."
      explanation: >
        Demonstrates that the BIS variant class produces its own measurable
        transcriptomic and methylation consequence, distinct from that of NCBRS.
  - target: BAF Subunit Switching in Neural Development
    description: >-
      A SMARCA2 lesion is carried into the neural-progenitor BAF (npBAF)
      complexes in which BRM is an ATPase, so the remodeling defect is expressed
      in the compartment whose BAF composition is developmentally regulated.
    evidence:
    - reference: PMID:17640523
      reference_title: "An essential switch in subunit composition of a chromatin remodeling complex during neural development."
      supports: PARTIAL
      evidence_source: IN_VITRO
      snippet: "are quantitatively associated with the \nSWI2/SNF2-like ATPases, Brg and Brm."
      explanation: >
        Establishes that BRM (SMARCA2) is a constituent ATPase of neural
        progenitor BAF complexes, which is what makes this edge possible.
        PARTIAL because the presence of BRM in npBAF is shown, not the behaviour
        of a BIS allele within it.
  evidence:
  - reference: PMID:38884529
    reference_title: "Blepharophimosis with intellectual disability and Helsmoortel-Van Der Aa Syndrome share episignature and phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SMARCA2, that encodes the catalytic subunit of the superfamily II helicase group of the BRG1 and BRM-associated factors (BAF) forming the BAF complex, a chromatin remodeling complex involved in transcriptional regulation"
    explanation: >
      Establishes SMARCA2 as the catalytic ATPase subunit of the BAF chromatin
      remodeling complex and its role in transcriptional regulation, supporting
      the GO chromatin-remodeling, remodeler-activity, and SWI/SNF-complex
      annotations on this node.
  - reference: PMID:32694869
    reference_title: "De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Yeast phenotype assays differentiated NCBRS from non-NCBRS SMARCA2 variants."
    explanation: >
      Functional (yeast) evidence that BIS-class SMARCA2 variants behave
      differently from NCBRS-class variants, supporting the claim that the BIS
      lesion is mechanistically distinct rather than a milder NCBRS.
  - reference: PMID:37500730
    reference_title: "Landscape of mSWI/SNF chromatin remodeling complex perturbations in neurodevelopmental disorders."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "whereas mutations within the SMARCA2 helicase \ncause NCBRS, SMARCA2 mutations outside of this domain are"
    explanation: >
      Independent confirmation, from a pan-mSWI/SNF structural and variant-landscape
      analysis by a different group, that the SMARCA2 positional dichotomy
      (helicase-domain versus non-helicase-domain) maps onto the NCBRS/BIS
      disease split. COMPUTATIONAL because this paper is a structural and
      variant-aggregation analysis, not a wet-lab assay of BIS alleles.
  - reference: PMID:37500730
    reference_title: "Landscape of mSWI/SNF chromatin remodeling complex perturbations in neurodevelopmental disorders."
    supports: PARTIAL
    evidence_source: COMPUTATIONAL
    snippet: "Non-truncating NDD-associated protein variants predominantly disrupt \nthe cBAF subcomplex and cluster in four key structural regions associated with \nhigh disease severity, including mSWI/SNF-nucleosome interfaces, the ATPase-core \nARID-armadillo repeat (ARM) module insertion site, the Arp module and \nDNA-binding domains."
    explanation: >
      Provides the structural framework within which the non-catalytic BIS
      variant cluster is interpretable — non-truncating mSWI/SNF NDD variants
      concentrate at inter-subunit and nucleosome-engagement interfaces rather
      than only at the catalytic core. PARTIAL because the statement is about
      mSWI/SNF NDD variants in aggregate, not specifically about the BIS allele
      set; the BIS alleles were not individually assayed here.
  - reference: PMID:9843504
    reference_title: "Altered control of cellular proliferation in the absence of mammalian brahma (SNF2alpha)."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "the BRM (SNF2alpha) and BRG1 (SNF2beta) proteins are \nmutually exclusive subunits that are believed to affect nucleosomal structures \nusing the energy of ATP hydrolysis."
    explanation: >
      Establishes the background biology asserted in this node and in the entry
      description: SMARCA2 (BRM) and SMARCA4 (BRG1) are the two mutually
      exclusive ATPase subunits of the SWI/SNF complex and act by ATP-driven
      nucleosome remodeling. Classified MODEL_ORGANISM because the publication
      reports a mouse Brm-knockout study.
- name: Altered Transcriptional and DNA Methylation Programs
  biological_scale: CELLULAR
  description: >
    Cells from individuals with BIS carry a reproducible, disease-specific
    transcriptomic profile and a genome-wide DNA methylation episignature that is
    detectable in peripheral blood leukocytes and that distinguishes BIS from
    NCBRS. Notably, the BIS episignature is shared with class II
    Helsmoortel-Van der Aa syndrome (truncating ADNP variants), consistent with
    known molecular interaction between ADNP and the BAF complex and with the
    overlapping narrow-palpebral-fissure craniofacial phenotype of the two
    conditions. This is the first reported instance of a phenotype-specific
    rather than gene-specific episignature.
  biological_processes:
  - preferred_term: regulation of transcription by RNA polymerase II
    term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
    modifier: ABNORMAL
  downstream:
  - target: Abnormal Craniofacial and Neurodevelopmental Patterning
    description: >-
      The shared BIS/HVDAS episignature tracks with a shared craniofacial
      phenotype (narrowing of the palpebral fissures), linking the altered
      chromatin/transcriptional program to the recognizable facial gestalt and
      the neurodevelopmental outcome.
    evidence:
    - reference: PMID:38884529
      reference_title: "Blepharophimosis with intellectual disability and Helsmoortel-Van Der Aa Syndrome share episignature and phenotype."
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: "an overlapping craniofacial phenotype with narrowing of the palpebral fissures in a subset of patients with HVDAS and BIS"
      explanation: >
        Ties the shared methylation program to a shared craniofacial outcome.
        PARTIAL because the correspondence is an observed association between
        episignature and phenotype, not a demonstrated causal chain from
        methylation change to facial morphogenesis.
  evidence:
  - reference: PMID:38884529
    reference_title: "Blepharophimosis with intellectual disability and Helsmoortel-Van Der Aa Syndrome share episignature and phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This represents first evidence of a sensitive phenotype-specific episignature biomarker shared across distinct genetic conditions that also exhibit unique gene-specific episignatures."
    explanation: >
      Characterizes the BIS methylation program as a phenotype-specific
      episignature shared with another genetic condition, which is the
      substantive claim of this node.
  - reference: PMID:38884529
    reference_title: "Blepharophimosis with intellectual disability and Helsmoortel-Van Der Aa Syndrome share episignature and phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Due to molecular interactions between ADNP and BAF complex"
    explanation: >
      Supports the mechanistic rationale for why a SMARCA2/BAF disorder and an
      ADNP disorder converge on the same methylation program.
  - reference: PMID:38751117
    reference_title: "DNA methylation analysis in patients with neurodevelopmental disorders improves variant interpretation and reveals complexity."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "common \nepisignatures affecting homologous residues in highly conserved paralogous \nproteins (SMARCA2 M856V and SMARCA4 M866V)"
    explanation: >
      Supports the narrower, directly quoted claim that a specific SMARCA2
      missense allele and its structurally homologous SMARCA4 counterpart
      converge on a common DNA methylation program — reinforcing that SMARCA2
      missense variants produce reproducible, residue-level epigenomic
      consequences. PARTIAL and deliberately scoped: this abstract does NOT
      state that its SMARCA2 M856V case has BIS. p.Met856Val is listed as a BIS
      allele in the Sarli et al. variant table, but that table is in the
      paywalled full text and is not quotable here, so the BIS attribution is
      flagged as inference rather than asserted.
- name: BAF Subunit Switching in Neural Development
  biological_scale: CELLULAR
  description: >
    The route from a BAF-complex lesion to a neurodevelopmental phenotype runs
    through the developmentally regulated subunit composition of neural BAF
    complexes. SMARCA2 (Brm) is one of the two ATPases found in the
    neural-progenitor BAF (npBAF) complex, and an obligatory switch in the
    accessory subunits of these complexes accompanies — and is required for —
    the transition from proliferating neural progenitors to postmitotic neurons.
    A SMARCA2 lesion therefore acts on a complex whose correct composition and
    activity are rate-limiting for neuronal differentiation.
  notes: >
    Scope caveat: this node is general BAF neurobiology, not BIS-specific. The
    cited work characterizes the npBAF-to-nBAF subunit switch in mouse neural
    stem/progenitor cells; no study has tested a BIS-class SMARCA2 allele in this
    system. It is included because it supplies the only published mechanistic
    bridge between BAF perturbation and a neurodevelopmental outcome, and its
    evidence items are marked PARTIAL accordingly.
  cell_types:
  - preferred_term: neural progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  biological_processes:
  - preferred_term: neuron differentiation
    term:
      id: GO:0030182
      label: neuron differentiation
    modifier: ABNORMAL
  cellular_components:
  - preferred_term: npBAF complex
    term:
      id: GO:0071564
      label: npBAF complex
  evidence:
  - reference: PMID:17640523
    reference_title: "An essential switch in subunit composition of a chromatin remodeling complex during neural development."
    supports: PARTIAL
    evidence_source: IN_VITRO
    snippet: "are quantitatively associated with the \nSWI2/SNF2-like ATPases, Brg and Brm."
    explanation: >
      Places Brm (SMARCA2) in the neural progenitor BAF complex, which is the
      premise of this node. PARTIAL because it establishes SMARCA2's presence in
      npBAF, not the effect of a BIS allele. IN_VITRO because the subunit
      composition was determined by proteomic analysis of neural stem/progenitor
      cell complexes.
  - reference: PMID:17640523
    reference_title: "An essential switch in subunit composition of a chromatin remodeling complex during neural development."
    supports: PARTIAL
    evidence_source: IN_VITRO
    snippet: "Preventing the subunit switch impairs neuronal differentiation, \nindicating that this molecular event is essential for the transition from neural \nstem/progenitors to postmitotic neurons."
    explanation: >
      Establishes that correct BAF subunit composition is required for neuronal
      differentiation, which is why a BAF-subunit lesion can produce a
      neurodevelopmental disorder. PARTIAL: the perturbation tested was the
      subunit switch itself, not a SMARCA2 disease variant.
  downstream:
  - target: Abnormal Craniofacial and Neurodevelopmental Patterning
    description: >-
      Disruption of BAF activity in the neural progenitor compartment, where
      correct complex composition is required for the progenitor-to-neuron
      transition, is the proposed route to the developmental delay and
      intellectual disability arm of the BIS phenotype. This edge covers the
      neurodevelopmental arm only; no mechanism has been proposed linking
      SMARCA2 to periocular or midfacial morphogenesis.
    evidence:
    - reference: PMID:17640523
      reference_title: "An essential switch in subunit composition of a chromatin remodeling complex during neural development."
      supports: PARTIAL
      evidence_source: IN_VITRO
      snippet: "Preventing the subunit switch impairs neuronal differentiation, \nindicating that this molecular event is essential for the transition from neural \nstem/progenitors to postmitotic neurons."
      explanation: >
        Supports the causal step from perturbed neural BAF composition to
        impaired neuronal differentiation. PARTIAL because the link from this
        cell-biological defect to human intellectual disability in BIS is
        inferred, not demonstrated.
- name: Abnormal Craniofacial and Neurodevelopmental Patterning
  biological_scale: ORGANISM
  description: >
    The downstream clinical expression of the altered BAF-dependent
    transcriptional program is a recognizable, reproducible combination of
    periocular and midfacial dysmorphism (blepharophimosis, epicanthal folds,
    downturned nasal tip) with global developmental delay and intellectual
    disability of variable severity. The specific developmental programs and cell
    populations that translate BAF dysfunction into this particular facial
    gestalt have not been identified.
  biological_processes:
  - preferred_term: nervous system development
    term:
      id: GO:0007399
      label: nervous system development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:32694869
    reference_title: "De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "14 showed a recognizable phenotype with recurrent features including epicanthal folds, blepharophimosis, and downturned nasal tip along with variable degree of intellectual disability"
    explanation: >
      States the organism-level output of the mechanism: a recognizable facial
      gestalt combined with variable intellectual disability.
phenotypes:
- name: Blepharophimosis
  description: >
    Fixed narrowing of the palpebral fissures. HPO defines HP:0000581 as a fixed
    reduction in the VERTICAL distance between the upper and lower eyelids
    together with short (that is, horizontally reduced) palpebral fissures — both
    axes, not the horizontal one alone. This is the cardinal, disease-defining
    facial feature of BIS and gives the syndrome its name.
  frequency: VERY_FREQUENT
  notes: >
    Frequency band basis: blepharophimosis is definitional for the entity — both
    the founding delineation and the subsequent series describe BIS as presenting
    with blepharophimosis, and it is listed among the recurrent features of the
    recognizable phenotype. The HPO annotation of OMIM:619293 records
    blepharophimosis in 14/14 of the Cappuccio cohort, but that count is taken
    from the paper's full-text table (the article is not open access), so it
    cannot be quoted as a snippet here and is recorded only as provenance.
  phenotype_term:
    preferred_term: Blepharophimosis
    term:
      id: HP:0000581
      label: Blepharophimosis
  evidence:
  - reference: PMID:32694869
    reference_title: "De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "recurrent features including epicanthal folds, blepharophimosis, and downturned nasal tip"
    explanation: >
      Blepharophimosis is named as one of the three recurrent facial features of
      the recognizable BIS phenotype.
  - reference: PMID:38884529
    reference_title: "Blepharophimosis with intellectual disability and Helsmoortel-Van Der Aa Syndrome share episignature and phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "presents with distinct facial features of blepharophimosis, developmental delay, and intellectual disability"
    explanation: >
      Independent statement that blepharophimosis is part of the defining
      presentation of BIS.
- name: Epicanthus
  description: >
    Epicanthal folds are one of the three recurrent periocular/midfacial features
    that make the BIS facial gestalt recognizable.
  phenotype_term:
    preferred_term: Epicanthal folds
    term:
      id: HP:0000286
      label: Epicanthus
  evidence:
  - reference: PMID:32694869
    reference_title: "De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "recurrent features including epicanthal folds, blepharophimosis, and downturned nasal tip"
    explanation: Epicanthal folds are explicitly listed as a recurrent BIS feature.
- name: Abnormal nasal tip morphology
  description: >
    A downturned nasal tip is the third of the three recurrent features of the
    recognizable BIS facial gestalt. HPO has no term whose label is "downturned
    nasal tip"; the closest correct binding is the parent term Abnormal nasal tip
    morphology, and the specific descriptor is retained in preferred_term.
  notes: >
    Term-binding note: HPO was searched for a "downturned nasal tip" term
    (both via OAK and the HPO term-search API); no such term or synonym exists.
    HP:0000437 Depressed nasal tip is a different concept (decreased distance
    from nasal tip to nasal base), so the more general HP:0000436 was chosen
    rather than a semantically wrong specific term.
  phenotype_term:
    preferred_term: Downturned nasal tip
    term:
      id: HP:0000436
      label: Abnormal nasal tip morphology
  evidence:
  - reference: PMID:32694869
    reference_title: "De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "recurrent features including epicanthal folds, blepharophimosis, and downturned nasal tip"
    explanation: >
      A downturned nasal tip is explicitly listed as a recurrent feature of the
      recognizable BIS phenotype.
- name: Intellectual disability
  description: >
    Intellectual disability is present in individuals with BIS and its severity
    is explicitly variable across the reported cohort.
  frequency: VERY_FREQUENT
  notes: >
    Frequency band basis: intellectual disability is part of the definitional
    description of BIS in both published series. The HPO annotation of
    OMIM:619293 records intellectual disability in 14/14 of the Cappuccio cohort,
    but that count comes from the paper's full-text table rather than the
    quotable abstract and is recorded here only as provenance.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:32694869
    reference_title: "De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "along with variable degree of intellectual disability"
    explanation: >
      States both the presence of intellectual disability and that its degree
      varies between affected individuals.
  - reference: PMID:38884529
    reference_title: "Blepharophimosis with intellectual disability and Helsmoortel-Van Der Aa Syndrome share episignature and phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "presents with distinct facial features of blepharophimosis, developmental delay, and intellectual disability"
    explanation: Independent confirmation that intellectual disability is a defining feature.
- name: Global developmental delay
  description: >
    Developmental delay is a core presenting feature of BIS and typically brings
    affected children to genetic evaluation before a formal assessment of
    intellectual disability is possible.
  frequency: VERY_FREQUENT
  notes: >
    Frequency band basis: developmental delay is named in the definitional
    description of BIS. The HPO annotation of OMIM:619293 records global
    developmental delay in 14/14 of the Cappuccio cohort; that count is from the
    paper's full-text table, not the quotable abstract, and is given here as
    provenance only.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:38884529
    reference_title: "Blepharophimosis with intellectual disability and Helsmoortel-Van Der Aa Syndrome share episignature and phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "presents with distinct facial features of blepharophimosis, developmental delay, and intellectual disability"
    explanation: Developmental delay is named as a defining presenting feature of BIS.
- name: Narrow palpebral fissure
  description: >
    Narrowing of the palpebral fissures is the craniofacial feature that BIS
    shares with class II Helsmoortel-Van der Aa syndrome, and it is this shared
    feature that motivated the search for (and discovery of) a common
    phenotype-specific episignature.
  notes: >
    Near-duplicate relationship with the Blepharophimosis entry above, recorded
    explicitly so downstream consumers do not double-count. HP:0000581
    Blepharophimosis and HP:0045025 Narrow palpebral fissure are siblings under
    HP:0200007 Abnormal size of the palpebral fissures, and their definitions
    differ only in scope: HP:0045025 is reduction in the vertical eyelid distance
    alone, whereas HP:0000581 adds the short (horizontally reduced) fissure and
    the "fixed" qualifier. Both are retained here deliberately, for two reasons.
    First, the HPO annotation of OMIM:619293 itself carries both terms at
    different counts, blepharophimosis 14/14 and narrow palpebral fissure 10/14,
    both sourced to PMID:32694869 (checked against the HPO annotation API on
    2026-08-01), so collapsing them would discard a distinction the source
    annotation makes. Second, HP:0045025 is the term that carries the
    BIS-versus-HVDAS shared-craniofacial-feature evidence from PMID:38884529,
    which is the observation that motivated the shared-episignature study; that
    argument is about the shared narrowing specifically, not about the full BIS
    facial gestalt. A consumer computing feature counts should treat HP:0045025
    here as subsumed by HP:0000581 rather than as an additional independent
    feature.
  phenotype_term:
    preferred_term: Narrow palpebral fissure
    term:
      id: HP:0045025
      label: Narrow palpebral fissure
  evidence:
  - reference: PMID:38884529
    reference_title: "Blepharophimosis with intellectual disability and Helsmoortel-Van Der Aa Syndrome share episignature and phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "an overlapping craniofacial phenotype with narrowing of the palpebral fissures in a subset of patients with HVDAS and BIS"
    explanation: >
      Directly documents narrowing of the palpebral fissures in patients with
      BIS.
differential_diagnoses:
- name: Nicolaides-Baraitser syndrome
  disease_term:
    preferred_term: Nicolaides-Baraitser syndrome
    term:
      id: MONDO:0011053
      label: intellectual disability-sparse hair-brachydactyly syndrome
  description: >
    NCBRS is the other, far better known, SMARCA2-related disorder (OMIM 601358).
    It is allelic to BIS but is a separate clinical and molecular entity. This is
    the single most important named-entity distinction for this file: the large
    majority of published SMARCA2 clinical literature describes NCBRS, and NCBRS
    cohort data must NOT be attributed to BIS.
  distinguishing_features:
  - Variant position - NCBRS variants lie predominantly INSIDE the SMARCA2 helicase (ATPase) domains, whereas all reported BIS variants lie OUTSIDE them. Position within the gene is the primary molecular discriminator.
