SMARCC1-associated Developmental Dysgenesis Syndrome

Mendelian MONDO:0700123 Pathograph 18 Show in embeddings browser BAFopathy

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Inheritance

1
Autosomal dominant HP:0000006
Dominant disorder caused by heterozygous SMARCC1 variants. Causal variants arise de novo in many probands but can also be transmitted from an apparently unaffected parent, consistent with incomplete penetrance.
Autosomal dominant inheritance Penetrance: INCOMPLETE
Show evidence (1 reference)
PMID:37285932 SUPPORT Human clinical
"Both identified variants are inherited from a healthy parent, which supports the reported incomplete penetrance of this gene"
Documents transmitted variants from unaffected parents, establishing incomplete penetrance of the dominant allele.
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Pathophysiology

7
SMARCC1 Loss-of-Function
Heterozygous, frequently de novo, loss-of-function or damaging missense variants in SMARCC1 reduce the dose of functional BAF155, a core scaffold subunit of the SWI/SNF (BAF) ATP-dependent chromatin-remodeling complex. Haploinsufficiency is the proposed disease mechanism.
SMARCC1 hgnc:11104 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SMARCC1 (hgnc:11104). hgnc:11104 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION
chromatin binding GO:0003682 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased chromatin binding (GO:0003682). GO:0003682 is a molecular function from the Gene Ontology.
Downstream
BAF Complex Chromatin-Remodeling Dysfunction
Show evidence (3 references)
PMID:38128548 SUPPORT Human clinical
"six rare, protein-altering de novo variants localized to highly conserved residues in key functional domains"
Establishes rare de novo protein-altering SMARCC1 variants in conserved functional domains as the genetic basis.
PMID:33077954 SUPPORT Human clinical
"These data suggest that SMARCC1 haploinsufficiency increases CH risk"
States haploinsufficiency as the mechanism by which SMARCC1 loss causes disease.
PMID:34906496 SUPPORT Human clinical
"We also identified de novo or predicted loss-of-function variants in 4 candidate BAFopathy genes, including ACTL6A, BICRA (implicated in Coffin-Siris syndrome during this study), PBRM1, and SMARCC1"
Independent clinical-exome cohort identifies de novo/loss-of-function SMARCC1 variants and places the gene among the BAFopathies.
BAF Complex Chromatin-Remodeling Dysfunction
Reduced BAF155 impairs the nucleosome-remodeling activity of the mSWI/SNF (BAF) complex, disrupting the chromatin-accessibility changes that normally program gene expression during brain development.
chromatin remodeling GO:0006338 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased chromatin remodeling (GO:0006338). GO:0006338 is a biological process from the Gene Ontology.
ATP-dependent chromatin remodeler activity GO:0140658 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased ATP-dependent chromatin remodeler activity (GO:0140658). GO:0140658 is a molecular function from the Gene Ontology.
Downstream
Aberrant H3K27me3 Accumulation
Abnormal heart morphology BAF-complex remodeling is also required for cardiac development; loss of SMARCC1 produces structural cardiac defects as an extra-neural arm of the syndrome.
Show evidence (1 reference)
PMID:37285932 SUPPORT BACKGROUND Human clinical
"SMARCC1 encodes a subunit of the mSWI/SNF complex and affects the chromatin structure and expression of several genes"
States that SMARCC1 loss alters chromatin structure and downstream gene expression.
Aberrant H3K27me3 Accumulation
Loss of BAF-complex remodeling impairs the H3K27 demethylases UTX/KDM6A and JMJD3/KDM6B, so repressive H3K27me3 marks accumulate at developmental genes. Established in Baf155/Baf170 conditional-knockout mouse forebrain rather than in the human heterozygous state.
histone H3K27me2/H3K27me3 demethylase activity GO:0071558 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased histone H3K27me2/H3K27me3 demethylase activity (GO:0071558). GO:0071558 is a molecular function from the Gene Ontology.
Downstream
De-repressed Wnt Signaling
Show evidence (1 reference)
PMID:26986003 SUPPORT Model organism
"BAF complexes globally control the key heterochromatin marks, H3K27me2 and -3, by directly modulating the enzymatic activity of the H3K27 demethylases, Utx and Jmjd3"
BAF complexes raise H3K27me2/3 by modulating the UTX/JMJD3 demethylases, so their loss lets the marks accumulate.
De-repressed Wnt Signaling
Loss of BAF complexes de-represses Wnt signaling and silences neuronal-differentiation genes while activating proliferation-associated genes. Established in Baf155/Baf170 conditional-knockout mouse forebrain rather than in the human heterozygous state.
canonical Wnt signaling pathway GO:0060070 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased canonical Wnt signaling pathway (GO:0060070). GO:0060070 is a biological process from the Gene Ontology.
Downstream
Dysregulated Neurodevelopmental Transcription
Show evidence (1 reference)
PMID:29779894 SUPPORT Model organism
"Inactivation of BAF complexes leads to H3K27me3-linked silencing of neuronal differentiation-related genes, with concurrent H3K4me2-mediated activation of proliferation-associated genes via de-repression of Wnt signaling"
Links BAF loss to H3K27me3-mediated silencing of differentiation genes and Wnt de-repression.
Dysregulated Neurodevelopmental Transcription
Loss of BAF-dependent chromatin remodeling dysregulates the transcriptional programs controlling mid-gestational neurogenesis, including the neurogenic transcription factors NEUROD2 and MAB21L2.
regulation of neurogenesis GO:0050767 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased regulation of neurogenesis (GO:0050767). GO:0050767 is a biological process from the Gene Ontology.
Downstream
Impaired Neurogenesis and Neuronal Differentiation
Show evidence (1 reference)
PMID:38128548 SUPPORT Human clinical
"altered expression of key genes linked to midgestational neurogenesis, including the transcription factors NEUROD2 and MAB21L2"
Human fetal brain transcriptomics show SMARCC1 variants dysregulate mid-gestational neurogenic gene expression.
Impaired Neurogenesis and Neuronal Differentiation
Dysregulated transcription impairs neuronal differentiation and neurogenic output of neural progenitors in the developing telencephalon, the proposed neural-stem-cell basis of SMARCC1-associated congenital hydrocephalus. The two mouse models disagree on the direction of the proliferation change: the Baf155/Baf170 forebrain conditional knockout keeps progenitors proliferating while blocking differentiation (PMID:29779894), whereas the Baf155msp/msp missense mouse shows reduced progenitor proliferation (PMID:33077954). Only the shared impaired-differentiation/neurogenesis outcome is asserted here; the proliferation direction is left unbound.
radial glial cell CL:0000681 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves radial glial cell (CL:0000681). CL:0000681 is a cell type from the Cell Ontology. neural stem cell CL:0000047 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neural stem cell (CL:0000047). CL:0000047 is a cell type from the Cell Ontology.
neuron differentiation GO:0030182 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased neuron differentiation (GO:0030182). GO:0030182 is a biological process from the Gene Ontology.
Animal models
Baf155msp/msp mouse Mouse partially recapitulates The homozygous missense mouse reproduces the neural stem cell proliferation defect and apoptosis that underlie the human mechanism. Note this model's reduced proliferation is the opposite direction to the Baf155/Baf170 forebrain conditional knockout, which retains proliferation while blocking differentiation.
Downstream
Structural Brain Dysgenesis
Show evidence (1 reference)
PMID:33077954 SUPPORT Human clinical
"SMARCC1 is an ATP-dependent chromatin remodeler that regulates gene expression required for NSC proliferation, differentiation and survival during telencephalon development"
States SMARCC1's role in regulating neural stem cell differentiation and survival during telencephalic development.
Structural Brain Dysgenesis
Impaired corticogenesis produces structural brain malformations - ventriculomegaly/hydrocephalus with aqueductal stenosis and corpus callosum abnormalities.
Animal models
Xenopus tropicalis Smarcc1 knockdown Xenopus tropicalis recapitulates Knockdown reproduces the aqueductal stenosis of the human structural brain malformation, with wild-type (but not variant) SMARCC1 rescue.
Downstream
Aqueductal stenosis
Abnormal corpus callosum morphology
Global developmental delay
Seizure
Show evidence (1 reference)
PMID:38128548 SUPPORT Human clinical
"characterized by variable presence of cerebral ventriculomegaly, aqueductal stenosis, developmental delay and a variety of structural brain or cardiac defects"
Defines the structural malformation spectrum resulting from the SMARCC1 mechanism.
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Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for SMARCC1-associated Developmental Dysgenesis 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