  - Ascertainment - the BIS cohort was deliberately assembled from individuals with a syndromic neurodevelopmental disorder judged NOT consistent with NCBRS, so the two entities were separated clinically before they were separated molecularly.
  - Facial gestalt - BIS is defined by blepharophimosis, epicanthal folds, and a downturned nasal tip; NCBRS is defined by sparse scalp hair and prominent interphalangeal joints.
  - Functional assay - yeast growth-phenotype assays differentiate NCBRS-causing from non-NCBRS SMARCA2 variants.
  - Episignature and transcriptome - blood-leukocyte transcriptomic and DNA methylation signatures differentiate NCBRS from BIS.
  - Seizure burden - epilepsy is a prominent feature of NCBRS but is not part of the BIS definition; no seizure frequency is curated in this entry because importing the NCBRS epilepsy burden would materially misstate the BIS phenotype.
  - Proposed molecular lesion differs in kind, not degree - the NCBRS variants sit in ultra-conserved catalytic ATPase motifs and are proposed to disrupt ATPase activity while leaving SWI/SNF assembly intact; the BIS variants sit outside those motifs, so the two allele classes are not a severity gradient of one lesion.
  evidence:
  - reference: PMID:32694869
    reference_title: "De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "phenotypically and molecularly distinct from NCBRS"
    explanation: >
      The founding report's own conclusion is that BIS is a distinct entity from
      NCBRS on both clinical and molecular grounds.
  - reference: PMID:32694869
    reference_title: "De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nontruncating variants in SMARCA2, encoding a catalytic subunit of SWI/SNF chromatin remodeling complex, cause Nicolaides-Baraitser syndrome (NCBRS), a condition with intellectual disability and multiple congenital anomalies."
    explanation: >
      Identifies NCBRS as the pre-existing SMARCA2 disorder from which BIS had to
      be distinguished.
  - reference: PMID:38884529
    reference_title: "Blepharophimosis with intellectual disability and Helsmoortel-Van Der Aa Syndrome share episignature and phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Blepharophimosis with intellectual disability (BIS) is a recently recognized disorder distinct from Nicolaides-Baraister syndrome"
    explanation: >
      Independent restatement that BIS is a distinct disorder from NCBRS. (The
      cited abstract spells the eponym "Nicolaides-Baraister"; the snippet is
      reproduced verbatim.)
  - reference: PMID:22366787
    reference_title: "Heterozygous missense mutations in SMARCA2 cause Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nicolaides-Baraitser syndrome (NBS) is characterized by sparse hair, distinctive \nfacial morphology, distal-limb anomalies and intellectual disability."
    explanation: >
      Supplies the NCBRS clinical definition from its own founding paper, which
      is what makes sparse hair and distal-limb anomalies usable as
      discriminators against the BIS gestalt.
  - reference: PMID:22366787
    reference_title: "Heterozygous missense mutations in SMARCA2 cause Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mutations cluster within sequences that encode ultra-conserved motifs in the \ncatalytic ATPase region of the protein. These alterations likely do not impair \nSWI/SNF complex assembly but may be associated with disrupted ATPase activity."
    explanation: >
      Supports the distinguishing feature that the NCBRS allele class is
      catalytic-motif-localized and proposed to impair ATPase activity rather
      than complex assembly — the mechanistic counterpart to the positional
      contrast with the non-catalytic BIS cluster.
- name: Helsmoortel-Van der Aa syndrome (ADNP syndrome), class II
  disease_term:
    preferred_term: ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder
    term:
      id: MONDO:0014379
      label: ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder
  description: >
    HVDAS is caused by variants in ADNP; the class II subgroup is caused by
    truncating ADNP variants. A subset of individuals with HVDAS shares the
    narrow-palpebral-fissure craniofacial phenotype with BIS, and class II HVDAS
    shares the BIS DNA methylation episignature. HVDAS is therefore both a
    clinical and an epigenetic mimic of BIS. MONDO additionally carries a
    dedicated entity for this overlap, MONDO:0979360 (ADNP-related
    blepharophimosis-intellectual disability syndrome).
  distinguishing_features:
  - Causal gene - HVDAS is caused by ADNP variants (specifically truncating variants for class II), not SMARCA2; sequencing resolves the two unambiguously.
  - Episignature does NOT discriminate - the shared episignature is phenotype-specific rather than gene-specific, so methylation testing alone cannot separate BIS from class II HVDAS and must be interpreted with the sequencing result.
  - Mechanistic basis of the overlap - ADNP interacts molecularly with the BAF complex of which SMARCA2 is the catalytic subunit, which is the proposed explanation for the convergent methylation profile.
  evidence:
  - reference: PMID:38884529
    reference_title: "Blepharophimosis with intellectual disability and Helsmoortel-Van Der Aa Syndrome share episignature and phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A distinct episignature was shared by 15 individuals with BIS-causing SMARCA2 pathogenic variants and 12 individuals with class II HVDAS caused by truncating pathogenic ADNP variants."
    explanation: >
      Establishes the shared episignature between BIS and class II HVDAS, which
      is what makes HVDAS a genuine epigenetic differential for BIS.
  - reference: PMID:38884529
    reference_title: "Blepharophimosis with intellectual disability and Helsmoortel-Van Der Aa Syndrome share episignature and phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals bearing variants within the bipartite nuclear localization (BNL) signal domain of ADNP present with the neurodevelopmental disorder known as Helsmoortel-Van Der Aa Syndrome (HVDAS)."
    explanation: Identifies ADNP as the causal gene of HVDAS, the discriminating feature.
- name: SMARCA2-variant carriers with a nonspecific dysmorphic phenotype
  description: >
    Not every individual with a rare SMARCA2 variant has BIS or NCBRS. In the
    founding cohort, six of twenty SMARCA2-variant carriers had only nonspecific
    dysmorphic features and could not be assigned to either syndrome even after
    functional, transcriptomic, and methylation analysis. Their variants remained
    unclassified. This group is a reminder that a rare SMARCA2 variant is not by
    itself a BIS diagnosis.
  distinguishing_features:
  - Absence of the recognizable BIS facial gestalt (blepharophimosis plus epicanthal folds plus downturned nasal tip).
  - Failure to match the BIS transcriptomic or DNA methylation signature.
  - Variant remains of uncertain significance after multimodal stratification.
  evidence:
  - reference: PMID:32694869
    reference_title: "De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the remaining six individuals with nonspecific dysmorphic features, clinical and molecular data did not permit variant reclassification."
    explanation: >
      Directly documents the unclassifiable subgroup and the limits of current
      SMARCA2 variant interpretation.
treatments:
- name: Genetic counseling
  action_category: COUNSELING_INFORMATIONAL
  description: >
    Counseling for an autosomal dominant condition in which all reported causal
    SMARCA2 variants have arisen de novo. Recurrence risk for siblings of a
    proband is correspondingly low, with the standard caveat that parental
    germline mosaicism cannot be excluded. Counseling should also cover the
    distinction from Nicolaides-Baraitser syndrome, since families may encounter
    NCBRS material when researching "SMARCA2".
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:32694869
    reference_title: "De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides-Baraitser syndrome."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "clustered de novo SMARCA2 variants outside the helicase domains"
    explanation: >
      Supports the de novo occurrence that determines the recurrence-risk content
      of counseling. PARTIAL because the cited paper reports the genetics, not a
      counseling recommendation; no BIS-specific management guideline exists.
animal_models:
- species: mouse (Mus musculus)
  genotype: Germline Brm (Smarca2) knockout
  category: Germline loss-of-function model
  genes:
  - preferred_term: SMARCA2
    term:
      id: hgnc:11098
      label: SMARCA2
  description: >
    The only long-established Smarca2 mouse model is a germline Brm knockout.
    It is explicitly NOT a model of BIS: homozygous null mice develop normally,
    apparently because BRG1 (SMARCA4) is upregulated and functionally substitutes
    for BRM. This is doubly informative — it argues against simple SMARCA2
    haploinsufficiency as the BIS mechanism, and it means a knockout cannot test
    the actual BIS lesion: deleting the gene removes the protein entirely, so a
    null model cannot report on a heterozygous de novo allele whose defining,
    directly evidenced property is WHERE in SMARCA2 it sits (clustered outside
    the helicase domains as the founding paper partitions them). No BIS hotspot
    knock-in mouse has been reported.
  associated_phenotypes:
  - Normal development in homozygous null mice
  - Increased adult body weight (approximately 15 percent over littermates)
  - Impaired G0/G1 cell-cycle arrest in mutant embryonic fibroblasts
  evidence:
  - reference: PMID:9843504
    reference_title: "Altered control of cellular proliferation in the absence of mammalian brahma (SNF2alpha)."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "BRM-/- mice develop normally, suggesting that an \nobserved up-regulation of the BRG1 protein can functionally replace BRM in the \nSWI-SNF complexes of mutant cells."
    explanation: >
      Documents both the normal phenotype of the Brm-null mouse and the proposed
      BRG1 compensation, which together explain why this model does not
      recapitulate a human SMARCA2 disorder.
  - reference: PMID:9843504
    reference_title: "Altered control of cellular proliferation in the absence of mammalian brahma (SNF2alpha)."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "mutant embryonic fibroblasts were significantly deficient in their ability to arrest in \nthe G0/G1 phase of the cell cycle in response to cell confluency or DNA damage."
    explanation: >
      The one reproducible cellular phenotype of Brm loss in this model. Recorded
      for completeness; its relevance to BIS neurodevelopment is unproven.
mechanistic_hypotheses:
- hypothesis_group_id: bis_interface_perturbation_vs_ncbrs_catalysis
  hypothesis_label: >-
    BIS alleles perturb BAF inter-subunit interfaces, whereas NCBRS alleles
    impair ATPase catalysis
  status: EMERGING
  description: >
    The leading explanatory model for why two allelic SMARCA2 disorders exist is
    that the two variant classes damage different properties of the same
    protein. NCBRS variants localize to ultra-conserved catalytic ATPase motifs
    and are proposed to impair ATPase activity while leaving complex assembly
    intact. BIS variants localize outside those motifs, and non-truncating
    mSWI/SNF neurodevelopmental variants in general concentrate at inter-subunit
    and nucleosome-engagement interfaces — suggesting that BIS is an
    assembly/engagement lesion rather than a catalytic one. Both classes act
    dominantly from heterozygous de novo variants. The argument against simple
    SMARCA2 haploinsufficiency deliberately does NOT rest on the BIS variant
    consequence class, which this entry does not assert (see genetic[].notes).
    It rests on two other observations: complete germline loss of mouse Brm
    yields a phenotypically normal animal through BRG1 compensation, so pure
    loss of SMARCA2 is buffered rather than pathogenic; and BIS individuals
    nevertheless carry a reproducible DNA methylation episignature — a positive,
    directional change in the chromatin output of the complex, not a silent
    dosage reduction.
  notes: >
    Status is EMERGING, not CANONICAL, deliberately. The NCBRS arm rests on the
    founding paper's own stated inference ("likely do not impair SWI/SNF complex
    assembly but may be associated with disrupted ATPase activity"), not on a
    direct assembly assay. The BIS arm rests on variant position plus a
    pan-mSWI/SNF structural analysis that did not assay BIS alleles, plus a yeast
    growth assay that shows only that the two classes differ. No biochemical
    measurement of BAF assembly, subunit engagement, or nucleosome remodeling has
    been published for any BIS allele.
  evidence:
  - reference: PMID:22366787
    reference_title: "Heterozygous missense mutations in SMARCA2 cause Nicolaides-Baraitser syndrome."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "These alterations likely do not impair \nSWI/SNF complex assembly but may be associated with disrupted ATPase activity."
    explanation: >
      The NCBRS arm of the hypothesis, stated by the authors as an inference
      ("likely", "may be") from variant position rather than from a direct assay
      — hence PARTIAL.
  - reference: PMID:37500730
    reference_title: "Landscape of mSWI/SNF chromatin remodeling complex perturbations in neurodevelopmental disorders."
    supports: PARTIAL
    evidence_source: COMPUTATIONAL
    snippet: "Non-truncating NDD-associated protein variants predominantly disrupt \nthe cBAF subcomplex and cluster in four key structural regions associated with \nhigh disease severity, including mSWI/SNF-nucleosome interfaces, the ATPase-core \nARID-armadillo repeat (ARM) module insertion site, the Arp module and \nDNA-binding domains."
    explanation: >
      The interface arm of the hypothesis: non-truncating mSWI/SNF NDD variants
      concentrate at structural interfaces. PARTIAL because this is an aggregate
      structural analysis across the complex, not a demonstration for BIS alleles.
  - reference: PMID:32694869
    reference_title: "De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides-Baraitser syndrome."
    supports: PARTIAL
    evidence_source: IN_VITRO
    snippet: "Yeast phenotype assays differentiated NCBRS from non-NCBRS SMARCA2 variants."
    explanation: >
      Functional support that the two allele classes are distinct, without
      identifying which property each one damages — the reason this hypothesis is
      EMERGING rather than CANONICAL.
discussions:
- discussion_id: gap_bis_smarca2_variant_mechanism
  kind: KNOWLEDGE_GAP
  prompt: >-
    What is the biochemical consequence of the BIS-class (non-helicase-domain)
    SMARCA2 variants, and is BIS a loss-of-function, gain-of-function, or
    dominant-negative disorder?
  rationale: >
    The BIS variant class is defined positionally (outside the helicase domains)
    and is known only to behave differently from NCBRS variants in a yeast growth
    assay. Whether these variants reduce ATPase-dependent remodeling, alter BAF
    complex assembly or genomic targeting, or perturb a non-catalytic regulatory
    function of SMARCA2 has not been established. Without this, the mechanism
    node in this entry can only be annotated as ABNORMAL rather than
    INCREASED/DECREASED, and no rational therapeutic target can be nominated.
  attaches_to:
  - pathophysiology#Non-Helicase-Domain SMARCA2 Variants Perturb the BAF Chromatin Remodeling Complex
  proposed_experiments:
  - experiment_id: exp_bis_baf_reconstitution
    name: Biochemical reconstitution of BIS-variant BAF complexes
    description: >-
      Reconstitute BAF complexes carrying BIS-class SMARCA2 variants and measure
      nucleosome remodeling and ATPase activity directly, in parallel with
      NCBRS-class variants and wild type.
  - experiment_id: exp_bis_baf_occupancy_chip
    name: Comparative BAF genomic occupancy in isogenic lines
    description: >-
      Perform ChIP-seq/CUT&RUN for BAF subunits in isogenic cell lines carrying
      BIS-class versus NCBRS-class SMARCA2 variants to test whether the BIS
      lesion alters genomic targeting rather than catalytic activity.
  - experiment_id: exp_bis_allele_series_organoid
    name: SMARCA2 allele-series modeling in human neural systems
    description: >-
      Model a SMARCA2 allele series (BIS variants, NCBRS variants, null) in human
      neural progenitors and cerebral organoids to test whether BIS variants
      phenocopy SMARCA2 knockout.
  evidence:
  - reference: PMID:32694869
    reference_title: "De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides-Baraitser syndrome."
    supports: PARTIAL
    evidence_source: IN_VITRO
    snippet: "Yeast phenotype assays differentiated NCBRS from non-NCBRS SMARCA2 variants."
    explanation: >
      Marks the current limit of functional knowledge: the only published
      functional discrimination of BIS-class SMARCA2 variants is a heterologous
      yeast growth phenotype, which establishes that they differ from NCBRS
      variants but not in which direction SMARCA2 function is altered. PARTIAL
      because it frames the gap rather than answering it.
- discussion_id: gap_bis_natural_history_and_management
  kind: KNOWLEDGE_GAP
  prompt: >-
    What is the natural history of BIS, and are there condition-specific
    surveillance or management recommendations?
  rationale: >
    BIS was delineated only in 2020 and has no GeneReviews chapter (searched:
    no GeneReviews article exists for BIS or for a SMARCA2 disorder other than
    the NCBRS chapter, PMID:26468571). Published data are cross-sectional
    dysmorphology and molecular analyses; there are no longitudinal outcome data,
    no reported adult outcomes, and no BIS-specific management or surveillance
    guideline. Management is therefore currently generic developmental-disability
    care, and this entry deliberately curates only genetic counseling rather than
    importing the NCBRS management plan.
  proposed_experiments:
  - experiment_id: exp_bis_natural_history_registry
    name: Prospective BIS natural-history registry
    description: >-
      Establish a prospective natural-history study or patient registry across
      the international BIS referral network, collecting uniform developmental,
      neurologic, ophthalmologic, and adult-outcome data.
  - experiment_id: exp_bis_ophthalmologic_assessment
    name: Systematic ophthalmologic assessment of BIS blepharophimosis
    description: >-
      Systematically assess visual axis obstruction, amblyopia risk, and surgical
      need in the blepharophimosis of BIS, to determine whether the eyelid
      surgery pathway used in other blepharophimosis syndromes applies here.
  evidence:
  - reference: PMID:38884529
    reference_title: "Blepharophimosis with intellectual disability and Helsmoortel-Van Der Aa Syndrome share episignature and phenotype."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Blepharophimosis with intellectual disability (BIS) is a recently recognized disorder"
    explanation: >
      Supports the premise of the gap: BIS was only recently delineated, which is
      why no longitudinal natural-history data or condition-specific management
      guideline yet exists. PARTIAL because it establishes the recency, not the
      absence of guidelines per se.
- discussion_id: mismatch_bis_smarca2_mouse_null
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Can any existing Smarca2 mouse model represent BIS, given that the germline
    Brm-null mouse develops normally through BRG1 compensation while BIS is
    caused by a heterozygous de novo allele clustered outside the helicase
    domains?
  rationale: >
    The available Smarca2 animal model is a germline knockout, and it does not
    reproduce a disease phenotype: Brm-null mice develop normally, apparently
    because BRG1 (SMARCA4) is upregulated and substitutes functionally. This is a
    genuine model/human mismatch rather than merely absent evidence. It matters in
    two directions. First, it is one of the strongest arguments that BIS is not
    caused by SMARCA2 haploinsufficiency, since removing the gene entirely in
    mouse produces nothing resembling the human disorder. Second, it means no
    existing in vivo system can test the actual BIS lesion, because a null allele
    cannot model a dominant, position-specific allele: complete deletion cannot
    report on a lesion whose only directly evidenced property is its location
    within SMARCA2. Nor does the null mouse produce the positive human readout
    of the BIS lesion, the DNA methylation episignature; whether a null allele
    could generate that signature has never been tested, which is itself part of
    the mismatch. (This entry does not assert the BIS variant consequence class;
    see genetic[].notes.) Any mouse-derived
    negative result about SMARCA2 loss must therefore not be read as evidence
    about BIS.
  attaches_to:
  - pathophysiology#Non-Helicase-Domain SMARCA2 Variants Perturb the BAF Chromatin Remodeling Complex
  proposed_experiments:
  - experiment_id: exp_bis_hotspot_knockin_mouse
    name: BIS hotspot knock-in mouse
    description: >-
      Generate heterozygous knock-in mice carrying a recurrent BIS hotspot allele
      (for example the Arg525 or Arg937 substitutions) rather than a null allele,
      and assess craniofacial morphogenesis, neurodevelopmental behaviour, and
      the blood methylation profile against the human episignature.
  - experiment_id: exp_bis_brg1_compensation_test
    name: Test BRG1 compensation in the presence of a BIS allele
    description: >-
      Determine whether SMARCA4/BRG1 upregulation can compensate for a BIS-class
      SMARCA2 allele as it does for a null allele, or whether the mutant BRM
      protein blocks compensation by occupying the complex.
  evidence:
  - reference: PMID:9843504
    reference_title: "Altered control of cellular proliferation in the absence of mammalian brahma (SNF2alpha)."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "BRM-/- mice develop normally, suggesting that an \nobserved up-regulation of the BRG1 protein can functionally replace BRM in the \nSWI-SNF complexes of mutant cells."
    explanation: >
      Directly documents the mismatch: complete loss of mouse Brm gives a normal
      animal, so this model cannot represent a dominant human SMARCA2 missense
      disorder, and BRG1 compensation is the proposed reason.
notes: >
  NEC (named entity confusion) guardrail for future curators: SMARCA2 causes TWO
  distinct disorders. This entry is BIS (OMIM:619293, MONDO:0859139). The other
  is Nicolaides-Baraitser syndrome (OMIM:601358, MONDO:0011053 — MONDO labels it
  "intellectual disability-sparse hair-brachydactyly syndrome"), which accounts
  for the large majority of published SMARCA2 clinical literature. Before adding
  any SMARCA2 evidence to this file, confirm the individuals described are BIS
  and not NCBRS.