8
Cardiovascular 1
Abnormal heart morphology FREQUENT HP:0001627 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cardiac defects, annotated with Abnormal heart morphology (HP:0001627). HP:0001627 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38128548 SUPPORT Human clinical
"Patients exhibited hydrocephalus with aqueductal stenosis; corpus callosum abnormalities, developmental delay, and cardiac defects were also common"
Cardiac defects are a common extra-neural feature of the syndrome.
Musculoskeletal 1
Abnormality of the skeletal system OCCASIONAL HP:0000924 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Skeletal abnormalities, annotated with Abnormality of the skeletal system (HP:0000924). HP:0000924 is a phenotype from the Human Phenotype Ontology.
Coarse binding: source unspecified
Show evidence (1 reference)
PMID:33077954 SUPPORT Human clinical
"all six patients with SMARCC1 mutations with available brain imaging data had aqueductal stenosis and corpus callosum abnormalities, along with cardiac (n = 3) and skeletal abnormalities (n = 2)"
Skeletal abnormalities were reported in 2 of 6 imaged SMARCC1 probands; the source names only "skeletal abnormalities" with no more specific finding, so the binding is left at the system level.
Nervous System 6
Hydrocephalus VERY_FREQUENT HP:0000238 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hydrocephalus (HP:0000238). HP:0000238 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38128548 SUPPORT Human clinical
"Patients exhibited hydrocephalus with aqueductal stenosis; corpus callosum abnormalities, developmental delay, and cardiac defects were also common"
Hydrocephalus is the cardinal feature of the syndrome.
Aqueductal stenosis VERY_FREQUENT HP:0002410 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Aqueductal stenosis (HP:0002410). HP:0002410 is a phenotype from the Human Phenotype Ontology.
Sequelae: Hydrocephalus Ventriculomegaly
Show evidence (1 reference)
PMID:33077954 SUPPORT Human clinical
"all six patients with SMARCC1 mutations with available brain imaging data had aqueductal stenosis and corpus callosum abnormalities, along with cardiac (n = 3) and skeletal abnormalities (n = 2)"
All imaged SMARCC1 probands had aqueductal stenosis, the obstructive basis of the hydrocephalus.
Ventriculomegaly VERY_FREQUENT HP:0002119 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ventriculomegaly (HP:0002119). HP:0002119 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37285932 SUPPORT Human clinical
"Ventriculomegaly is the common feature in those fetuses"
Ventriculomegaly is the common presenting feature, including antenatally.
Abnormal corpus callosum morphology VERY_FREQUENT HP:0001273 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Corpus callosum abnormalities, annotated with Abnormal corpus callosum morphology (HP:0001273). HP:0001273 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33077954 SUPPORT Human clinical
"all six patients with SMARCC1 mutations with available brain imaging data had aqueductal stenosis and corpus callosum abnormalities, along with cardiac (n = 3) and skeletal abnormalities (n = 2)"
Corpus callosum abnormalities were present in all imaged SMARCC1 probands.
Global developmental delay FREQUENT HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33077954 SUPPORT Human clinical
"developmental delay and epilepsy were additional common features in both TRIM71 and SMARCC1 mutant probands"
Developmental delay is a common feature in SMARCC1 probands.
Seizure FREQUENT HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Epilepsy, annotated with Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33077954 SUPPORT Human clinical
"developmental delay and epilepsy were additional common features in both TRIM71 and SMARCC1 mutant probands"
Epilepsy is reported as an additional common feature in SMARCC1 probands.
🧬

Genetic Associations

1
SMARCC1
Gene: SMARCC1 hgnc:11104 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SMARCC1 (hgnc:11104). hgnc:11104 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID:37285932 SUPPORT Human clinical
"Most of the reported variants are loss of function (LoF) and are often inherited from unaffected parents"
Characterizes the SMARCC1 variant spectrum as predominantly loss-of-function with frequent transmission from unaffected parents.
💊

Medical Actions

1
Neurosurgical CSF diversion
Action: cerebrospinal fluid diversion (ventricular shunting)NCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is cerebrospinal fluid diversion (ventricular shunting), annotated with Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Surgery
Ventricular shunting (ventriculoperitoneal shunt) or endoscopic third ventriculostomy to decompress ventriculomegaly/hydrocephalus, the latter particularly for the obstructive aqueductal-stenosis physiology. It can acutely reduce ventricular size, but carries high morbidity and failure rates and, in developmental (primary) congenital hydrocephalus, may fail to reduce ventriculomegaly or improve neurodevelopmental outcomes.
Mechanism Target:
Hydrocephalus — CSF diversion addresses the hydrocephalus/ventriculomegaly without correcting the underlying neurodevelopmental mechanism.
Show evidence (1 reference)
PMID:33077954 SUPPORT Human clinical
"neurosurgical CSF diversion (via ventricular shunting or brain endoscopy) can acutely decrease ICP and ventricular size"
Supports CSF diversion as the intervention targeting the ventricular enlargement.
Show evidence (2 references)
PMID:33077954 SUPPORT Human clinical
"Neurosurgical CSF diversion when undertaken in this context can fail to reduce ventriculomegaly or improve neurodevelopmental outcomes"
Documents the limited efficacy of CSF diversion in developmental congenital hydrocephalus.
PMID:42829386 SUPPORT BACKGROUND Human clinical
"The pooled prevalence of 30-day shunt failure was 13.8% (95% CI 11.2-16.8)"
Quantifies the early-failure rate of ventricular shunting in pediatric hydrocephalus generally, supporting the stated high failure rate.
🔬

Diagnosis

1
Molecular genetic testing
Diagnosis is molecular: trio whole-exome or whole-genome sequencing identifying a damaging (usually de novo) SMARCC1 variant, supported by brain MRI (ventriculomegaly, aqueductal stenosis, callosal anomalies) and echocardiography for cardiac defects.
trio whole-exome/whole-genome sequencing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:38128548 SUPPORT Human clinical
"These results highlight utility of trio-based whole-exome sequencing for identifying pathogenic variants in sporadic congenital structural brain disorders and suggest whole-exome sequencing may be a valuable adjunct in clinical management of congenital hydrocephalus patients"
Establishes trio whole-exome sequencing as the diagnostic modality for identifying the causal SMARCC1 variant.
🐁

Animal Models

2
Xenopus tropicalis Smarcc1 knockdown
Smarcc1 depletion in Xenopus tropicalis recapitulates aqueductal stenosis and cardiac defects; the phenotype is rescued by wild-type but not patient-specific variant SMARCC1, demonstrating variant pathogenicity.
Species
Xenopus tropicalis
Genotype
Smarcc1 morpholino knockdown
Publication
PMID:38128548
Pathograph links
Structural Brain Dysgenesis recapitulates fidelity: moderate observes: tissue Knockdown reproduces the aqueductal stenosis of the human structural brain malformation, with wild-type (but not variant) SMARCC1 rescue.
Limitations: Amphibian morpholino knockdown models acute gene depletion rather than a heterozygous human germline variant, and cannot reproduce the full human neurodevelopmental phenotype.
Readouts
Cerebral aqueduct patency (optical coherence tomography)
Direction: ALTERED
Interpretation: Smarcc1-depleted tadpoles develop aqueductal stenosis, the structural correlate of the human lesion.
Show evidence (1 reference)
PMID:38128548 SUPPORT Model organism
"Xenopus knockdowns recapitulated both aqueductal stenosis and cardiac defects and were rescued by wild-type but not patient-specific variant SMARCC1"
Reports the aqueductal stenosis and cardiac readouts and the wild-type-specific rescue.
Show evidence (1 reference)
PMID:38128548 SUPPORT Model organism
"Xenopus knockdowns recapitulated both aqueductal stenosis and cardiac defects and were rescued by wild-type but not patient-specific variant SMARCC1"
Establishes the Xenopus knockdown as informative for the human structural malformation mechanism.
Baf155msp/msp mouse
Mice homozygous for the Smarcc1 missense allele Baf155msp exhibit exencephaly due to defective neural stem cell proliferation and increased apoptosis, supporting the neural-progenitor basis of the human disease.
Species
Mouse
Genotype
Smarcc1 (Baf155) msp/msp homozygous missense
Publication
PMID:33077954
Pathograph links
Impaired Neurogenesis and Neuronal Differentiation partially recapitulates fidelity: moderate observes: cellular The homozygous missense mouse reproduces the neural stem cell proliferation defect and apoptosis that underlie the human mechanism. Note this model's reduced proliferation is the opposite direction to the Baf155/Baf170 forebrain conditional knockout, which retains proliferation while blocking differentiation.
Limitations: The mouse carries a homozygous missense allele rather than the human heterozygous loss-of-function state, and its neural-tube phenotype is exencephaly rather than the hydrocephalus/aqueductal stenosis seen in patients, so the structural outcome is not directly reproduced.
Show evidence (1 reference)
PMID:33077954 SUPPORT Model organism
"exhibit exencephaly similar to Trim71 mutant mice as a result of defective NSC proliferation and increased apoptosis"
Reports the neural stem cell proliferation defect and apoptosis in the Smarcc1 missense mouse.
{ }