  Worked NEC exclusions from this curation round — these SMARCA2 papers were read
  and deliberately NOT used as BIS evidence:
  PMID:40513420 (Seizure 2025, genotype-phenotype in epilepsy patients with
  SMARCA2 variants) reports that 77.3 percent of variants across its combined
  cohort lie in the SNF2-ATPase domain, i.e. the NCBRS allele class, so its
  epilepsy and antiseizure-medication data describe NCBRS-type disease, not BIS.
  PMID:38877377 (Prenat Diagn 2024, caudal regression with a de novo SMARCA2
  variant) is framed within the NCBRS spectrum. PMID:42528014, PMID:34906496,
  PMID:34706719 and PMID:38751117 are multi-gene BAFopathy or chromatin-remodeling
  cohort papers whose abstracts do not state which SMARCA2 disorder their patients
  have. (PMID:38751117 is cited once, but only for a residue-level paralog
  observation, with the BIS attribution flagged as inference — see the
  episignature pathophysiology node.) PMID:26468571 is the GeneReviews chapter for
  NCBRS and is not applicable here.

  Two general-biology papers that are NOT about BIS are cited on purpose, each
  clearly scoped: PMID:17640523 (npBAF/nBAF subunit switching in mouse neural
  progenitors) and PMID:9843504 (Brm-null mouse). Their evidence items are
  PARTIAL or explicitly labelled as background/model-mismatch, never as BIS
  clinical data. PMID:37500730 is a pan-mSWI/SNF structural analysis that does
  contain an explicit BIS-versus-NCBRS statement, quoted directly.

  Evidence-base limitation: both primary BIS papers are paywalled and are not in
  PMC or Europe PMC, so only their abstracts are cached and quotable. This caps
  the phenotype detail that can be evidenced here. The HPO annotation of
  OMIM:619293 (all sourced to PMID:32694869) records a much richer feature list
  with n/N counts drawn from the paper's full-text tables — including hypotonia,
  thin upper lip vermilion, sparse eyebrows and eyelashes, wide nasal bridge,
  tapered fingers, hypertelorism, frontal bossing, and flexion contractures —
  none of which can be quoted verbatim from the abstracts. Those features are
  deliberately NOT curated as phenotype entries rather than being asserted
  without evidence; they are the obvious enrichment target if full text becomes
  available.

  Orphanet (ORPHA:637013) also indexes this disorder and would supply
  frequency-banded HPO annotations, but the pinned Orphadata snapshot in
  data/orphadata/MANIFEST.yaml no longer matches the upstream files (checksum
  mismatch on download), and bumping that manifest is out of scope for a
  single-disorder PR. No ORPHA evidence is therefore cited. A ClinGen
  gene-disease validity or dosage record for SMARCA2 is likewise not cited: no
  SMARCA2 record exists in this repository's ClinGen cache, and refreshing it
  would require touching data/clingen*/MANIFEST.yaml.

  No GeneReviews chapter exists for BIS. This was checked with three PubMed
  queries (blepharophimosis GeneReviews, SMARCA2 GeneReviews,
  Nicolaides-Baraitser GeneReviews); the only SMARCA2 chapter returned is
  PMID:26468571, "SMARCA2-Related Nicolaides-Baraitser Syndrome", which is the
  other disorder and is therefore not used as a phenotype baseline here.

  INVERSE-PHARMACOLOGY GUARDRAIL — SMARCA2-lowering oncology drugs are NOT a BIS
  therapy and must never be curated as one. A live clinical drug class targets
  SMARCA2 (BRM) for REMOVAL, as a synthetic-lethal strategy in SMARCA4
  (BRG1)-deficient cancers. Verified against ClinicalTrials.gov on 2026-08-01:
  the SMARCA2 degraders PRT7732 (NCT06560645, terminated), PRT3789 (NCT05639751,
  completed; and PRT3789 plus pembrolizumab, NCT06682806, terminated) and
  PLX-61639 (NCT07284186, recruiting, officially titled a first-in-human study
  of "the SMARCA2 Degrader, PLX-61639"), together with the selective SMARCA2/BRM
  INHIBITOR LY4050784 (NCT06561685, recruiting). Note that LY4050784 is an
  inhibitor rather than a degrader; both modalities reduce SMARCA2 function and
  both are therefore inverse to a SMARCA2-opathy. BIS is caused by a
  heterozygous de novo SMARCA2 variant, so lowering SMARCA2 dose or activity
  further is the opposite of therapeutic intent. The trial protocols themselves
  point the same way: NCT07284186 excludes participants with "Known SMARCA2
  mutation or loss of expression", and NCT06561685 excludes participants with
  known or likely SMARCA2 loss-of-function alteration. None of these agents is
  curated as a BIS treatment and none should be. An automated pipeline mining
  "SMARCA2 + drug" or "SMARCA2 + NCT" will surface this entire class; it must be
  filtered out of BIS treatment curation. Recorded per the deep-research
  report's explicit critical-negative instruction (section 12.3).
references:
- reference: PMID:32694869
  title: "De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides-Baraitser syndrome."
- reference: PMID:38884529
  title: "Blepharophimosis with intellectual disability and Helsmoortel-Van Der Aa Syndrome share episignature and phenotype."
- reference: PMID:37500730
  title: "Landscape of mSWI/SNF chromatin remodeling complex perturbations in neurodevelopmental disorders."
- reference: PMID:22366787
  title: "Heterozygous missense mutations in SMARCA2 cause Nicolaides-Baraitser syndrome."
- reference: PMID:38751117
  title: "DNA methylation analysis in patients with neurodevelopmental disorders improves variant interpretation and reveals complexity."
- reference: PMID:17640523
  title: "An essential switch in subunit composition of a chromatin remodeling complex during neural development."
- reference: PMID:9843504
  title: "Altered control of cellular proliferation in the absence of mammalian brahma (SNF2alpha)."
📚

References & Deep Research

References

7
PMID:32694869
De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides-Baraitser syndrome.
No top-level findings curated for this source.
PMID:38884529
Blepharophimosis with intellectual disability and Helsmoortel-Van Der Aa Syndrome share episignature and phenotype.
No top-level findings curated for this source.
PMID:37500730
Landscape of mSWI/SNF chromatin remodeling complex perturbations in neurodevelopmental disorders.
No top-level findings curated for this source.
PMID:22366787
Heterozygous missense mutations in SMARCA2 cause Nicolaides-Baraitser syndrome.
No top-level findings curated for this source.
PMID:38751117
DNA methylation analysis in patients with neurodevelopmental disorders improves variant interpretation and reveals complexity.
No top-level findings curated for this source.
PMID:17640523
An essential switch in subunit composition of a chromatin remodeling complex during neural development.
No top-level findings curated for this source.
PMID:9843504
Altered control of cellular proliferation in the absence of mammalian brahma (SNF2alpha).
No top-level findings curated for this source.

Deep Research

1
Claude Code ▸
Blepharophimosis‑Impaired Intellectual Development Syndrome (BIS) — Comprehensive Research Report
claude-haiku-4-5-20251001, claude-opus-5[1m] 23 citations 2026-08-01T09:54:21.897148

Blepharophimosis‑Impaired Intellectual Development Syndrome (BIS) — Comprehensive Research Report

Prepared: 2026‑08‑01 · Target entity: MONDO:0859139 · Gene: SMARCA2 (hgnc:11098) · Category: Mendelian, autosomal dominant, ultra‑rare

Verification note for curators. Quotes marked [V] were confirmed character‑for‑character against a cached PubMed abstract (references_cache/PMID_32694869.md, references_cache/PMID_38884529.md), against the open‑access Sarli et al. 2024 PDF read directly, or against a verbatim E‑utilities abstract fetch. Quotes marked [V?] were returned by a fetch layer that may have normalized whitespace — re‑run just fetch-reference and just validate-references before committing them as evidence snippet: values. Statements with no quote are attributed but not quotable.

NEC (Named Entity Confusion) preflight — this disease is HIGH RISK. "Blepharophimosis–intellectual disability syndrome" is a family of mechanistically unrelated MONDO entities: MONDO:0017393 (generic), MONDO:0011365 SBBYS type (KAT6B), MONDO:0010477 MKB type (MASP1), MONDO:0009583 Ohdo type, MONDO:0011432 Verloes type, MONDO:0979360 ADNP‑related, and MONDO:0859139 — the SMARCA2 entity that is the subject of this report. Any deep‑research output for this disease must be gene‑checked (SMARCA2) and OMIM‑checked (619293) before use. The MONDO↔OMIM↔ORPHA identity triple was confirmed in this session (see §1).

1. Disease Information

1.1 Overview

Blepharophimosis‑impaired intellectual development syndrome (BIS) is a congenital, recognizable neurodevelopmental/malformation syndrome defined in 2020 by Cappuccio et al. It is caused by de novo, non‑truncating (missense) heterozygous variants in SMARCA2 that cluster outside the ATPase/helicase domains, and it is clinically and molecularly distinct from the other SMARCA2 disorder, Nicolaides‑Baraitser syndrome (NCBRS, OMIM 601358), whose variants sit inside the ATPase domain.

[V] "Of 20 individuals, 14 showed a recognizable phenotype with recurrent features including epicanthal folds, blepharophimosis, and downturned nasal tip along with variable degree of intellectual disability (or blepharophimosis intellectual disability syndrome [BIS])." — Cappuccio et al., Genet Med 2020 (PMID:32694869; DOI 10.1038/s41436-020-0898-y)

[V] "We identified a novel recognizable syndrome named BIS associated with clustered de novo SMARCA2 variants outside the helicase domains, phenotypically and molecularly distinct from NCBRS." — PMID:32694869

[V] "Blepharophimosis with intellectual disability (BIS) is a recently recognized disorder distinct from Nicolaides-Baraister syndrome that presents with distinct facial features of blepharophimosis, developmental delay, and intellectual disability." — Sarli et al., Am J Med Genet C 2024 (PMID:38884529; DOI 10.1002/ajmg.c.32089)

The cardinal triad is blepharophimosis + epicanthus + developmental delay/intellectual disability, each present in 14/14 (100%) of the founding cohort, with a downturned/short nose, sparse eyebrows and eyelashes, thin upper lip vermilion, and broad nasal bridge completing a recognizable gestalt.

1.2 Identifiers

Resource Identifier Notes
MONDO MONDO:0859139 label: blepharophimosis-impaired intellectual development syndrome; synonym SMARCA2-related blepharophimosis-intellectual disability syndrome (verified via OLS4)
OMIM (phenotype) #619293 BLEPHAROPHIMOSIS‑IMPAIRED INTELLECTUAL DEVELOPMENT SYNDROME; BIS
OMIM (gene) 600014 SMARCA2
Orphanet ORPHA:637013 preferred term "SMARCA2-related blepharophimosis-intellectual disability syndrome"; disorder type malformation syndrome (Orphadata rd-cross-referencing API)
ICD‑10 Q87.0 via Orphanet, mapping type NTBT (ORPHA narrower than ICD code) — "Congenital malformation syndromes predominantly affecting facial appearance"
ICD‑11 not asserted in the retrieved Orphanet record gap
UMLS C5443984 (MONDO xref) and C5816784 (Orphanet xref) two CUIs map to this entity — flag for mapping curation
MedGen 1779966 concept C5443984
MeSH no dedicated descriptor indexed under Blepharophimosis, Intellectual Disability, Transcription Factors
Gene SMARCA2, hgnc:11098, Entrez 6595, Ensembl ENSG00000080503, UniProt P51531, RefSeq NM_003070, locus 9p24.3 (HGNC REST, verified)

1.3 Synonyms

  • BIS
  • Blepharophimosis with intellectual disability
  • Blepharophimosis intellectual disability syndrome
  • SMARCA2‑related blepharophimosis‑intellectual disability syndrome
  • Blepharophimosis‑impaired intellectual development syndrome

Do not use the bare string "blepharophimosis‑intellectual disability syndrome" as an unqualified synonym — it collides with ≥5 other MONDO entities (see NEC warning).

1.4 Provenance of information

All information is disease‑level aggregated (case series + ontology/database aggregation). There is no EHR‑derived or registry‑derived cohort for BIS. The evidence base is essentially two publications plus database curation:

  1. Cappuccio et al. 2020 (PMID:32694869) — 20 individuals/18 families ascertained by NGS; 14 with the BIS gestalt. This is the source of the OMIM clinical synopsis and of essentially all HPO annotations.
  2. Sarli et al. 2024 (PMID:38884529) — 15 individuals with BIS‑causing SMARCA2 variants (10 previously reported), 12 with class II ADNP HVDAS; episignature study.

[V] "The 15 individuals with de novo missense SMARCA2 variants all had the BIS phenotype and 10 of them were previously described (Cappuccio et al., 2020)." — Sarli et al. 2024, Results

Cumulative published BIS individuals as of mid‑2026: ≈19–20 (14 + 5 new in Sarli), plus 4 individuals labelled "BIS_atypical". This is a genuinely ultra‑rare, thinly reported entity.

2. Etiology

2.1 Primary cause

BIS is a monogenic, de novo dominant disorder. The cause is a heterozygous non‑truncating (missense) germline variant in SMARCA2, arising de novo in all reported cases.

[V] "In contrast to most NCBRS variants, all SMARCA2 variants associated with BIS are localized outside the helicase domains." — PMID:32694869

There is no known environmental, infectious, or multifactorial contribution. No teratogen, exposure, or maternal factor has been implicated.

2.2 Genetic risk factors

  • Causal: de novo missense SMARCA2 variants in two hotspot regions (see §4).
  • Susceptibility loci: none identified. No GWAS applies (ultra‑rare Mendelian).
  • Modifier genes: none identified. Phenotypic variability (e.g., ambulation, speech, seizures) is unexplained; the founding cohort is too small to detect modifiers. Explicit knowledge gap.
  • Recurrent alleles — the strongest genotype signal is recurrence of the same amino acid changes in unrelated probands, which is itself evidence of mutational hotspots at functionally constrained residues (Arg525, Arg937, Leu529, Gly513 — §4).

2.3 Environmental risk factors

None known. Advanced paternal age is a generic risk factor for de novo missense variants across NDDs and is biologically plausible here, but has not been specifically studied in BIS — do not curate it as a BIS risk factor without a BIS‑specific citation.

2.4 Protective factors

None known, genetic or environmental. Not applicable to a de novo dominant developmental disorder.

2.5 Gene–environment interactions

None reported. Not applicable.

3. Phenotypes

3.1 Frequency table — HPO annotations derived from OMIM:619293

Retrieved from the HPO/Monarch annotation API (ontology.jax.org/api/network/annotation/OMIM:619293). Denominators reflect Cappuccio's 14 BIS individuals (some features scored in subsets). These n/N fractions are the single best source for dismech frequency: bands, and each fraction is itself the quantitative justification the frequency‑evidence SOP requires.

Cardinal / obligate features (100%)

HPO Term Fraction Suggested band
HP:0000581 Blepharophimosis 14/14 OBLIGATE / VERY_FREQUENT
HP:0000286 Epicanthus 14/14 OBLIGATE / VERY_FREQUENT
HP:0001263 Global developmental delay 14/14 OBLIGATE / VERY_FREQUENT
HP:0001249 Intellectual disability 14/14 OBLIGATE / VERY_FREQUENT

Craniofacial (the recognizable gestalt)

HPO Term Fraction %
HP:0000219 Thin upper lip vermilion 12/14 86
HP:0000653 Sparse eyelashes 11/14 79
HP:0045075 Sparse eyebrow 11/14 79
HP:0000431 Wide nasal bridge 10/14 71
HP:0045025 Narrow palpebral fissure 10/14 71
HP:0002553 Highly arched eyebrow 10/14 71
HP:0002263 Exaggerated cupid's bow 8/14 57
HP:0002007 Frontal bossing 7/14 50
HP:0000430 Underdeveloped nasal alae 7/14 50
HP:0010751 Dimple chin 6/14 43
HP:0012368 Flat face 5/14 36
HP:0000664 Synophrys 4/14 29
HP:0000322 Short philtrum 4/14 29
HP:0000418 Narrow nasal ridge 4/14 29
HP:0000445 Wide nose 4/14 29
HP:0002209 Sparse scalp hair 4/14 29
HP:0000463 Anteverted nares 3/14 21
HP:0000294 Low anterior hairline 3/13 23
HP:0001357 Plagiocephaly 3/14 21
HP:0000154 Wide mouth 2/14 14
HP:0000527 Long eyelashes 2/14 14
HP:0002307 Drooling 2/14 14
HP:0000574 Thick eyebrow 1/14 7

Curation note: sparse scalp hair is present in only 4/14 (29%) of BIS but ~97% of NCBRS — this is one of the two most discriminating features between the allelic disorders (the other being blepharophimosis, absent in NCBRS).

Nervous system / neurodevelopment

HPO Term Fraction %
HP:0031936 Delayed ability to walk 10/14 71
HP:0000750 Delayed speech and language development 9/13 69
HP:0001252 Hypotonia 9/12 75
HP:0001250 Seizure 3/14 21
HP:0000744 Low frustration tolerance 2/13 15
HP:0033725 Thin corpus callosum 1/14 7
HP:0012110 Hypoplasia of the pons 1/14 7
HP:0002308 Chiari malformation 1/9 11
HP:0000729 Autistic behavior 1/13 8
HP:0007018 Attention deficit hyperactivity disorder 1/13 8
HP:0000733 Motor stereotypy 1/13 8
HP:0100025 Overfriendliness 1/13 8

Eye / vision

HPO Term Fraction %
HP:0000316 Hypertelorism 8/14 57
HP:0000508 Ptosis 2/14 14

Sarli Table 2 (BIS column, sourced from Cappuccio 2020) additionally records vision issue 64%, myopia/hypermetropia 42%, strabismus 14%. OMIM's clinical synopsis lists astigmatism, hyperopia, esotropia, myopia, and cortical visual impairment. HPO terms to consider: HP:0000545 Myopia, HP:0000540 Hypermetropia, HP:0000486 Strabismus, HP:0000642 Astigmatism, HP:0100704 Cerebral visual impairment (verify each with OAK before use — not verified in this session).

Limbs, skeleton, connective tissue

HPO Term Fraction %
HP:0001182 Tapered finger 8/14 57
HP:0001371 Flexion contracture 6/14 43
HP:0001763 Pes planus 4/13 31
HP:0010624 Aplastic/hypoplastic toenail 4/11 36
HP:0002650 Scoliosis 3/12 25
HP:0001382 Joint hypermobility 3/12 25
HP:0001762 Talipes equinovarus 2/14 14
HP:0009882 Short distal phalanx of finger 2/12 17
HP:0004209 Clinodactyly of the 5th finger 2/14 14
HP:0001385 Hip dysplasia 2/14 14
HP:0002750 Delayed skeletal maturation 1/6 17

Contrast with NCBRS: prominent interphalangeal joints (84% in NCBRS) is not a BIS feature; BIS limb findings are contractures, tapering fingers, and foot deformity.

Growth (from Sarli Table 2, BIS column, "From Cappuccio et al. 2020")

Feature BIS %
Microcephaly 43
Low birth weight 36
Short birth length 29
Short stature (≤2 SD) 25
Macrocephaly – (not seen)

HPO terms: HP:0000252 Microcephaly, HP:0001518 Small for gestational age, HP:0004322 Short stature (verify with OAK).

Other systems

HPO Term Fraction %
HP:0002020 Gastroesophageal reflux 4/13 31
HP:0011968 Feeding difficulties 2/13 15
HP:0000028 Cryptorchidism 3/7 males 43
HP:0000047 Hypospadias 1/7 males 14
HP:0000010 Recurrent urinary tract infections 1/13 8
HP:0000066 Labial hypoplasia 1/5 females 20
HP:0000805 Enuresis 1/14 7
HP:0002837 Recurrent bronchitis 3/14 21
HP:0006532 Recurrent pneumonia 1/14 7
HP:0001643 Patent ductus arteriosus 1/13 8
HP:0000369 Low-set ears 2/14 14
HP:0000358 Posteriorly rotated ears 1/14 7
HP:0006297 Enamel hypoplasia 1/12 8
HP:0000689 Dental malocclusion 1/12 8
HP:0000691 Microdontia 1/12 8

Sarli Table 2 records GI/feeding issues 46%, abnormal ears 64%, hearing loss 0% (a useful negative — HPO "EXCLUDED" candidate for HP:0000365 Hearing impairment), brain abnormalities ~40%.

3.2 Phenotype characteristics

  • Type mix: predominantly congenital physical/dysmorphic manifestations (craniofacial, ocular adnexal, limb) plus neurodevelopmental/behavioral features. No BIS‑specific laboratory abnormality exists — there is no biochemical marker. The only laboratory‑style biomarker is the peripheral‑blood DNA methylation episignature (§6, §10).
  • Onset: congenital for the facial gestalt and structural anomalies; developmental delay evident in infancy. HPO onset term: HP:0003577 Congenital onset (verify).
  • Severity: variable — ID ranges from mild to severe; 35% never develop speech ("absent speech", Sarli Table 2), 30% do not achieve independent walking (inferred from 70% "delayed walking" plus OMIM's "sometimes with inability to walk").
  • Progression: non‑progressive / static developmental disorder. Unlike NCBRS, there is no report of progressive facial coarsening (coarse face only 17% in BIS vs ~80% in NCBRS) and no neurodegeneration. Seizures, when present, are not described as intractable in BIS. Musculoskeletal features (contractures, scoliosis) may progress mechanically with growth.
  • Episodic elements: seizures (21%) and recurrent respiratory infections (~21–50%) are the episodic components.

3.3 Quality‑of‑life impact

No BIS‑specific QoL instrument data exist (no EQ‑5D, SF‑36, PROMIS, or disease‑specific PRO study). Explicit gap. Inferred per‑phenotype impact:

Phenotype QoL domain affected
Intellectual disability / absent speech (35%) communication, independence, education, lifelong care needs — dominant driver
Delayed/absent ambulation (~30% non‑ambulant) mobility, self‑care
Blepharophimosis + ptosis + narrow fissures visual field (if severe), social/facial recognition, potential amblyopia risk
Vision issues (64%) learning, mobility
Feeding difficulties / GERD (46%) nutrition, aspiration risk, caregiver burden
Behavioral problems (65%) family/school functioning
Contractures, scoliosis, foot deformity mobility, pain, orthopedic burden
Seizures (21%) safety, medication burden

4. Genetic / Molecular Information

4.1 Causal gene

SMARCA2 (hgnc:11098; "SWI/SNF related BAF chromatin remodeling complex subunit ATPase 2"; aliases BRM, SNF2L2, hSNF2a, BAF190) at 9p24.3, 34 exons, RefSeq NM_003070.3, protein P51531, 1,590 aa. OMIM gene 600014.

SMARCA2 is one of the two mutually exclusive catalytic ATPase subunits of the mammalian SWI/SNF (mSWI/SNF, BAF) complex; the paralog is SMARCA4 (BRG1).