Source YAML

click to show 
name: SMARCC1-associated Developmental Dysgenesis Syndrome
creation_date: "2026-11-04T00:00:00Z"
category: Mendelian
synonyms:
- SMARCC1-related neurodevelopmental disorder
- BAF155-associated developmental dysgenesis
- SMARCC1-related congenital hydrocephalus
disease_term:
  preferred_term: SMARCC1-associated developmental dysgenesis syndrome
  term:
    id: MONDO:0700123
    label: SMARCC1-associated developmental dysgenesis syndrome
parents:
- BAFopathy
notes: >-
  The VERY_FREQUENT neurological phenotype frequencies are derived from cohorts
  ascertained on ventriculomegaly or neurosurgically-treated congenital
  hydrocephalus, so they are likely inflated relative to the full SMARCC1
  mutational spectrum; the defining study (Singh et al., 2024) describes
  "variable presence" of these features.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  description: >-
    Dominant disorder caused by heterozygous SMARCC1 variants. Causal variants
    arise de novo in many probands but can also be transmitted from an
    apparently unaffected parent, consistent with incomplete penetrance.
  evidence:
  - reference: PMID:37285932
    reference_title: "First reports of fetal SMARCC1 related hydrocephalus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both identified variants are inherited from a healthy parent, which supports the reported incomplete penetrance of this gene"
    explanation: Documents transmitted variants from unaffected parents, establishing incomplete penetrance of the dominant allele.
pathophysiology:
- name: SMARCC1 Loss-of-Function
  biological_scale: MOLECULAR
  description: >-
    Heterozygous, frequently de novo, loss-of-function or damaging missense
    variants in SMARCC1 reduce the dose of functional BAF155, a core scaffold
    subunit of the SWI/SNF (BAF) ATP-dependent chromatin-remodeling complex.
    Haploinsufficiency is the proposed disease mechanism.
  genes:
  - preferred_term: SMARCC1
    term:
      id: hgnc:11104
      label: SMARCC1
  molecular_functions:
  - preferred_term: chromatin binding
    modifier: DECREASED
    term:
      id: GO:0003682
      label: chromatin binding
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
    zygosity: HETEROZYGOUS
  evidence:
  - reference: PMID:38128548
    reference_title: "A novel SMARCC1 BAFopathy implicates neural progenitor epigenetic dysregulation in human hydrocephalus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "six rare, protein-altering de novo variants localized to highly conserved residues in key functional domains"
    explanation: Establishes rare de novo protein-altering SMARCC1 variants in conserved functional domains as the genetic basis.
  - reference: PMID:33077954
    reference_title: "Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These data suggest that SMARCC1 haploinsufficiency increases CH risk"
    explanation: States haploinsufficiency as the mechanism by which SMARCC1 loss causes disease.
  - reference: PMID:34906496
    reference_title: "Retrospective analysis of a clinical exome sequencing cohort reveals the mutational spectrum and identifies candidate disease-associated loci for BAFopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We also identified de novo or predicted loss-of-function variants in 4 candidate BAFopathy genes, including ACTL6A, BICRA (implicated in Coffin-Siris syndrome during this study), PBRM1, and SMARCC1"
    explanation: Independent clinical-exome cohort identifies de novo/loss-of-function SMARCC1 variants and places the gene among the BAFopathies.
  downstream:
  - target: BAF Complex Chromatin-Remodeling Dysfunction
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31020615
      reference_title: "RBM15 Modulates the Function of Chromatin Remodeling Factor BAF155 Through RNA Methylation in Developing Cortex."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: BACKGROUND
      snippet: "As a core and scaffold subunit of the BAF (SWI/SNF-like) complex, BAF155 is capable of regulating the stability and function of the BAF complex"
      explanation: BAF155 is the scaffold subunit that maintains BAF-complex stability and function, so its loss impairs the complex.
- name: BAF Complex Chromatin-Remodeling Dysfunction
  biological_scale: MOLECULAR
  description: >-
    Reduced BAF155 impairs the nucleosome-remodeling activity of the mSWI/SNF
    (BAF) complex, disrupting the chromatin-accessibility changes that normally
    program gene expression during brain development.
  molecular_functions:
  - preferred_term: ATP-dependent chromatin remodeler activity
    modifier: DECREASED
    term:
      id: GO:0140658
      label: ATP-dependent chromatin remodeler activity
  biological_processes:
  - preferred_term: chromatin remodeling
    modifier: DECREASED
    term:
      id: GO:0006338
      label: chromatin remodeling
  evidence:
  - reference: PMID:37285932
    reference_title: "First reports of fetal SMARCC1 related hydrocephalus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "SMARCC1 encodes a subunit of the mSWI/SNF complex and affects the chromatin structure and expression of several genes"
    explanation: States that SMARCC1 loss alters chromatin structure and downstream gene expression.
  downstream:
  - target: Aberrant H3K27me3 Accumulation
    causal_link_type: DIRECT
  - target: Abnormal heart morphology
    causal_link_type: DIRECT
    description: >-
      BAF-complex remodeling is also required for cardiac development; loss of
      SMARCC1 produces structural cardiac defects as an extra-neural arm of the
      syndrome.
    evidence:
    - reference: PMID:38128548
      reference_title: "A novel SMARCC1 BAFopathy implicates neural progenitor epigenetic dysregulation in human hydrocephalus."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Xenopus knockdowns recapitulated both aqueductal stenosis and cardiac defects and were rescued by wild-type but not patient-specific variant SMARCC1"
      explanation: Smarcc1 knockdown reproduces cardiac defects, supporting BAF dysfunction as their cause.
- name: Aberrant H3K27me3 Accumulation
  biological_scale: MOLECULAR
  description: >-
    Loss of BAF-complex remodeling impairs the H3K27 demethylases UTX/KDM6A and
    JMJD3/KDM6B, so repressive H3K27me3 marks accumulate at developmental genes.
    Established in Baf155/Baf170 conditional-knockout mouse forebrain rather than
    in the human heterozygous state.
  molecular_functions:
  - preferred_term: histone H3K27me2/H3K27me3 demethylase activity
    modifier: DECREASED
    term:
      id: GO:0071558
      label: histone H3K27me2/H3K27me3 demethylase activity
  evidence:
  - reference: PMID:26986003
    reference_title: "Epigenetic regulation by BAF (mSWI/SNF) chromatin remodeling complexes is indispensable for embryonic development."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "BAF complexes globally control the key heterochromatin marks, H3K27me2 and -3, by directly modulating the enzymatic activity of the H3K27 demethylases, Utx and Jmjd3"
    explanation: BAF complexes raise H3K27me2/3 by modulating the UTX/JMJD3 demethylases, so their loss lets the marks accumulate.
  downstream:
  - target: De-repressed Wnt Signaling
    causal_link_type: DIRECT
- name: De-repressed Wnt Signaling
  biological_scale: MOLECULAR
  description: >-
    Loss of BAF complexes de-represses Wnt signaling and silences
    neuronal-differentiation genes while activating proliferation-associated
    genes. Established in Baf155/Baf170 conditional-knockout mouse forebrain
    rather than in the human heterozygous state.
  biological_processes:
  - preferred_term: canonical Wnt signaling pathway
    modifier: INCREASED
    term:
      id: GO:0060070
      label: canonical Wnt signaling pathway
  evidence:
  - reference: PMID:29779894
    reference_title: "Epigenetic Regulation by BAF Complexes Limits Neural Stem Cell Proliferation by Suppressing Wnt Signaling in Late Embryonic Development."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Inactivation of BAF complexes leads to H3K27me3-linked silencing of neuronal differentiation-related genes, with concurrent H3K4me2-mediated activation of proliferation-associated genes via de-repression of Wnt signaling"
    explanation: Links BAF loss to H3K27me3-mediated silencing of differentiation genes and Wnt de-repression.
  downstream:
  - target: Dysregulated Neurodevelopmental Transcription
    causal_link_type: DIRECT
- name: Dysregulated Neurodevelopmental Transcription
  biological_scale: MOLECULAR
  description: >-
    Loss of BAF-dependent chromatin remodeling dysregulates the transcriptional
    programs controlling mid-gestational neurogenesis, including the
    neurogenic transcription factors NEUROD2 and MAB21L2.
  biological_processes:
  - preferred_term: regulation of neurogenesis
    modifier: DECREASED
    term:
      id: GO:0050767
      label: regulation of neurogenesis
  evidence:
  - reference: PMID:38128548
    reference_title: "A novel SMARCC1 BAFopathy implicates neural progenitor epigenetic dysregulation in human hydrocephalus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "altered expression of key genes linked to midgestational neurogenesis, including the transcription factors NEUROD2 and MAB21L2"
    explanation: Human fetal brain transcriptomics show SMARCC1 variants dysregulate mid-gestational neurogenic gene expression.
  downstream:
  - target: Impaired Neurogenesis and Neuronal Differentiation
    causal_link_type: DIRECT
- name: Impaired Neurogenesis and Neuronal Differentiation
  biological_scale: CELLULAR
  description: >-
    Dysregulated transcription impairs neuronal differentiation and neurogenic
    output of neural progenitors in the developing telencephalon, the proposed
    neural-stem-cell basis of SMARCC1-associated congenital hydrocephalus. The
    two mouse models disagree on the direction of the proliferation change: the
    Baf155/Baf170 forebrain conditional knockout keeps progenitors proliferating
    while blocking differentiation (PMID:29779894), whereas the Baf155msp/msp
    missense mouse shows reduced progenitor proliferation (PMID:33077954). Only
    the shared impaired-differentiation/neurogenesis outcome is asserted here;
    the proliferation direction is left unbound.
  cell_types:
  - preferred_term: radial glial cell
    term:
      id: CL:0000681
      label: radial glial cell
  - preferred_term: neural stem cell
    term:
      id: CL:0000047
      label: neural stem cell
  biological_processes:
  - preferred_term: neuron differentiation
    modifier: DECREASED
    term:
      id: GO:0030182
      label: neuron differentiation
  evidence:
  - reference: PMID:33077954
    reference_title: "Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SMARCC1 is an ATP-dependent chromatin remodeler that regulates gene expression required for NSC proliferation, differentiation and survival during telencephalon development"
    explanation: States SMARCC1's role in regulating neural stem cell differentiation and survival during telencephalic development.
  downstream:
  - target: Structural Brain Dysgenesis
    causal_link_type: DIRECT
- name: Structural Brain Dysgenesis
  biological_scale: TISSUE
  description: >-
    Impaired corticogenesis produces structural brain malformations -
    ventriculomegaly/hydrocephalus with aqueductal stenosis and corpus callosum
    abnormalities.
  evidence:
  - reference: PMID:38128548
    reference_title: "A novel SMARCC1 BAFopathy implicates neural progenitor epigenetic dysregulation in human hydrocephalus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characterized by variable presence of cerebral ventriculomegaly, aqueductal stenosis, developmental delay and a variety of structural brain or cardiac defects"
    explanation: Defines the structural malformation spectrum resulting from the SMARCC1 mechanism.
  downstream:
  - target: Aqueductal stenosis
  - target: Abnormal corpus callosum morphology
  - target: Global developmental delay
  - target: Seizure
phenotypes:
- name: Hydrocephalus
  category: Neurologic
  phenotype_term:
    preferred_term: Hydrocephalus
    term:
      id: HP:0000238
      label: Hydrocephalus
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:38128548
    reference_title: "A novel SMARCC1 BAFopathy implicates neural progenitor epigenetic dysregulation in human hydrocephalus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients exhibited hydrocephalus with aqueductal stenosis; corpus callosum abnormalities, developmental delay, and cardiac defects were also common"
    explanation: Hydrocephalus is the cardinal feature of the syndrome.
- name: Aqueductal stenosis
  category: Neurologic
  phenotype_term:
    preferred_term: Aqueductal stenosis
    term:
      id: HP:0002410
      label: Aqueductal stenosis
  frequency: VERY_FREQUENT
  sequelae:
  - target: Hydrocephalus
    causal_link_type: DIRECT
    description: Obstruction of the cerebral aqueduct impedes CSF flow, producing non-communicating hydrocephalus.
  - target: Ventriculomegaly
    causal_link_type: DIRECT
    description: CSF outflow obstruction enlarges the cerebral ventricles.
  evidence:
  - reference: PMID:33077954
    reference_title: "Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "all six patients with SMARCC1 mutations with available brain imaging data had aqueductal stenosis and corpus callosum abnormalities, along with cardiac (n = 3) and skeletal abnormalities (n = 2)"
    explanation: All imaged SMARCC1 probands had aqueductal stenosis, the obstructive basis of the hydrocephalus.
- name: Ventriculomegaly
  category: Neurologic
  phenotype_term:
    preferred_term: Ventriculomegaly
    term:
      id: HP:0002119
      label: Ventriculomegaly
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:37285932
    reference_title: "First reports of fetal SMARCC1 related hydrocephalus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ventriculomegaly is the common feature in those fetuses"
    explanation: Ventriculomegaly is the common presenting feature, including antenatally.
- name: Abnormal corpus callosum morphology
  category: Neurologic
  phenotype_term:
    preferred_term: Corpus callosum abnormalities
    term:
      id: HP:0001273
      label: Abnormal corpus callosum morphology
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:33077954
    reference_title: "Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "all six patients with SMARCC1 mutations with available brain imaging data had aqueductal stenosis and corpus callosum abnormalities, along with cardiac (n = 3) and skeletal abnormalities (n = 2)"
    explanation: Corpus callosum abnormalities were present in all imaged SMARCC1 probands.
- name: Abnormal heart morphology
  category: Cardiovascular
  phenotype_term:
    preferred_term: Cardiac defects
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  frequency: FREQUENT
  evidence:
  - reference: PMID:38128548
    reference_title: "A novel SMARCC1 BAFopathy implicates neural progenitor epigenetic dysregulation in human hydrocephalus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients exhibited hydrocephalus with aqueductal stenosis; corpus callosum abnormalities, developmental delay, and cardiac defects were also common"
    explanation: Cardiac defects are a common extra-neural feature of the syndrome.
- name: Global developmental delay
  category: Neurologic
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  frequency: FREQUENT
  evidence:
  - reference: PMID:33077954
    reference_title: "Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "developmental delay and epilepsy were additional common features in both TRIM71 and SMARCC1 mutant probands"
    explanation: Developmental delay is a common feature in SMARCC1 probands.
- name: Seizure
  category: Neurologic
  phenotype_term:
    preferred_term: Epilepsy
    term:
      id: HP:0001250
      label: Seizure
  frequency: FREQUENT
  evidence:
  - reference: PMID:33077954
    reference_title: "Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "developmental delay and epilepsy were additional common features in both TRIM71 and SMARCC1 mutant probands"
    explanation: Epilepsy is reported as an additional common feature in SMARCC1 probands.
- name: Abnormality of the skeletal system
  category: Skeletal
  phenotype_term:
    preferred_term: Skeletal abnormalities
    term:
      id: HP:0000924
      label: Abnormality of the skeletal system
    coarse_binding_basis: SOURCE_UNSPECIFIED
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:33077954
    reference_title: "Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "all six patients with SMARCC1 mutations with available brain imaging data had aqueductal stenosis and corpus callosum abnormalities, along with cardiac (n = 3) and skeletal abnormalities (n = 2)"
    explanation: Skeletal abnormalities were reported in 2 of 6 imaged SMARCC1 probands; the source names only "skeletal abnormalities" with no more specific finding, so the binding is left at the system level.
diagnosis:
- name: Molecular genetic testing
  description: >-
    Diagnosis is molecular: trio whole-exome or whole-genome sequencing
    identifying a damaging (usually de novo) SMARCC1 variant, supported by brain
    MRI (ventriculomegaly, aqueductal stenosis, callosal anomalies) and
    echocardiography for cardiac defects.
  diagnosis_term:
    preferred_term: trio whole-exome/whole-genome sequencing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:38128548
    reference_title: "A novel SMARCC1 BAFopathy implicates neural progenitor epigenetic dysregulation in human hydrocephalus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These results highlight utility of trio-based whole-exome sequencing for identifying pathogenic variants in sporadic congenital structural brain disorders and suggest whole-exome sequencing may be a valuable adjunct in clinical management of congenital hydrocephalus patients"
    explanation: Establishes trio whole-exome sequencing as the diagnostic modality for identifying the causal SMARCC1 variant.
genetic:
- name: SMARCC1
  gene_term:
    preferred_term: SMARCC1
    term:
      id: hgnc:11104
      label: SMARCC1
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    Dominant; variants are frequently de novo but also transmitted from
    unaffected parents with incomplete penetrance. Most reported variants are
    loss of function, consistent with a haploinsufficiency mechanism.
  gene_disease_validity:
  - validity_classification: DEFINITIVE
    classified_by: CLINGEN
    external_id: CGGV:assertion_bb13d681-db77-4219-93ce-a9eefbd2839c-2023-04-11T160000.000Z
    evidence:
    - reference: CGGV:assertion_bb13d681-db77-4219-93ce-a9eefbd2839c-2023-04-11T160000.000Z
      reference_title: "SMARCC1 / SMARCC1-associated developmental dysgenesis syndrome (Definitive)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "SMARCC1 | HGNC:11104 | SMARCC1-associated developmental dysgenesis syndrome | MONDO:0700123 | AD | Definitive | SOP9 | Brain Malformations Gene Curation Expert Panel | 2023-04-11T16:00:00.000Z"
      explanation: ClinGen Brain Malformations GCEP classifies the SMARCC1-disease relationship as Definitive (autosomal dominant).
  evidence:
  - reference: PMID:37285932
    reference_title: "First reports of fetal SMARCC1 related hydrocephalus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most of the reported variants are loss of function (LoF) and are often inherited from unaffected parents"
    explanation: Characterizes the SMARCC1 variant spectrum as predominantly loss-of-function with frequent transmission from unaffected parents.
animal_models:
- name: Xenopus tropicalis Smarcc1 knockdown
  species: Xenopus tropicalis
  genotype: Smarcc1 morpholino knockdown
  publication: PMID:38128548
  description: >-
    Smarcc1 depletion in Xenopus tropicalis recapitulates aqueductal stenosis
    and cardiac defects; the phenotype is rescued by wild-type but not
    patient-specific variant SMARCC1, demonstrating variant pathogenicity.
  modeled_mechanisms:
  - target: Structural Brain Dysgenesis
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Knockdown reproduces the aqueductal stenosis of the human structural brain
      malformation, with wild-type (but not variant) SMARCC1 rescue.
    limitations: >-
      Amphibian morpholino knockdown models acute gene depletion rather than a
      heterozygous human germline variant, and cannot reproduce the full human
      neurodevelopmental phenotype.
    readouts:
    - name: Cerebral aqueduct patency (optical coherence tomography)
      target: Structural Brain Dysgenesis
      direction: ALTERED
      interpretation: Smarcc1-depleted tadpoles develop aqueductal stenosis, the structural correlate of the human lesion.
      evidence:
      - reference: PMID:38128548
        reference_title: "A novel SMARCC1 BAFopathy implicates neural progenitor epigenetic dysregulation in human hydrocephalus."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Xenopus knockdowns recapitulated both aqueductal stenosis and cardiac defects and were rescued by wild-type but not patient-specific variant SMARCC1"
        explanation: Reports the aqueductal stenosis and cardiac readouts and the wild-type-specific rescue.
    evidence:
    - reference: PMID:38128548
      reference_title: "A novel SMARCC1 BAFopathy implicates neural progenitor epigenetic dysregulation in human hydrocephalus."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Xenopus knockdowns recapitulated both aqueductal stenosis and cardiac defects and were rescued by wild-type but not patient-specific variant SMARCC1"
      explanation: Establishes the Xenopus knockdown as informative for the human structural malformation mechanism.
- name: Baf155msp/msp mouse
  species: Mouse
  genotype: Smarcc1 (Baf155) msp/msp homozygous missense
  publication: PMID:33077954
  description: >-
    Mice homozygous for the Smarcc1 missense allele Baf155msp exhibit
    exencephaly due to defective neural stem cell proliferation and increased
    apoptosis, supporting the neural-progenitor basis of the human disease.
  modeled_mechanisms:
  - target: Impaired Neurogenesis and Neuronal Differentiation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      The homozygous missense mouse reproduces the neural stem cell
      proliferation defect and apoptosis that underlie the human mechanism. Note
      this model's reduced proliferation is the opposite direction to the
      Baf155/Baf170 forebrain conditional knockout, which retains proliferation
      while blocking differentiation.
    limitations: >-
      The mouse carries a homozygous missense allele rather than the human
      heterozygous loss-of-function state, and its neural-tube phenotype is
      exencephaly rather than the hydrocephalus/aqueductal stenosis seen in
      patients, so the structural outcome is not directly reproduced.
    evidence:
    - reference: PMID:33077954
      reference_title: "Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "exhibit exencephaly similar to Trim71 mutant mice as a result of defective NSC proliferation and increased apoptosis"
      explanation: Reports the neural stem cell proliferation defect and apoptosis in the Smarcc1 missense mouse.
treatments:
- name: Neurosurgical CSF diversion
  description: >-
    Ventricular shunting (ventriculoperitoneal shunt) or endoscopic third
    ventriculostomy to decompress ventriculomegaly/hydrocephalus, the latter
    particularly for the obstructive aqueductal-stenosis physiology. It can
    acutely reduce ventricular size, but carries high morbidity and failure
    rates and, in developmental (primary) congenital hydrocephalus, may fail to
    reduce ventriculomegaly or improve neurodevelopmental outcomes.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: cerebrospinal fluid diversion (ventricular shunting)
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_mechanisms:
  - target: Hydrocephalus
    description: CSF diversion addresses the hydrocephalus/ventriculomegaly without correcting the underlying neurodevelopmental mechanism.
    evidence:
    - reference: PMID:33077954
      reference_title: "Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "neurosurgical CSF diversion (via ventricular shunting or brain endoscopy) can acutely decrease ICP and ventricular size"
      explanation: Supports CSF diversion as the intervention targeting the ventricular enlargement.
  evidence:
  - reference: PMID:33077954
    reference_title: "Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neurosurgical CSF diversion when undertaken in this context can fail to reduce ventriculomegaly or improve neurodevelopmental outcomes"
    explanation: Documents the limited efficacy of CSF diversion in developmental congenital hydrocephalus.
  - reference: PMID:42829386
    reference_title: "Predictors and causes of 30-day failure after shunt placement in pediatric hydrocephalus: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "The pooled prevalence of 30-day shunt failure was 13.8% (95% CI 11.2-16.8)"
    explanation: Quantifies the early-failure rate of ventricular shunting in pediatric hydrocephalus generally, supporting the stated high failure rate.
references:
- reference: PMID:38128548
  title: "A novel SMARCC1 BAFopathy implicates neural progenitor epigenetic dysregulation in human hydrocephalus."
📚