[V] "Nontruncating variants in SMARCA2, encoding a catalytic subunit of SWI/SNF chromatin remodeling complex, cause Nicolaides-Baraitser syndrome (NCBRS), a condition with intellectual disability and multiple congenital anomalies." — PMID:32694869

[V] "BIS is caused by pathogenic variants in SMARCA2, that encodes the catalytic subunit of the superfamily II helicase group of the BRG1 and BRM-associated factors (BAF) forming the BAF complex, a chromatin remodeling complex involved in transcriptional regulation." — PMID:38884529

4.2 Protein architecture (UniProt P51531, verified this session)

Domain Residues
QLQ 173–208
HSA (helicase/SANT‑associated; binds the actin‑related protein "Arp" module: ACTL6A/ACTB) 436–508
Helicase ATP‑binding (DExx, RecA‑like lobe 1) 736–901
Helicase C‑terminal (RecA‑like lobe 2) 1054–1216
Bromodomain 1378–1506

4.3 The two BIS variant clusters

Per OMIM 619293's molecular genetics narrative: the BIS mutations "clustered in 2 regions located outside of the catalytic ATPase helicase domains. Some occurred in exons 8 or 9, corresponding to a region between the HSA and helicase ATP-binding domain, whereas others occurred in exon 19, mapping to the linker region located between the DExx helicase ATP-binding and helicase C-terminal domains." [V?]

Mechanistic interpretation:

[V] "BIS-causing variants were found to cluster around an alpha-helix domain, that defines an interaction surface with other subunits of the BAF complex." — Sarli et al. 2024, Introduction

4.4 Reported BIS variants (NM_003070.3 / P51531)

From Sarli et al. 2024 Table 1 (read directly from the open‑access PDF; ACMG codes as published). This is the most complete public variant list for BIS.

Protein change cDNA Cases Region ACMG codes (as published)
p.(Glu512Lys) c.1534G>A 1 post‑HSA cluster PS2, PS3, PM1, PP2, PM2, PM5
p.(Gly513Val) c.1538G>T 1 post‑HSA cluster PS2, PS3, PM1, PP2, PM2, PM5
p.(Arg525Cys) c.1573C>T 2 post‑HSA cluster PS2, PS3, PM1, PP2, PM2, PM5
p.(Arg525His) c.1574G>A 1 post‑HSA cluster PS2, PS3, PM1, PP2, PM2, PM5
p.(Leu529Val) c.1585G>C 2 (+1 validation) post‑HSA cluster PS2, PM1, PP2, PP3, PM2 (case 13)
p.(Met856Val) c.2566A>G 1 ATPase lobe 1 / linker cluster PS2, PS3, PM1, PP2, PM2, PM5
p.(Arg937Cys) c.2809C>T 3 lobe1–lobe2 linker PS2, PM1, PP2, PP3, PM2, PM5
p.(Arg937His) c.2810G>A 3 lobe1–lobe2 linker PS2, PM1, PP2, PP3, PM2, PM5
p.(Asp510Gly) c.6286C>A (as printed) 1 (validation) post‑HSA cluster NA
p.(Leu766Val) c.2296C>G 3 ATPase lobe 1 NA — labelled "BIS_atypical"
p.(Asn486Lys) c.1458C>A 1 HSA domain NA — labelled "BIS_atypical"

Two curation cautions:

  1. The p.(Asp510Gly) row's cDNA notation (c.6286C>A) is internally inconsistent with the protein change and with the 4,773‑nt CDS implied by a 1,590‑aa protein. Treat the cDNA as a probable typographical error in the published table; cite the protein change only, or omit.
  2. p.(Met856Val) and p.(Leu766Val) fall inside UniProt's annotated helicase ATP‑binding domain (736–901), which is in tension with the paper's blanket statement that BIS variants are "outside the helicase domains." The discrepancy is a domain‑boundary definitional difference (the authors' "helicase domains" correspond to the ultra‑conserved catalytic motifs, not the full InterPro/UniProt DExx span). Curate the "outside the helicase domain" claim as the authors' framing, and do not assert that residue 856 lies outside UniProt's DExx domain. This is a legitimate, citable nuance — and it is precisely why p.(Leu766Val) is classified "atypical."

Hotspot summary: two clusters — ~486–534 (HSA C‑terminus / post‑HSA α‑helix, exons 8–9) and ~766–937 (ATPase lobe 1 and the lobe1–lobe2 linker, exon 19). Arg525 and Arg937 are recurrent, multi‑allelic hotspot residues (Arg→Cys and Arg→His at both), a classic signature of a constrained protein–protein interaction surface.

4.5 ClinVar landscape

ClinVar (db=clinvar, SMARCA2[gene] AND "blepharophimosis-impaired intellectual development syndrome"[dis]) returns 46 records. Selected germline classifications:

Variant Classification Submitted condition
c.1574G>A p.(Arg525His) Pathogenic/Likely pathogenic BIS
c.1601A>G p.(Asp534Gly) Likely pathogenic BIS
c.1390G>A p.(Glu464Lys) Likely pathogenic BIS
c.2870A>G p.(Gln957Arg) Likely pathogenic BIS
c.1874C>T p.(Pro625Leu) Likely pathogenic BIS
c.4466A>G p.(Tyr1489Cys) Likely pathogenic BIS
c.1537G>A p.(Gly513Ser) Conflicting BIS
c.1541A>G p.(Tyr514Cys) Conflicting BIS
c.2296C>G p.(Leu766Val) Uncertain significance BIS
c.1259G>T p.(Arg420Leu) Uncertain significance BIS
c.31C>T p.(Pro11Ser) Benign/Likely benign BIS
whole‑gene‑spanning deletion c.(-37+1_-36-1)_(3981+1_3982-1)del Likely pathogenic BIS

Critical interpretation caveat: the ClinVar "condition" field is submitter‑assigned, so any SMARCA2 variant submitted under the BIS condition label appears here — including benign variants and a multi‑exon deletion whose mechanism (haploinsufficiency) is inconsistent with the published BIS missense/hotspot model. Do not treat ClinVar condition labels as evidence that these variants cause BIS. Only p.(Arg525His), p.(Arg525Cys), p.(Glu512Lys), p.(Gly513Val), p.(Leu529Val), p.(Met856Val), p.(Arg937Cys/His) are literature‑anchored BIS alleles. Variants such as p.(Glu464Lys), p.(Asp534Gly), p.(Gln957Arg), p.(Pro625Leu), and p.(Tyr1489Cys) represent a plausible but unpublished phenotypic/allelic expansion — worth flagging as a KNOWLEDGE_GAP discussion, not as curated genetics.

4.6 Population allele frequency

All reported BIS alleles are absent from population databases (gnomAD/1000G/ExAC), consistent with ACMG PM2 applied throughout Sarli Table 1. I was unable to retrieve gnomAD constraint metrics (pLI/LOEUF/missense Z) in this session — the gnomAD GraphQL endpoint is not reachable via plain GET. Do not curate numeric constraint values from memory. Fetch them separately if needed.

4.7 Somatic vs germline

Germline, de novo. Not a somatic/cancer mechanism in BIS. Note for disambiguation: SMARCA2 is heavily studied in oncology as a synthetic‑lethal target in SMARCA4‑deficient cancers (PROTAC degraders — PMIDs 36357397, 36216795, 38557192, 39378885). That is mechanistically inverse to BIS and must not be conflated with BIS treatment (§12).

4.8 Functional consequence — loss of function, dominant negative, or gain of function?

The mechanism is not simple haploinsufficiency. Convergent lines of evidence:

  1. ClinGen dosage sensitivity curation (SMARCA2, CCID:007899, last evaluated 2013‑03‑27): haploinsufficiency score 0 ("No Evidence for Haploinsufficiency"); triplosensitivity score 0. The curation notes that in the NCBRS/CSS papers "in neither paper is evidence provided for a loss of function effect of the mutation" [V?], that authors invoked a "gain of function effect of the mutant protein" [V?], that patients with 9p deletions overlapping SMARCA2 did not present with the NCBRS phenotype, and that SMARCA2 knockout mice are "viable and fertile."
  2. All disease alleles are non‑truncating. Truncating SMARCA2 variants are not the established mechanism for either allelic disorder.
  3. For NCBRS, the founding paper explicitly separates assembly from catalysis: [V] "The mutations cluster within sequences that encode ultra-conserved motifs in the catalytic ATPase region of the protein. These alterations likely do not impair SWI/SNF complex assembly but may be associated with disrupted ATPase activity." — Van Houdt et al., Nat Genet 2012 (PMID:22366787)
  4. For BIS, the variant location implies the complementary defect: not catalysis but complex interface integrity — the residues sit on an α‑helix forming an interaction surface with other BAF subunits (Sarli 2024, quoted above). Cappuccio's yeast assay result supports a distinct functional class: [V] "Yeast phenotype assays differentiated NCBRS from non-NCBRS SMARCA2 variants."

Best current model: BIS alleles are hypomorphic/dominant‑interfering variants that perturb BAF module assembly or subunit engagement, whereas NCBRS alleles are ATPase‑catalysis‑impairing variants. Both are incorporated into complexes (hence dominant, non‑haploinsufficient behavior). Direct biochemical proof for the BIS class — complex co‑IP, nucleosome remodeling assays, ATAC‑seq in patient‑relevant cells — has not been published. This is the single largest mechanistic gap and is a strong candidate for a KNOWLEDGE_GAP discussion entry.

4.9 Modifier genes

None identified.

4.10 Epigenetic information

This is BIS's most distinctive molecular dimension, and unusually strong for so rare a disorder.

  • BIS has its own peripheral‑blood DNA methylation episignature, distinguishable from NCBRS: [V] "Transcriptomic and DNA methylation signatures differentiated NCBRS from BIS and those with nonspecific phenotype." (PMID:32694869)
  • BIS is a clinically available EpiSign™ episignature disorder — the London Health Sciences Centre/EpiSign conditions list includes the row "Blepharophimosis-impaired intellectual development syndrome (BIS) — SMARCA2 (619293)" under "Episignature Disorders", separately from "Nicolaides-Baraitser syndrome (NCBRS) — SMARCA2 (601358)" and "Helsmoortel-van der Aa syndrome (HVDAS) — ADNP (615873)." (verified by reading the EpiSign Conditions List PDF, June 2024 revision)
  • BIS shares a phenotype‑specific episignature with class II HVDAS: [V] "A distinct episignature was shared by 15 individuals with BIS-causing SMARCA2 pathogenic variants and 12 individuals with class II HVDAS caused by truncating pathogenic ADNP variants." — PMID:38884529
  • [V] "This represents first evidence of a sensitive phenotype-specific episignature biomarker shared across distinct genetic conditions that also exhibit unique gene-specific episignatures." — PMID:38884529
  • Technical parameters (Sarli 2024, read from PDF): Illumina EPIC array; 31 individuals total (16 F/15 M); discovery n=23, validation n=4, non‑NCBRS‑non‑BIS n=4; 772,557 probes after filtering; 200 DMPs in initial selection, refined to a final set of 239 differentially methylated CpG probes; SVM classifier with MVP scores ~1 for cases; robustness by 20 rounds of leave‑25%‑out cross‑validation; the BIS‑HVDAS profile is relatively hypomethylated; highest DMP overlap with the HVDAS_C (ADNP central) cohort at 26%; of 4 "BIS_atypical" samples only 1 (case 31, p.Asn486Lys) clustered with the BIS‑HVDAS positives.
  • Paralog convergence at the methylation level: an independent cohort found "common episignatures affecting homologous residues in highly conserved paralogous proteins (SMARCA2 M856V and SMARCA4 M866V)" [V] — Levy/Ciaccio et al., HGG Adv 2024 (PMID:38751117). This is direct evidence that the BIS Met856 allele and its SMARCA4 paralogous counterpart converge on one epigenomic consequence — excellent support for a shared‑mechanism pathophysiology node.

4.11 Chromosomal abnormalities

Not a mechanism for BIS. Distinguish carefully from 9p24.3/9p deletion syndromes, which delete SMARCA2 among many genes and produce a different phenotype (see PMIDs 41137173, 40196253, 41995485, 40836298 for contemporary 9p deletion cohorts). This distinction is itself the key argument against haploinsufficiency (§4.8).

5. Environmental Information

  • Environmental factors: none known. No toxicant, radiation, pollutant, or occupational exposure implicated.
  • Lifestyle factors: none. Not applicable to a de novo germline dominant disorder.
  • Infectious agents: none causal. Recurrent bronchitis (21%) and pneumonia (7%) are secondary complications — plausibly related to hypotonia, GERD, and aspiration — not etiologic agents.

Section 5 is genuinely "not applicable" for BIS. Do not populate speculative environmental content.

6. Mechanism / Pathophysiology

6.1 Causal chain (proposed pathograph for dismech)

[MOLECULAR] De novo missense SMARCA2 variant in one of two hotspot clusters
    (HSA-adjacent α-helix ~486–534; ATPase lobe1/linker ~766–937)
    │
    ▼
[MOLECULAR] Altered SMARCA2 interaction surface with partner BAF subunits
    (α-helix at the inter-subunit interface; HSA-proximal Arp-module contact)
    → perturbed BAF (mSWI/SNF) complex assembly / subunit engagement,
      WITHOUT haploinsufficiency and WITHOUT the catalytic-motif lesion of NCBRS
    │
    ▼
[MOLECULAR] Impaired ATP-dependent nucleosome remodeling by BRM-containing BAF
    (GO:0140658 ATP-dependent chromatin remodeler activity ↓/ABNORMAL;
     GO:0006338 chromatin remodeling ABNORMAL)
    │
    ▼
[MOLECULAR] Altered chromatin accessibility at BAF-dependent enhancers/promoters
    → BIS-specific transcriptomic signature AND BIS-specific
      genome-wide DNA methylation episignature in peripheral blood
    │
    ▼
[CELLULAR]  Dysregulated BAF-dependent transcriptional programs in neural
    progenitors and differentiating neurons (npBAF→nBAF subunit switching;
    GO:0071564 npBAF complex)
    │
    ▼
[TISSUE]    Abnormal CNS development (thin corpus callosum, pontine hypoplasia,
    Chiari malformation in a minority; ~40% any brain abnormality)
    AND abnormal craniofacial / periocular morphogenesis
    (blepharophimosis, epicanthus, narrow palpebral fissures, nasal shape)
    │
    ▼
[ORGANISM]  Global developmental delay, intellectual disability, hypotonia,
    delayed/absent speech and ambulation, behavioral phenotype,
    recognizable facial gestalt, contractures/foot deformity,
    feeding difficulties/GERD, seizures (21%)

Convergent parallel arm (shared final common pathway, well supported):

Truncating ADNP variant in the bipartite nuclear localization (BNL) domain (class II HVDAS)
   → mutant ADNP retains/loses nuclear import but cannot recruit BAF
   → same disruption of BAF chromatin-remodeling output
   → SHARED phenotype-specific episignature + overlapping narrow-palpebral-fissure craniofacial phenotype

[V] "We speculate that class II ADNP variants and BIS-causing SMARCA2 variants disrupt the chromatin remodeling activity of the BAF complexes, thus explaining their functional overlap." — Sarli et al. 2024, Discussion

[V] "ADNP was found to bind directly to SMARCA2, SMARCA4, and SMARCC2 through its C-terminal end (Helsmoortel et al., 2014)." — Sarli et al. 2024, citing PMID reference to Helsmoortel et al. 2014

Sarli's Discussion also notes the mechanistic hypothesis that mutant ADNP "still binds to the DNA, but is no longer capable of recruiting the BAF complex, leading to diminished functionality of the complex and ultimately to deregulation of several genes" [V?].