References & Deep Research

References

1
PMID:38128548
A novel SMARCC1 BAFopathy implicates neural progenitor epigenetic dysregulation in human hydrocephalus.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: SMARCC1-associated Developmental Dysgenesis Syndrome · 2026-11-04T18:50:38Z · View source

De-novo curation of the SMARCC1 BAFopathy (MONDO:0700123, SMARCC1/hgnc:11104, ClinGen Definitive AD, Brain Malformations GCEP). Deep research: openscientist (preflight-dr PASS, SMARCC1=56 mentions; report reference_validation 21/21 verified, term_validation 22/22, needs_review only benign label mismatches). Primary sources: PMID:38128548 (defining Brain 2024 cohort + Xenopus model), PMID:33077954 (Jin 2020 Nat Med CH exome + Baf155msp mouse), PMID:37285932 (fetal cases, incomplete penetrance), PMID:26986003 & PMID:29779894 (BAF/H3K27me3/Wnt epigenetic mechanism), PMID:34906496 (independent BAFopathy cohort). Pathograph: SMARCC1 LoF -> BAF remodeling dysfunction -> aberrant H3K27me3/de-repressed Wnt -> dysregulated neurodevelopmental transcription -> impaired neural progenitor proliferation -> structural brain dysgenesis; 7/7 phenotypes connected. Xenopus and mouse animal models with modeled_mechanisms. No GeneReviews chapter (verified offline + online). Validated: just validate-disorders PASS (26/26 snippets), terms/entity-refs/causal-targets/logical-rules/gene-validity/coarse/enum/duplicate-keys all clean.

OpenScientist ▸
SMARCC1-associated Developmental Dysgenesis Syndrome — Comprehensive Disease Report
openscientist-autonomous 21 citations 2026-11-04T18:43:19.901713

SMARCC1-associated Developmental Dysgenesis Syndrome — Comprehensive Disease Report

MONDO ID: MONDO:0700123 · Causal gene: SMARCC1 (BAF155; HGNC:11104; OMIM gene 601732; UniProt Q92922) · Classification: Mendelian, autosomal-dominant BAFopathy (subclass of MONDO:0700120) · Synonym: SMARCC1-related BAFopathy

Summary

SMARCC1-associated Developmental Dysgenesis Syndrome is an autosomal-dominant, de-novo-dominated Mendelian neurodevelopmental disorder caused by haploinsufficient/damaging variants in SMARCC1, the gene encoding BAF155 — the core scaffold subunit of the BAF (mammalian SWI/SNF) ATP-dependent chromatin-remodeling complex. The disease was defined by Singh et al. (2024) through a large genetic-association study of ventriculomegalic trios, in which rare, protein-altering de novo SMARCC1 variants surpassed genome-wide significance. The clinical core comprises cerebral ventriculomegaly / congenital hydrocephalus, aqueductal stenosis, corpus callosum abnormalities, developmental delay, and structural cardiac defects, with variable expressivity.

Mechanistically, the disorder is not a disease of impaired cerebrospinal fluid (CSF) dynamics but of genetic disruption of prenatal neural stem/progenitor biology. SMARCC1/BAF155 is a scaffold subunit that controls BAF-complex stability; its loss destabilizes the complex and dysregulates the epigenetic landscape of neural progenitors — elevating the repressive histone mark H3K27me3 (via control of the demethylases UTX/JMJD3), de-repressing Wnt signaling, and shifting the balance toward excess progenitor proliferation and impaired neuronal differentiation. Downstream, pro-neurogenic transcription factors NEUROD2 and MAB21L2 are dysregulated. In vivo Xenopus tropicalis modeling recapitulated both aqueductal stenosis and cardiac defects and was rescued by wild-type but not patient-variant SMARCC1, establishing loss-of-function pathogenicity.

The entity is newly described and minimally curated: MONDO places it under BAFopathy and links it to SMARCC1, but there are no OMIM/Orphanet/ICD cross-references and no curated HPO phenotype annotations yet, so all phenotype terms here are literature-derived. Population frequency, penetrance, prognosis, and treatment are therefore characterized qualitatively. Management is supportive and follows general congenital-hydrocephalus practice (CSF diversion via shunt or endoscopic third ventriculostomy, developmental support). No targeted or disease-specific therapy exists.