6.2 Molecular pathways

  • mSWI/SNF (BAF) ATP‑dependent chromatin remodeling — the sole primary pathway. Not a signaling cascade disorder (no Wnt/MAPK/mTOR/PI3K primary lesion). Reactome/KEGG coverage of SWI/SNF is thin; the authoritative mechanistic reviews are Nucleus 2023 "Mechanism of action of the SWI/SNF family complexes" (PMID:36633435) and the cryo‑EM structural literature.
  • Downstream: BAF‑dependent transcriptional regulation by RNA polymerase II at enhancers; neural progenitor proliferation/differentiation programs.

6.3 Cellular processes

  • Chromatin remodeling and nucleosome repositioning at BAF target loci.
  • Neural progenitor self‑renewal → neuronal differentiation transition. BAF subunit switching is the canonical mechanism: [V?] "these subunits are replaced by the homologous BAF45b, BAF45c, and BAF53b" as progenitors differentiate, and blocking the switch impairs neuronal differentiation — Lessard et al., Neuron 2007 (PMID:17640523). UniProt's function annotation for P51531 likewise records participation in "neural development transitions between stem/progenitor and postmitotic states."
  • Cell‑cycle control — BRM loss impairs G0/G1 arrest in response to confluency or DNA damage (Reyes et al. 1998, PMID:9843504). Relevance to BIS neurodevelopment is plausible but unproven.
  • Not implicated: apoptosis‑centric, autophagy, inflammasome, or fibrotic mechanisms. No conforms_to fit with the fibrotic/senescence/hallmark modules.

6.4 Protein dysfunction

Altered protein–protein interaction surface rather than misfolding, aggregation, or catalytic‑site destruction. The BIS α‑helix cluster is predicted to sit at a BAF inter‑subunit interface. This places BIS squarely within the framework of Valencia et al.'s pan‑BAF structural analysis:

[V?] "Whereas mutations within the SMARCA2 helicase cause NCBRS, SMARCA2 mutations outside of this domain are implicated in a distinct disorder, blepharophimosis-impaired intellectual disability syndrome." — Valencia et al., Nat Genet 2023;55:1400–1412 (PMID:37500730, PMC10412456)

Valencia et al. establish that BAF‑complex genes "harbor the greatest number of de novo missense and protein-truncating variants among nuclear protein complexes" and that non‑truncating NDD variants "cluster in four key structural regions associated with high disease severity, including mSWI/SNF-nucleosome interfaces, the ATPase-core ARID-armadillo repeat (ARM) module insertion site, the Arp module and DNA-binding domains." [V?] The BIS HSA‑adjacent cluster is topologically consistent with the Arp‑module interface arm of that framework (the HSA helix engages ACTL6A/ACTB). Note: Valencia et al. is a structural/computational analysis — it reports no wet‑lab assay of the specific BIS alleles.

Newer BAF structural biology worth tracking for mechanism: a SWI/SNF‑specific Ig‑like domain ("SWIFT") acting as a transcription‑factor binding platform, Science 2026 (PMID:41477818).

6.5 Metabolic changes

None known. BIS is not a metabolic disorder; there is no enzyme deficiency, no accumulating metabolite, no metabolomic signature. Do not model against metabolic_intoxication_decompensation or lysosomal_substrate_accumulation.

6.6 Immune system involvement

No primary immune mechanism. Recurrent bronchitis/pneumonia are best explained by hypotonia/aspiration rather than immunodeficiency; no immunologic workup abnormality is reported. Do not curate an immunodeficiency claim.

6.7 Tissue damage mechanisms

Not a tissue‑injury disorder — the pathology is developmental (morphogenetic and neurodevelopmental), not degenerative. No oxidative stress, ischemia, fibrosis, or necrosis mechanism.

6.8 Biochemical abnormalities

None measurable clinically. No enzyme assay, receptor assay, or ion‑channel defect. The measurable molecular abnormality is epigenomic (methylation array), not biochemical.

6.9 Molecular profiling

Modality Status in BIS
Transcriptomics Performed on blood leukocytes in the founding study; a BIS transcriptomic signature distinguishes BIS from NCBRS [V] (PMID:32694869). No tissue‑level or neural transcriptome exists.
DNA methylation / epigenomics Strongest data; see §4.10. EPIC array, 239‑probe classifier, clinically deployed via EpiSign.
Proteomics None for BIS. General BAF proteomics (Lessard 2007; Mashtalir et al.) informs the mechanism only.
Metabolomics / lipidomics None. Not expected to be informative.
Single‑cell / spatial transcriptomics None for BIS. A high‑value gap — single‑cell analysis of BAF‑dependent programs in human neural progenitors and periocular/craniofacial neural crest would directly test the mechanism.
Functional genomics (CRISPR/RNAi) No BIS‑allele‑specific screen. SMARCA2 appears in DepMap as a paralog‑dependency node in SMARCA4‑mutant lines — cancer context, not BIS.
AI/multimodal diagnostics "Artificial intelligence-driven genotype-epigenotype-phenotype approaches to resolve challenges in syndrome diagnostics" — EBioMedicine 2025 (PMID:40280028) — relevant because BIS is defined by a recognizable gestalt plus an episignature, the exact combination such models exploit.

6.10 Suggested ontology terms for the pathograph

Verified in this session via OLS4:

Term ID Use
chromatin remodeling GO:0006338 ABNORMAL on the remodeling node
ATP‑dependent chromatin remodeler activity GO:0140658 molecular_functions, DECREASED/ABNORMAL
SWI/SNF superfamily‑type complex GO:0070603 cellular component anchor
npBAF complex GO:0071564 neural progenitor BAF specialization
neural progenitor cell CL:0011020 cell_types
eyelid UBERON:0001711 anatomical site of blepharophimosis

Plausible but NOT verified this session — run just validate-terms before use: GO:0006357 (regulation of transcription by RNA polymerase II), GO:0030182 (neuron differentiation), GO:0007399 (nervous system development), GO:0071565 (nBAF complex), CL:0000681 (radial glial cell — verified label in the CL search above), UBERON:0000955 (brain), UBERON:0002336 (corpus callosum), UBERON:0000988 (pons), CHEBI:15422 (ATP).

7. Anatomical Structures Affected

7.1 Organ level

Primary: - Central nervous system — global developmental delay/ID (100%), hypotonia (75%), seizures (21%), structural brain anomalies in ~40% (thin corpus callosum, pontine hypoplasia, Chiari malformation each ~1/14). - Periocular / eyelid and adnexal structures — blepharophimosis (100%), narrow palpebral fissures (71%), epicanthus (100%), ptosis (14%), sparse eyelashes (79%). - Craniofacial skeleton and soft tissue — nasal bridge/alae/tip, philtrum, upper lip vermilion, chin, forehead, ears (64%).

Secondary / variable: - Musculoskeletal — contractures (43%), tapering fingers (57%), pes planus (31%), talipes equinovarus (14%), scoliosis (25%), hip dysplasia (14%), toenail hypoplasia (36%). - Gastrointestinal — GERD (31%), feeding difficulties (15%). - Respiratory — recurrent bronchitis (21%), pneumonia (7%) (secondary). - Genitourinary — cryptorchidism (43% of males), hypospadias (14% of males), labial hypoplasia. - Cardiovascular — patent ductus arteriosus (1/13) — isolated report; not an established BIS feature. - Dentition — enamel hypoplasia, malocclusion, microdontia (each ~1/12 in BIS; note that dental disease is far more prominent in SMARCA2‑related epilepsy cohorts overall, 52.8%, which are ATPase‑domain/NCBRS‑weighted).

Body systems: nervous, visual/ocular adnexal, musculoskeletal, digestive, genitourinary, integumentary (hair/nails), respiratory (secondary).

Notably spared: hearing (0% hearing loss in BIS vs 32% in HVDAS — a useful discriminator); no hepatic, renal‑parenchymal, endocrine, or hematologic involvement reported.

7.2 Tissue and cell level

Because the lesion is in a broadly expressed chromatin remodeler, the affected cell populations are inferred from BAF developmental biology rather than measured in BIS tissue:

  • Neural progenitor cells / radial glia (CL:0011020, CL:0000681) — npBAF‑dependent proliferation.
  • Postmitotic differentiating neurons — nBAF‑dependent maturation, dendritic outgrowth.
  • Cranial neural crest–derived mesenchyme and periocular mesenchyme — the presumed substrate for the blepharophimosis/epicanthus/nasal phenotype. This is an inference: no BIS study has examined periocular or neural‑crest tissue. Flag as a HUMAN_MODEL_MISMATCH/KNOWLEDGE_GAP rather than asserting it.
  • Eyelid epithelium and tarsal plate (UBERON:0003844/0003845, UBERON:0004773/0004774) — anatomically implicated by the phenotype.

7.3 Subcellular level

  • Nucleus (primary compartment; UniProt: nucleus, also localizes to sites of DNA damage).
  • Chromatin / nucleosome — the functional substrate.
  • SWI/SNF superfamily‑type complex (GO:0070603) and npBAF complex (GO:0071564) as the molecular machines.

7.4 Localization and lateralization

Bilateral and symmetric. Blepharophimosis, epicanthus, narrow palpebral fissures, contractures, and foot deformities are described bilaterally. Plagiocephaly (21%) is the only asymmetric craniofacial finding recorded. No lateralized/unilateral pattern is reported.

8. Temporal Development

8.1 Onset

  • Congenital. Facial gestalt, epicanthus, blepharophimosis, and structural anomalies are present at birth. Low birth weight (36%) and short birth length (29%) indicate prenatal onset of the growth phenotype.
  • Onset pattern: insidious recognition of the neurodevelopmental component during infancy; delayed walking and delayed speech become apparent in the first 1–3 years.
  • Prenatal detectability: limited. No BIS‑specific prenatal ultrasound signature exists. For orientation only, a fetus with a de novo SMARCA2 pathogenic variant presented with caudal regression, sacral agenesis, and congenital vertical talus (PMID:38877377, Prenat Diagn 2024) — but that report frames the findings as an expansion of the NCBRS spectrum, not BIS. Do not attribute caudal regression to BIS.

8.2 Progression

  • Course: static / non‑progressive developmental disorder with a chronic, lifelong duration.
  • Stages: no formal staging system exists or is appropriate.
  • Rate: not applicable — developmental trajectory, not degeneration.
  • Ages reported: Sarli's BIS subjects spanned 1 to 17.5 years; the oldest published individuals are adolescents/young adults. There is no adult natural‑history data at all. Whether the BIS facial gestalt evolves with age (as NCBRS coarsening does) is unknown — a concrete, high‑value gap, and a point of practical diagnostic importance since gestalt recognition drives ascertainment.
  • Distinguishing feature vs NCBRS: BIS shows only 17% coarse facies vs ~80% in NCBRS, and no reported progressive coarsening; BIS seizures (21%) are neither as frequent nor as refractory as NCBRS epilepsy (65%, "often difficult to manage" per GeneReviews).

8.3 Patterns

  • Remission: none; not applicable.
  • Critical periods: (a) embryonic/fetal craniofacial and CNS morphogenesis — the window in which the malformation phenotype is determined and therefore not therapeutically accessible postnatally; (b) infancy–early childhood — the actionable window for early intervention, feeding/GERD management, and amblyopia prevention; (c) growth years — contracture, scoliosis, and foot‑deformity surveillance.

9. Inheritance and Population

9.1 Epidemiology

  • Prevalence: no published estimate. The Orphanet epidemiology endpoint returned no prevalence record for ORPHA:637013 in this session; MONDO/OMIM carry none.
  • Reported cases: ≈19–20 published individuals (14 in Cappuccio 2020 + 5 new in Sarli 2024), plus 4 "BIS_atypical". By any reasonable reading this is ultra‑rare, i.e. CASES_IN_LITERATURE with prevalence_class: NOT_YET_DOCUMENTED or ULTRA_RARE in dismech terms. Do not fabricate a numeric rate.
  • For calibration, the allelic disorder is itself vanishingly rare: [V?] "The prevalence of SMARCA2-NCBRS is not known, but is estimated to be extremely low. Fewer than 100 affected individuals have been described." — GeneReviews, SMARCA2‑Related Nicolaides‑Baraitser Syndrome (NBK321516)
  • Incidence: unknown; not estimable.
  • Ascertainment bias: BIS is diagnosed by exome/genome sequencing in syndromic NDD cohorts, then gestalt‑confirmed. It is almost certainly under‑diagnosed, because (i) the gestalt was only described in 2020, (ii) non‑ATPase‑domain SMARCA2 missense variants would previously have been called VUS, and (iii) episignature testing that resolves them is not universally available.

9.2 Inheritance genetics

Parameter BIS
Pattern Autosomal dominant (HP:0000006), de novo in all reported cases
Penetrance Presumed complete for de novo pathogenic hotspot variants; no unaffected carrier reported. No incomplete‑penetrance evidence exists — but with n≈20 and 100% de novo ascertainment, penetrance is effectively untested.
Expressivity Variable — ID severity, ambulation, speech acquisition, seizures, and skeletal involvement all vary among carriers of the same recurrent allele (e.g., three individuals with p.Arg937His). This intra‑allelic variability is itself notable and unexplained.
Anticipation Not applicable (no repeat expansion).
Germline/gonadal mosaicism Not reported in BIS. By analogy, GeneReviews notes for NCBRS that sib recurrence risk is elevated only if parental gonadal mosaicism is suspected. Treat mosaicism as theoretically possible, undocumented.
Founder effects None.
Consanguinity No role (dominant, de novo).
Carrier frequency Not applicable.
Recurrence risk Empirically ~0 for siblings of a proband with a confirmed de novo variant (standard low residual risk for undetected parental mosaicism, conventionally quoted ~1%); 50% for the offspring of an affected individual, though no reproduction by an affected individual has been reported.

9.3 Population demographics

  • Ethnic/geographic distribution: The founding cohort was ascertained across Italy, France, UK, Portugal, Czech Republic, Netherlands, Japan, Canada, USA; Sarli added Turin, Milan, Rome, Caen, Dijon, Coimbra, Birmingham, Manchester, Oxford, Tokyo, and Greenwood SC. There is no evidence of ethnic or geographic clustering — the distribution reflects the geography of the collaborating clinical‑genetics networks, not disease biology.
  • Variant geography: none. Recurrent alleles (Arg525, Arg937) recur across unrelated families in different countries, consistent with independent de novo mutational hotspots rather than shared ancestry.
  • Sex ratio: approximately balanced. Sarli's 15 BIS individuals were 8 female / 7 male; the founding HPO denominators imply 7 males and 5 females scored for sex‑specific features. No sex bias; no X‑linked or sex‑limited component.
  • Age distribution of affected individuals: children and adolescents (1–17.5 years reported). Adults are absent from the literature — an ascertainment artifact of a 2020 disease definition, not evidence of reduced survival.

10. Diagnostics

10.1 Diagnostic strategy (recommended pathway)

  1. Clinical recognition of the gestalt: blepharophimosis + epicanthus + narrow palpebral fissures + sparse eyebrows/eyelashes + broad nasal bridge + short nose with downturned tip + thin upper lip + DD/ID.
  2. Exome or genome sequencing (or a comprehensive ID/NDD gene panel including SMARCA2) — the route used in the founding cohort: [V] "By next-generation sequencing, we identified candidate variants in SMARCA2 in 20 individuals from 18 families with a syndromic neurodevelopmental disorder not consistent with NCBRS."
  3. Variant localization — determine whether the missense variant falls in a BIS hotspot (outside the catalytic ATPase motifs, in the HSA‑adjacent α‑helix ~486–534 or the lobe1/linker region ~766–937) vs an NCBRS ATPase‑motif position. Domain position is the primary genotype–phenotype discriminator.
  4. Trio testing to establish de novo status (ACMG PS2 — applied to every BIS variant in Sarli Table 1).
  5. Episignature testing (EpiSign™) for VUS resolution and confirmation. BIS is an explicitly listed EpiSign episignature disorder (SMARCA2, OMIM 619293), distinct from the NCBRS entry.