1. Disease Information

Overview. SMARCC1-associated Developmental Dysgenesis Syndrome is a Mendelian BAFopathy caused by germline (overwhelmingly de novo) variants in SMARCC1, which encodes BAF155, a core scaffold subunit of the BAF/mSWI/SNF chromatin-remodeling complex. It manifests as a prenatal brain developmental disorder with variable cerebral ventriculomegaly, aqueductal stenosis, corpus callosum anomalies, developmental delay, and cardiac defects (Findings F001, F006; PMID: 38128548).

Key identifiers.

Resource Identifier Status
MONDO MONDO:0700123 Confirmed (name: "SMARCC1-associated developmental dysgenesis syndrome"); subclass of MONDO:0700120 (BAFopathy)
Causal gene SMARCC1 (HGNC:11104; OMIM 601732; Ensembl ENSG00000173473; chr3p21.31) Confirmed
OMIM (disease/phenotype) Not recorded No dedicated phenotype MIM yet
Orphanet Not recorded —
ICD-10 / ICD-11 Not recorded —
MeSH Not recorded —
UniProt (protein) Q92922 (SMARCC1/BAF155, 1105 aa) Confirmed

The MONDO term and its parentage/gene link were verified via EBI OLS4 and the Monarch Initiative API (Findings F011, F012).

Synonyms. SMARCC1-related BAFopathy (MONDO synonym); informally "SMARCC1 BAFopathy."

Information source. Derived from aggregated disease-level resources and primary literature, principally the defining cohort study (Singh et al. 2024) combining whole-exome sequencing of 2,697 ventriculomegalic trios with functional modeling — a research cohort rather than routine EHR. MONDO/Monarch provide ontology placement but no patient-level data.

2. Etiology

Primary cause — genetic. The disease is caused by rare, protein-altering, predominantly de novo variants in SMARCC1. Singh et al. identified six such variants at highly conserved residues in key functional domains, exceeding genome-wide significance in a cohort of 2,697 ventriculomegalic trios / 8,091 exomes (2016–2023) versus 1,798 control exomes (Findings F001, F006; PMID: 38128548). An independent clinical-exome cohort separately identified de novo/loss-of-function SMARCC1 variants and classified it as a BAFopathy gene (Finding F001; PMID: 34906496).

Genetic risk architecture. The core mechanism is haploinsufficiency: SMARCC1 is extremely intolerant to loss of function (gnomAD v2.1.1 pLI ≈ 1.00, observed/expected LoF = 43/147.4 = 0.29, LOEUF = 0.38, LoF Z = 7.30; missense Z = 3.01) — a constraint profile consistent with a single damaging allele being sufficient to cause disease (Finding F004). No susceptibility loci or polygenic contributors are established for this monogenic disorder; modifier genes are not yet defined.

Environmental / protective / lifestyle factors. None are established. As a de novo dominant developmental disorder, there are no documented environmental triggers, protective alleles, dietary or lifestyle modifiers, infectious agents, or gene-environment interactions — not applicable / not available for this entity (Section 5 likewise).

3. Phenotypes

Because MONDO:0700123 carries zero curated HPO annotations (Finding F012, Monarch API disease-to-phenotype count = 0), all phenotype terms below are literature-derived from the defining cohort and should be treated as provisional frequencies.

Phenotype Type Suggested HPO Onset Notes / frequency (qualitative)
Cerebral ventriculomegaly Imaging/structural sign HP:0002119 (Ventriculomegaly) Congenital/prenatal Core feature; variable presence
Congenital hydrocephalus Clinical sign HP:0000238 (Hydrocephalus) Congenital Core; neurosurgically treated in cohort
Aqueductal stenosis Structural sign HP:0002410 (Aqueductal stenosis) Congenital Prominent; recapitulated in frog model
Corpus callosum abnormality Structural sign HP:0001273 (Abnormal corpus callosum) Congenital "Common" in cohort
Developmental delay Behavioral/neurodevelopmental HP:0001263 (Global developmental delay) Infancy/childhood Common
Structural cardiac defect Physical/structural HP:0001627 (Abnormal heart morphology) Congenital Common; recapitulated in Xenopus

Characteristics. Onset is congenital/prenatal for structural brain and cardiac features; developmental delay emerges in infancy–childhood. Severity and progression are variable — the defining paper explicitly describes "variable presence of cerebral ventriculomegaly, aqueductal stenosis, developmental delay and a variety of structural brain or cardiac defects" (PMID: 38128548, Finding F006). Quantitative frequencies, QoL instruments (EQ-5D/SF-36/PROMIS), and per-phenotype severity grading are not yet available.

4. Genetic / Molecular Information

Causal gene. SMARCC1 (BAF155), HGNC:11104, OMIM 601732, Ensembl ENSG00000173473, chr3:47,585,269–47,782,106 (3p21.31). Encodes a 1105-aa core/scaffold subunit of the BAF complex (UniProt Q92922).

Protein domain architecture and variant localization (Finding F011; PMID: 33953332, PMID: 28438634):

Domain Residues (aa) Function
N-terminal module 28–302 DNA contact / assembly
— MarR-like (putative DNA-binding) 38–164 DNA binding
— BRCT (N) 168–211 Protein interaction
— Chromo domain 217–245 Chromatin engagement
— BRCT (C) 261–285 Protein interaction
SWIRM domain 449–546 Binds SMARCB1/BAF47 (complex assembly)
SANT domain 618–669 Histone-tail / DNA binding
Disordered regions 296–439, 745–860, 956–1028, 1041–1105 Flexible linkers

Pathogenic de novo variants cluster at highly conserved residues within these functional domains (Findings F006, F011).

Variant classification and population frequency. ClinVar contains 287 SMARCC1 records — 68 Pathogenic, 17 Likely pathogenic, remainder VUS/benign (Finding F010); note this count mixes germline developmental submissions with somatic/cancer classifications, so it is an upper bound on developmental-disease variants. Variant types in the developmental syndrome are missense (de novo, conserved residues) and predicted loss-of-function (nonsense/frameshift/splice); pathogenic alleles are effectively absent from population databases (gnomAD), consistent with de novo origin and strong constraint.

Origin and functional consequence. Germline de novo in the developmental syndrome; functional consequence is loss of function / haploinsufficiency (not gain-of-function or dominant-negative, per rescue data). A distinct somatic role exists in cancer (Finding F009): somatic SMARCC1 deletion acts as a tumor suppressor (oral squamous cell carcinoma, PMID: 26934577; biallelic loss in malignant mesothelioma, PMID: 24916674). >20–25% of human cancers carry mutations in SWI/SNF/BAF subunit genes (PMID: 35158202). These somatic contexts are mechanistically and clinically separate from the germline developmental disorder.

Modifier genes. Not yet defined.

Epigenetic information. The disease mechanism is intrinsically epigenetic: BAF complexes globally control H3K27me2/3 by modulating the demethylases UTX and JMJD3 (PMID: 26986003, Finding F003). A disease-specific methylation episignature for SMARCC1 is not yet reported.

Chromosomal abnormalities. Large 3p21.31 interstitial deletions encompassing SMARCC1 (among many genes) have been described with developmental delay and dysmorphism (PMID: 27385966), but phenotypes in those cases are contiguous-gene effects (e.g., SETD2), not the isolated SMARCC1 syndrome.

5. Environmental Information

Not applicable. No environmental, lifestyle, or infectious factors are established for this monogenic de novo dominant disorder. No toxins, radiation, occupational exposures, dietary factors, or pathogens are implicated.