10.2 Genetic testing modalities

Modality Utility for BIS
WES High — primary diagnostic route; all reported cases found by NGS.
WGS High; adds non‑coding/structural resolution but no BIS‑specific advantage.
Multigene ID/NDD panels Useful if SMARCA2 is included. SMARCA2 is a Genomics England PanelApp gene on the Intellectual disability panel.
Single‑gene SMARCA2 sequencing Reasonable when the gestalt is recognized; must cover the full CDS, not only ATPase exons (historic NCBRS‑focused assays may have targeted the helicase region).
Chromosomal microarray Low yield for BIS, but essential to exclude 9p24.3/9p deletion syndromes, which overlap in gene content but not phenotype.
Karyotype / FISH Not indicated.
mtDNA testing Not indicated.
Repeat expansion testing Not indicated.
Prenatal / postnatal targeted testing Targeted testing for a known familial variant is feasible; de novo prenatal diagnosis of BIS is not currently practicable on ultrasound findings alone.

10.3 Omics‑based diagnostics

  • Epigenomics — clinically actionable. Genome‑wide methylation (Illumina EPIC) episignature analysis, delivered as EpiSign™, is the one omics assay in routine diagnostic use for BIS. It resolves SMARCA2 VUS and separates BIS from NCBRS. Caveat to curate: BIS and class II HVDAS share the phenotype‑specific episignature (PMID:38884529), so a positive BIS‑HVDAS signature is not by itself gene‑specific — it must be interpreted alongside the sequencing result.
  • Transcriptomics — used as a research‑grade discriminator in the founding study (blood leukocytes); not a routine clinical test.
  • Proteomics / metabolomics / liquid biopsy — no role.

10.4 Variant‑interpretation tooling

A gene‑specific machine‑learning pathogenicity predictor has been developed using SMARCA2 and SMARCA4 NDD variants — reported accuracy 0.93 on holdout data for the gene‑specific model and 0.91 for the generalized BAF‑subunit predictor, outperforming generic tools; the authors emphasize "gene-specific calibration of predictors" (Reilly et al., HGG Adv 2026, PMID:41764075; preprint PMID:41000737). This is directly relevant to reclassifying the numerous SMARCA2 VUS submitted under the BIS condition label (§4.5).

10.5 Non‑genetic clinical tests

There is no diagnostic biochemical, imaging, or electrophysiologic test for BIS. The following are management/complication assessments, not diagnostics:

Test Purpose Expected findings
Brain MRI Structural assessment Normal in ~60%; thin corpus callosum, pontine hypoplasia, or Chiari malformation each in ~1/14
EEG If seizures suspected Seizures in 21%; BAF‑complex disorders more broadly associated with "slow background activity on EEG" (PMID:42528014)
Ophthalmologic exam Blepharophimosis, ptosis, refractive error, strabismus, amblyopia risk vision issue 64%, refractive error 42%, strabismus 14%, ptosis 14%
Audiologic assessment Baseline (standard NDD care) hearing loss 0% in BIS
Swallow study / pH‑impedance Feeding difficulty, GERD GI/feeding issues 46%
Skeletal survey / spine and hip imaging Contractures, scoliosis, hip dysplasia contractures 43%, scoliosis 25%
Dental evaluation Enamel/eruption anomalies uncommon in BIS; prominent in SMARCA2 epilepsy cohorts overall (52.8%)
Developmental / cognitive assessment Severity, service eligibility ID 100%, absent speech 35%
Biopsy / histopathology No role. No characteristic tissue pathology exists.

10.6 Clinical criteria and differential diagnosis

No formal consensus diagnostic criteria exist for BIS (as is also true for NCBRS per GeneReviews). Diagnosis = suggestive gestalt + de novo non‑truncating SMARCA2 variant at a hotspot position, ideally with episignature support.

Differential diagnosis — the discriminating features that matter:

Condition Gene(s) MONDO Discriminators from BIS
Nicolaides‑Baraitser syndrome SMARCA2 (ATPase domain) — (OMIM 601358) Allelic. NCBRS: sparse scalp hair 97%, prominent interphalangeal joints 84%, coarse facies ~80%, epilepsy 65% often refractory, progressive coarsening. BIS: blepharophimosis 100% (absent in NCBRS), sparse hair only 29%, seizures 21%, no progressive coarsening. Distinct episignature; distinct yeast‑assay behavior.
Helsmoortel‑Van der Aa syndrome, class II ADNP (BNL‑domain truncating) MONDO:0979360 (ADNP‑related BIS) Shares the episignature and narrows the palpebral fissures. Distinguishers: HVDAS has downslanting palpebral fissures (33%) and hearing loss (32%), autism ~67%, sleep disturbance 65%; BIS has 0% hearing loss and no downslanting fissures. Sequencing is required to separate them — the methylation biomarker cannot.
Ohdo syndrome, SBBYS variant KAT6B MONDO:0011365 Blepharophimosis + ID + patellar hypoplasia, long thumbs/great toes, dental anomalies, hypothyroidism.
Ohdo syndrome, MKB (Maat‑Kievit‑Brunner) type MASP1 MONDO:0010477 X‑linked; 3MC spectrum features.
Blepharophimosis‑ID, Verloes type / Ohdo type unresolved MONDO:0011432 / MONDO:0009583 Historic clinical entities; molecularly undefined — a frequent source of literature confusion.
Sifrim‑Hitz‑Weiss syndrome CHD4 — Short palpebral fissures + ID + congenital anomalies; ADNP interacts with CHD4 (noted in Sarli's Discussion).
Coffin‑Siris syndrome 1–4 ARID1B, ARID1A, SMARCB1, SMARCA4 — BAFopathy sibs; 5th‑digit/nail hypoplasia, hypertrichosis rather than sparse hair.
Blepharophimosis‑ptosis‑epicanthus inversus syndrome (BPES) FOXL2 — Eyelid phenotype without ID; premature ovarian insufficiency in type I.
Baraitser‑Winter syndrome ACTB, ACTG1 — Ptosis, iris/retinal coloboma, pachygyria; ACTB is an Arp‑module BAF subunit, so mechanistic proximity is real.
Kabuki syndrome KMT2D, KDM6A — Long palpebral fissures with everted lower lids — the opposite eyelid morphology.
9p24.3 / distal 9p deletion syndrome contiguous, incl. SMARCA2 — CNV, not missense; different phenotype; the key argument against SMARCA2 haploinsufficiency.

10.7 Screening

  • Newborn screening: not applicable and not appropriate (no treatable metabolic component; no NBS assay).
  • Carrier screening: not applicable (de novo dominant).
  • Cascade screening: not applicable for de novo variants; would apply only to the offspring of an affected individual.
  • Reverse‑phenotyping screening: the practically useful "screen" is retrospective re‑analysis of unsolved NDD cohorts for non‑ATPase‑domain SMARCA2 missense variants, followed by episignature confirmation — the approach that generated the entity in the first place.

11. Outcome / Prognosis

11.1 Survival and mortality

  • No mortality data exist for BIS. No deaths are reported among the ~20 published individuals.
  • Life expectancy: unknown, presumed not markedly shortened in the absence of severe epilepsy or major organ malformation. There is no cardiac, renal, hepatic, or oncologic component to drive excess mortality. Recurrent respiratory infections (21–50%) and aspiration risk from feeding difficulty/GERD (46%) are the plausible mortality contributors in the most severely affected, non‑ambulant subset — by analogy with severe NDDs generally, not from BIS data.
  • 5‑/10‑year survival, disease‑specific mortality: not applicable / not measured. Do not populate numeric survival fields.

11.2 Morbidity and function

  • Dominant morbidity is neurodevelopmental disability: ID 100%; absent speech 35%; non‑ambulant ~30%; behavioral problems 65%. Most affected individuals will require lifelong support, with a substantial minority (those with absent speech and no independent ambulation) requiring full‑time care.
  • Secondary morbidity: orthopedic (contractures 43%, scoliosis 25%), nutritional/GI (46%), ophthalmologic (64%), respiratory infections.
  • Quality‑of‑life instruments: none administered. ICF‑based functional outcome data: none. Explicit gap.

11.3 Disease course and complications

Chronic, stable, lifelong. Complications to anticipate: aspiration pneumonia, failure to thrive, amblyopia/uncorrected refractive error, progressive contracture and scoliosis with growth, seizure emergence, dental disease, behavioral escalation in adolescence. Recovery potential: none — this is a static developmental disorder. Function improves with development and intervention; the underlying chromatin lesion is not reversible.

11.4 Prognostic prediction

  • Best candidate prognostic factor: variant position. In the allelic disorder this is established — [V?] "All individuals with a pathogenic variant within the C-terminal helicase region of the ATPase domain have severe intellectual disability and epilepsy, a frequency higher than that in individuals with pathogenic variants in other parts of the gene." (GeneReviews NBK321516, NCBRS). For BIS specifically, no intra‑BIS genotype–severity correlation has been established — indeed three individuals sharing p.Arg937His differ phenotypically, arguing that variant identity alone is insufficient. Curate this as an open question, not as a correlation.
  • Prognostic biomarkers: none. The episignature is diagnostic, not prognostic — MVP score has no demonstrated relationship to severity.
  • Practical early prognostic indicators (severity of hypotonia, age at walking, speech acquisition by age 3, seizure onset) are generic NDD predictors, not BIS‑validated.

12. Treatment

There is no disease‑modifying or targeted therapy for BIS. Management is entirely supportive, anticipatory, and multidisciplinary. No published BIS‑specific management guideline exists; the closest applicable framework is the GeneReviews management section for SMARCA2‑related NCBRS, which states that no cure exists and care is supportive and multidisciplinary.

12.1 Supportive / rehabilitative management (the core of care)

Intervention Indication in BIS Suggested NCIT treatment_term therapeutic_modality
Early intervention / developmental therapy DD/ID 100% NCIT:C15315 Rehabilitation BEHAVIORAL
Physical therapy Hypotonia 75%, delayed walking 71%, contractures 43% NCIT:C15302 Physical Therapy BEHAVIORAL
Occupational therapy Fine motor, ADLs, hand contractures NCIT:C121351 Occupational Therapy BEHAVIORAL
Speech and language therapy / AAC Speech delay 69%, absent speech 35% NCIT:C159273 Speech Therapy BEHAVIORAL
Nutritional support / feeding management Feeding difficulty 15%, GERD 31%, poor growth NCIT:C15433 Nutritional Support (determine per agent — do not auto‑tag BEHAVIORAL)
Anti‑seizure medication Seizures 21% NCIT:C15986 Pharmacotherapy SMALL_MOLECULE
Ophthalmologic correction (refraction, amblyopia therapy, ptosis/blepharophimosis surgery where visual axis is compromised) Vision issue 64%, ptosis 14% NCIT:C15329 Surgical Procedure / NCIT:C49236 Therapeutic Procedure SURGERY / DEVICE
Orthopedic management (orthoses, serial casting, tenotomy, scoliosis and clubfoot surgery) Contractures, talipes 14%, scoliosis 25%, hip dysplasia 14% NCIT:C16186 Orthopedic Surgical Procedure SURGERY
Dental care Enamel/eruption anomalies NCIT:C15747 Supportive Care —
Behavioral / ADHD / autism support Behavioral problems 65% NCIT:C181743 Behavioral Counseling BEHAVIORAL
Genetic counseling Recurrence risk, family planning NCIT:C15240 Genetic Counseling BEHAVIORAL
Supportive care (general) Multisystem NCIT:C15747 Supportive Care —

NCIT IDs above are drawn from the dismech‑vetted list in CLAUDE.md; verify NCIT:C15315, C49236, C181743 with OAK before use.

12.2 Pharmacotherapy specifics

  • Anti‑seizure medications: no BIS‑specific evidence. Extrapolatable data: in a SMARCA2‑related epilepsy cohort (24 own + 46 literature cases, mostly ATPase‑domain variants), seizure control was achieved in 45.8% using valproate or levetiracetam (PMID:40513420, Seizure 2025). GeneReviews likewise notes levetiracetam and valproic acid often show initial response in NCBRS. Curate this as extrapolated, NCBRS/ATPase‑weighted evidence, not BIS evidence — BIS epilepsy is both rarer (21%) and apparently milder.
  • Pharmacogenomics: no BIS‑specific PGx. Standard CPIC guidance applies to the drugs used (e.g., HLA‑B*15:02/carbamazepine, CYP2C9/phenytoin) — general practice, not disease‑specific.

12.3 Advanced therapeutics — status: none, and one important negative

  • Gene therapy / gene editing: none. Conceptually challenging: the phenotype is largely prenatal and morphogenetic (craniofacial structure is fixed before birth), and the mechanism is a dominant‑interfering missense allele in a broadly required chromatin regulator — allele‑specific silencing (ASO/siRNA against the mutant allele) is the only theoretically coherent modality, and no such program exists.
  • ASOs / siRNA / mRNA: none. Note SMARCA2 has no ASO program; the mechanism does not fit any of the three FDA‑approved ASO paradigms cleanly (there is no splice lesion and no accumulating toxic transcript in the usual sense).
  • Cell therapy, immunotherapy: not applicable.
  • ⚠ Critical negative to record — SMARCA2 degraders are NOT a BIS therapy. Multiple clinical programs target SMARCA2 for degradation in SMARCA4‑deficient cancers (NCT06560645 PRT7732, terminated; NCT05639751 PRT3789, completed; NCT06682806, terminated; NCT06561685 LY4050784; NCT07284186 PLX‑61639; preclinical PMIDs 36357397, 36216795, 38557192, 39378885, 40280558, 41184243). These reduce SMARCA2 and would be expected to be harmful, not helpful, in a SMARCA2‑opathy. An automated pipeline mining "SMARCA2 + drug" will surface these; they must be explicitly excluded from BIS treatment curation.

12.4 Trials and registries

No interventional trial for BIS exists. Relevant observational studies that may enroll BIS individuals: - NCT01793168 — Rare Disease Patient Registry & Natural History Study (CoRDS, Sanford), recruiting, observational. - NCT04463316 — "GROWing Up With Rare GENEtic Syndromes", recruiting, observational.

12.5 Treatment outcomes, adverse events, algorithms

  • Response rates: none reported (no trials).
  • Adverse events: those of the individual supportive interventions; nothing BIS‑specific.
  • Algorithms / combination therapy / genotype‑guided treatment: none exist. Explicit gap — a BIS management guideline is an unmet need, and the NCBRS GeneReviews surveillance schedule (growth, seizures, development at each visit; dental review at least every 6 months) is the best available proxy.

13. Prevention

13.1 Prevention levels

  • Primary prevention: not possible. De novo germline missense variants are not preventable. No modifiable exposure exists.
  • Secondary prevention (early detection and intervention): the actionable level. Early molecular diagnosis via ES/GS in infants with DD + blepharophimosis enables early intervention, feeding/GERD management, amblyopia prevention, and avoids the diagnostic odyssey. Episignature testing shortens time‑to‑diagnosis for SMARCA2 VUS.
  • Tertiary prevention (complication avoidance): the practical mainstay — aspiration prevention (feeding/GERD management), amblyopia prevention (refractive correction, ptosis surgery where the visual axis is obstructed), contracture and scoliosis prevention (PT, orthoses, positioning), seizure control, dental prophylaxis, nutritional optimization.

13.2 Immunization

No disease‑specific vaccine. Routine immunization is important and should be emphasized, given recurrent bronchitis (21%) and pneumonia (7%) — including influenza and pneumococcal vaccination per standard schedules for children with neurodisability.

13.3 Screening and reproductive options

  • Population screening: none; not justified for an ultra‑rare de novo disorder.
  • Genetic counseling: indicated for every family. Key messages: (i) the variant is de novo, (ii) sibling recurrence risk is very low (residual risk for undetected parental gonadal mosaicism, conventionally ~1%), (iii) offspring risk for an affected individual is 50%.
  • Prenatal testing / PGT: technically available for a known familial variant (relevant only in the theoretical case of a transmitting affected parent, or for reassurance in a subsequent pregnancy). PGT‑M is not indicated for a proven de novo variant other than at parental request.
  • Risk stratification: not applicable.

13.4 Behavioral, public health, environmental interventions, prophylaxis

Not applicable to etiology. The only public‑health‑relevant lever is access to exome/genome sequencing and to episignature testing in NDD diagnostic pathways — a health‑systems issue, not an environmental one. No prophylactic medication is indicated.

14. Other Species / Natural Disease

  • Taxonomy: Homo sapiens (NCBITaxon:9606) is the only species in which BIS occurs. BIS is a human clinical entity defined by a human gestalt.
  • Breed (VBO): not applicable. No breed‑associated SMARCA2 disorder is known.
  • Orthologous genes: mouse Smarca2 (MGI:99603, verified via MGI), with orthologs across vertebrates (rat, zebrafish smarca2), and the deeply conserved yeast ortholog SNF2 in Saccharomyces cerevisiae — the ortholog that made the founding functional assay possible. Retrieve NCBI Gene IDs for non‑human orthologs before curating them; I verified only the mouse MGI ID in this session.
  • Naturally occurring animal disease: none reported. No OMIA entry for a SMARCA2 Mendelian disorder in a domestic species. BIS has no natural animal counterpart.
  • Veterinary relevance: none.
  • Comparative pathology: the informative comparison is negative and mechanistically important — mouse Smarca2/Brm null animals do not model BIS or NCBRS: [V?] "BRM-/- mice develop normally, suggesting that an observed up-regulation of the BRG1 protein can functionally replace BRM." (Reyes et al., EMBO J 1998, PMID:9843504). ClinGen's dosage curation cites exactly this — SMARCA2 knockout mice are "viable and fertile" — as evidence against a loss‑of‑function mechanism.
  • Evolutionary conservation: very high. The ATPase/helicase motifs are described as "ultra-conserved" (Van Houdt 2012 [V]), and BAF/SWI‑SNF architecture is conserved from yeast Snf2 to human BRM/BRG1 — the basis for the yeast complementation strategy. Separately, the human paralogs SMARCA2/SMARCA4 converge at homologous residues (M856V/M866V, shared episignature; PMID:38751117), evidence of conserved residue‑level function within the paralog pair.
  • Zoonotic potential / cross‑species susceptibility: not applicable (genetic disorder).

15. Model Organisms

15.1 Yeast (Saccharomyces cerevisiae) — the model that defined BIS

The only model system with published, BIS‑allele‑specific data. Cappuccio et al. expressed the human variants in the context of the yeast Snf2 ortholog and used growth/phenotype assays as a functional stratifier:

[V] "To stratify variant interpretation, we functionally analyzed SMARCA2 variants in yeasts and performed transcriptomic and genome methylation analyses on blood leukocytes."

[V] "Yeast phenotype assays differentiated NCBRS from non-NCBRS SMARCA2 variants."

Structural inference from the yeast Snf2 homolog placed the mutated BIS residues on an α‑helix at the SWI/SNF inter‑subunit interface [V] (Sarli 2024 Introduction, summarizing Cappuccio 2020).

  • Strengths: deep conservation of the Snf2 ATPase; tractable, quantitative, scalable; directly discriminated the two disease classes — exactly the assay a variant‑classification pipeline needs.
  • Limitations: yeast has no nervous system, no eyelids, no craniofacial development, and lacks the metazoan BAF subunit repertoire (no ADNP, no BAF45/53 paralog switching, no cBAF/PBAF/ncBAF diversification). It can report on catalysis and complex integrity, not on phenotype. Curate yeast results as evidence_source: IN_VITRO (or OTHER for a heterologous‑organism assay) — not as evidence for human phenotypes.

15.2 Mouse (Mus musculus) — available but non‑recapitulating

  • Gene: Smarca2, MGI:99603. 10 mutant alleles across endonuclease‑mediated (5), targeted (4), and gene‑trapped (1) categories (MGI, verified).
  • Reported mutant phenotype systems: behavior/neurological, growth/body size, homeostasis/metabolism, muscle physiology, reproductive system. MGI notes homozygotes for a targeted mutation "may exhibit infertility and a slightly increased body weight in some genetic backgrounds."
  • Founding characterization (Reyes et al. 1998, PMID:9843504): null mice develop normally with BRG1 upregulation compensating; adults ~15% heavier; increased hepatic mitotic index; mutant embryonic fibroblasts [V?] "deficient...ability to arrest in the G0/G1 phase of the cell cycle in response to cell confluency or DNA damage."
  • Phenotype recapitulation: poor to absent. No mouse shows blepharophimosis, ID, or the BIS craniofacial gestalt. No knock‑in mouse carrying a BIS hotspot allele (e.g., Arg525His, Arg937His, Met856Val) has been reported.
  • This is a textbook HUMAN_MODEL_MISMATCH, not a KNOWLEDGE_GAP: model‑organism evidence exists (Smarca2‑null mice), but its translational validity is the open question — because the null does not model a dominant‑interfering missense allele, and BRG1 compensation in mouse may not mirror human BRM/BRG1 dosage relationships. The obvious resolving experiment is a conditional knock‑in of a BIS hotspot allele with craniofacial and neurodevelopmental phenotyping.

15.3 Human cellular models

  • Patient peripheral blood leukocytes — the substrate for both the BIS transcriptomic and DNA methylation signatures (Cappuccio 2020; Sarli 2024). Accessible, clinically validated, but not the affected tissue — an inherent limitation: a blood episignature is a surrogate readout of chromatin dysregulation, not a measure of neural or periocular pathobiology.
  • iPSC‑derived neurons / neural progenitors / organoids: none reported for BIS. This is the highest‑value missing model. A BAF‑relevant precedent exists in the MorPhiC framework (iPSC‑derived multicellular systems, null alleles, category: Cellular phenotypes, evidence_source: IN_VITRO), but SMARCA2 is not among the flagged MorPhiC anchor genes (ISL1, EOMES, GCM1, NKX2‑1) and no MorPhiC SMARCA2 dataset was identified.
  • Cell lines / biochemical reconstitution: extensive SMARCA2 biochemistry exists in the cancer literature (degrader pharmacology, SMARCA4‑deficient synthetic lethality). None of it interrogates BIS alleles. Reconstituted BAF complexes with BIS variants — testing assembly, ACTL6A/Arp‑module engagement, nucleosome remodeling, and ATPase activity — is the missing biochemistry.

15.4 Zebrafish, Drosophila, C. elegans

  • Zebrafish smarca2 ortholog exists; no BIS model reported. Zebrafish would be a reasonable system for craniofacial/neural‑crest patterning readouts.
  • Drosophila brm is the founding family member and the source of the name "brahma"; classic developmental genetics, but no BIS allele modeling.
  • C. elegans — not used.

15.5 Model resources

MGI (informatics.jax.org, MGI:99603), IMPC/KOMP/IMSR for Smarca2 allele availability, ZFIN for smarca2, FlyBase for brm, SGD for SNF2, Alliance of Genome Resources for cross‑species integration, Cellosaurus/ATCC for cell lines.

15.6 Research applications and the honest bottom line

Existing models can address: BAF catalytic mechanism (yeast, biochemistry), BAF subunit switching in neural development (mouse, Lessard 2007), and variant classification (yeast assay, ML predictors). No existing model addresses the two questions that matter most for BIS: why these specific interface variants cause blepharophimosis, and what the dominant‑interfering allele does to BAF function in human neural and periocular tissue.

Appendix A — Reference list with verification status

PMID / ID Citation Role Cache status
32694869 Cappuccio G, Sayou C, Tanno PL, et al. De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides-Baraitser syndrome. Genet Med 2020;22(11):1838‑1850. DOI 10.1038/s41436-020-0898-y Founding / defining publication ✅ cached, abstract verbatim available
38884529 Sarli C, van der Laan L, Reilly J, et al. Blepharophimosis with intellectual disability and Helsmoortel-Van Der Aa Syndrome share episignature and phenotype. Am J Med Genet C 2024;196(4):e32089. DOI 10.1002/ajmg.c.32089 Episignature; variant table; phenotype frequencies; open access (CC BY) ✅ cached, abstract verbatim; full text read
22366787 Van Houdt JKJ, et al. Heterozygous missense mutations in SMARCA2 cause Nicolaides-Baraitser syndrome. Nat Genet 2012 NCBRS mechanism; ATPase‑motif clustering verbatim abstract retrieved; needs just fetch-reference
37500730 Valencia AM, Sankar A, van der Sluijs PJ, et al. Landscape of mSWI/SNF chromatin remodeling complex perturbations in neurodevelopmental disorders. Nat Genet 2023;55:1400‑1412 (PMC10412456) BAF structural framework; explicit BIS vs NCBRS statement needs fetch
38751117 DNA methylation analysis in patients with neurodevelopmental disorders improves variant interpretation and reveals complexity. HGG Adv 2024 (PMC11216013) SMARCA2 M856V / SMARCA4 M866V paralog episignature convergence verbatim abstract retrieved; needs fetch
40513420 Genotype and phenotype correlation in epilepsy patients with SMARCA2 variants. Seizure 2025;131:73‑83 SMARCA2 epilepsy (ATPase‑weighted); ASM response needs fetch; quotes [V?] only
17640523 Lessard J, et al. An essential switch in subunit composition of a chromatin remodeling complex during neural development. Neuron 2007;55:201‑15 npBAF→nBAF switching needs fetch
9843504 Reyes JC, Barra J, Muchardt C, et al. Altered control of cellular proliferation in the absence of mammalian brahma (SNF2alpha). EMBO J 1998;17:6979‑91 Brm‑null mouse; model mismatch needs fetch
42528014 Genotypic and Phenotypic Profile of 50 Cases With Chromatin Remodeling Complexes-Related Neurological Disorders. CNS Neurosci Ther 2026 BAF vs CHD clinical patterns needs fetch
41764075 / 41000737 Gene-specific pathogenicity predictor for chromatin remodeling BAF complex-associated NDDs. HGG Adv 2026 / bioRxiv 2025 SMARCA2/4 VUS classification, acc. 0.93/0.91 needs fetch
40280028 AI-driven genotype-epigenotype-phenotype approaches to resolve challenges in syndrome diagnostics. EBioMedicine 2025 gestalt + episignature diagnostics needs fetch
36633435 Mechanism of action of the SWI/SNF family complexes. Nucleus 2023 mechanism review needs fetch
41477818 A SWI/SNF-specific Ig-like domain, SWIFT, is a transcription factor binding platform. Science 2026 current BAF structural biology needs fetch
38877377 Caudal regression in fetus with de novo SMARCA2 pathogenic variant. Prenat Diagn 2024 prenatal; framed as NCBRS spectrum, not BIS needs fetch; use with caution
34521483 Nicolaides-Baraitser syndrome in a patient with hypertrophic cardiomyopathy and SMARCA2 gene deletion. Cardiol Young 2022;32:821‑823 complicates the deletion/haploinsufficiency picture needs fetch
NBK321516 GeneReviews®: SMARCA2-Related Nicolaides-Baraitser Syndrome NCBRS comparator; prevalence; management; genotype‑phenotype not a PMID — cite as GeneReviews/Bookshelf
ORPHA:637013 Orphanet, SMARCA2-related blepharophimosis-intellectual disability syndrome identifiers, ICD‑10 Q87.0, disorder type ⚠ no ORPHA_637013 cache exists in this repo — run just structured-rebuild-orphanet --id 637013
OMIM 619293 BLEPHAROPHIMOSIS-IMPAIRED INTELLECTUAL DEVELOPMENT SYNDROME; BIS clinical synopsis; two‑cluster variant narrative omim.org returns 403 to automated fetch; text obtained indirectly — treat the exon 8/9 + exon 19 sentence as [V?]
— HPO/Monarch annotation API, OMIM:619293 all n/14 phenotype frequencies retrieved directly ✅
— EpiSign™ Conditions List (London Health Sciences Centre, rev. June 2024) BIS as a clinically available episignature disorder PDF read directly ✅
— ClinGen Dosage Sensitivity, SMARCA2, CCID:007899 (eval. 2013‑03‑27) HI score 0; anti‑haploinsufficiency argument consider ingesting as CGDS:HGNC_11098 via just clingen-dosage-rebuild
NCT01793168, NCT04463316 CoRDS registry; GROWing Up With Rare GENEtic Syndromes observational enrollment options fetch via just fetch-reference NCT…

Appendix B — Prioritized knowledge gaps (candidate discussions entries)

  1. KNOWLEDGE_GAP — mechanism of the BIS allele class. No biochemical assay of BIS variants on BAF assembly, Arp‑module engagement, nucleosome remodeling, or ATPase activity. attaches_to the interface/remodeling nodes. Proposed experiments: co‑IP/mass spec of BAF from BIS‑variant cells; in vitro reconstitution + remodeling assay; ATAC‑seq/CUT&RUN in isogenic knock‑ins.
  2. KNOWLEDGE_GAP — why blepharophimosis? No mechanistic account links SMARCA2 interface variants to periocular/eyelid morphogenesis. Nothing is known about BRM function in periocular neural crest.
  3. HUMAN_MODEL_MISMATCH — mouse Smarca2 null is viable, fertile, and normal‑appearing, so it cannot model a dominant‑interfering missense allele; BRG1 compensation may not translate. Resolving experiment: BIS hotspot knock‑in mouse.
  4. KNOWLEDGE_GAP — no adult natural history. All reported individuals are ≤17.5 years. Unknown whether the gestalt evolves, whether new complications emerge, and what adult function/QoL look like.
  5. KNOWLEDGE_GAP — intra‑BIS genotype–phenotype correlation. Three individuals share p.Arg937His yet differ phenotypically; no severity predictor exists, and no modifier has been sought.
  6. KNOWLEDGE_GAP — allelic/phenotypic expansion outside ClinVar's literature. Several SMARCA2 variants classified Likely pathogenic for BIS in ClinVar (p.Glu464Lys, p.Asp534Gly, p.Gln957Arg, p.Pro625Leu, p.Tyr1489Cys) sit outside the two published clusters and are unpublished. Do the clusters need redefining, or are these mislabeled?
  7. Data‑quality flags: (a) the p.(Asp510Gly)/c.6286C>A inconsistency in Sarli Table 1; (b) UniProt places p.Met856Val and p.Leu766Val inside the annotated helicase ATP‑binding domain (736–901), in tension with "outside the helicase domains"; (c) two UMLS CUIs (C5443984, C5816784) map to MONDO:0859139.
  8. Diagnostic caveat worth curating explicitly: the BIS episignature is phenotype‑specific, not gene‑specific — it is shared with class II ADNP HVDAS, so a positive result requires sequencing to assign the gene.

Sources: - Cappuccio et al. 2020, Genetics in Medicine (PMID:32694869) · publisher - Sarli et al. 2024, Am J Med Genet C (PMID:38884529) · open-access PDF - Van Houdt et al. 2012, Nature Genetics (PMID:22366787) - Valencia et al. 2023, Nature Genetics (PMID:37500730 / PMC10412456) - DNA methylation analysis in NDDs, HGG Advances 2024 (PMID:38751117) - Genotype and phenotype correlation in epilepsy patients with SMARCA2 variants, Seizure 2025 (PMID:40513420) - Lessard et al. 2007, Neuron (PMID:17640523) - Reyes et al. 1998, EMBO J (PMID:9843504) - SMARCA2-Related Nicolaides-Baraitser Syndrome, GeneReviews (NBK321516) - OMIM #619293 · MedGen C5443984 · Monarch MONDO:0859139 - Orphadata cross-referencing API, ORPHA:637013 - HPO annotation API, OMIM:619293 - UniProt P51531 · HGNC:11098 · MGI:99603 - ClinGen Dosage Sensitivity, SMARCA2 - EpiSign Conditions List (June 2024) - ClinicalTrials.gov API v2 · Genomics England PanelApp, SMARCA2