6. Mechanism / Pathophysiology

Ordered causal chain

  1. A de novo damaging/loss-of-function variant in SMARCC1 (missense at conserved domain residues, or LoF) arises in the germline → reduces functional BAF155 (haploinsufficiency) (demonstrated: genetic constraint pLI≈1, de novo enrichment; F004, F006).
  2. Reduced BAF155 scaffold → destabilizes the BAF (mSWI/SNF) chromatin-remodeling complex, because BAF155 regulates complex stability and assembly (demonstrated in mouse/in vitro; F003; PMID: 31020615).
  3. BAF dysfunction → loss of BAF-mediated control over H3K27 demethylases UTX/JMJD3 → global increase in repressive H3K27me2/3 (demonstrated in mouse forebrain; F003; PMID: 26986003).
  4. Altered histone-methylation balance (↑H3K27me3 on neuronal-differentiation genes; ↑H3K4me2 on proliferation genes) → de-repression of Wnt signaling (demonstrated in mouse late corticogenesis; F005; PMID: 29779894).
  5. Wnt de-repression → increased proliferation of neuroepithelial-like neural stem cells and impaired neuronal differentiation (demonstrated; F005).
  6. Imbalanced progenitor proliferation/differentiation → dysregulation of midgestational neurogenesis transcription factors NEUROD2 and MAB21L2 (demonstrated across human fetal brain and Xenopus; F007; PMID: 38128548).
  7. Disrupted neuro-gliogenesis → structural brain dysgenesis: aqueductal stenosis, cerebral ventriculomegaly/hydrocephalus, corpus callosum anomalies — i.e., the primary lesion is developmental, not impaired CSF dynamics (inferred for human from model + cohort transcriptomics; supported by F002; PMID: 33077954).
  8. Branch — cardiac: BAF dysfunction in cardiac progenitors → structural cardiac defects (demonstrated by Xenopus knockdown recapitulation and rescue; F007).
  9. Brain dysgenesis + hydrocephalus → developmental delay and the clinical syndrome (clinical observation; F006).
 SMARCC1 de novo LoF/missense
  │ (haploinsufficiency)
  ▼
 BAF/mSWI-SNF complex destabilized
  │
  ▼
 ↑H3K27me3 (UTX/JMJD3 dysregulation)
  │
  ▼
 Wnt signaling de-repressed
  │
     ┌────┴───────────────┐
     ▼                     ▼
 ↑NSC proliferation   NEUROD2/MAB21L2
 ↓neuronal diff.      dysregulated
     │                     │
     └────────┬────────────┘
      ▼
  Disrupted neuro-gliogenesis ──► aqueductal stenosis,
  (NOT impaired CSF dynamics)      ventriculomegaly, callosal anomaly
      │
      ├──► (branch) cardiac progenitor defect ─► structural cardiac defects
      ▼
  Developmental delay + clinical syndrome

Molecular pathways: Wnt signaling (de-repressed; KEGG hsa04310); chromatin remodeling / histone methylation (H3K27me2/3; H3K4me2). Cellular processes: neural stem cell proliferation (GO:0050767 regulation of neurogenesis), neuronal differentiation (GO:0030182), chromatin remodeling (GO:0006338), histone H3-K27 methylation (GO:0070734). Protein dysfunction: loss of scaffold function → complex instability (not aggregation). Cell types: neural stem/progenitor cells (CL:0000047 neuronal stem cell; CL:0000031 neuroblast; CL:0000681 radial glial cell), cardiac progenitors. Subcellular: nucleus / nuclear chromatin (GO:0000785 chromatin; GO:0016514 SWI/SNF complex; GO:0071564 npBAF complex). Multi-omics / functional genomics: cross-species transcriptomics (human fetal brain RNA-seq + Xenopus) converging on shared neurogenesis genes (F007); Xenopus knockdown-rescue as the in vivo functional assay (F007).

Upstream nodes = SMARCC1 loss → BAF instability → histone-methylation shift; downstream = Wnt/progenitor imbalance → transcription-factor dysregulation → structural malformation.

7. Anatomical Structures Affected

  • Primary organ: brain (UBERON:0000955), especially cerebral ventricles (UBERON:0002285 lateral ventricle), cerebral aqueduct (UBERON:0002289; aqueductal stenosis), corpus callosum (UBERON:0002336), neocortex and hippocampus (implicated by BAF-loss cortical models, F005).
  • Secondary / branch organ: heart (UBERON:0000948) — structural cardiac defects.
  • Body systems: central nervous system (developmental) and cardiovascular system.
  • Tissue/cell level: neuroepithelium / neural stem & progenitor cells (CL:0000047, CL:0000681 radial glia, CL:0000031 neuroblast); cardiac progenitor cells.
  • Subcellular: nucleus / chromatin (GO:0000785); BAF/SWI-SNF complex (GO:0016514, GO:0071564).
  • Localization / lateralization: midline and bilateral CNS structures; ventriculomegaly typically bilateral. Precise lateralization not systematically reported.

8. Temporal Development

  • Onset: congenital/prenatal for brain and cardiac malformations (detectable as fetal/neonatal ventriculomegaly); developmental delay apparent in infancy–childhood. Onset pattern is chronic/congenital, arising during midgestational neurogenesis — the critical developmental window (F002, F007).
  • Progression: structural malformations are fixed at birth; hydrocephalus may require intervention. Developmental delay is generally stable to slowly evolving rather than neurodegenerative. Formal natural-history/longitudinal data are not available.
  • Critical period: fetal neuro-gliogenesis (midgestation) is the window of vulnerability and the only plausible window for mechanistic intervention — likely inaccessible postnatally.
  • Remission: none intrinsic; hydrocephalus is managed surgically (symptomatic, not curative).

9. Inheritance and Population

  • Inheritance pattern: autosomal dominant, overwhelmingly de novo (F001, F006).
  • Penetrance / expressivity: expressivity is explicitly variable; penetrance not precisely quantified given small cohort.
  • Anticipation / mosaicism / founder effects / consanguinity: not reported / not applicable (de novo dominant, not a repeat-expansion or recessive disorder). Germline/gonadal mosaicism is a theoretical source of recurrence risk.
  • Carrier frequency: not applicable (de novo dominant); pathogenic alleles essentially absent from gnomAD.
  • Epidemiology: prevalence and incidence are not established — the syndrome is newly defined from a research cohort and carries no Orphanet/registry prevalence figure. It represents a rare, genetically defined subset within the broader congenital-hydrocephalus and BAFopathy populations.
  • Demographics / geography / sex ratio / age distribution: no population-specific enrichment, geographic clustering, or sex bias established; affected individuals are identified in the prenatal/pediatric period.

For context, the broader Coffin-Siris/Nicolaides-Baraitser BAFopathy family may account for ~1% of intellectual disability (PMID: 25249037, F008) — but SMARCC1 disease is a distinct, much rarer entity within that family.

10. Diagnostics

  • Genetic testing is the definitive diagnostic. Trio whole-exome sequencing (WES) or whole-genome sequencing (WGS) identifying a de novo damaging SMARCC1 variant is the basis of diagnosis (the entity was defined by trio WES; F001, F006). Single-gene testing and BAFopathy/congenital-hydrocephalus gene panels including SMARCC1 are appropriate. Chromosomal microarray may detect 3p21.31 deletions but typically as contiguous-gene events (PMID: 27385966).
  • Variant interpretation: ACMG/AMP classification against ClinVar (68 P / 17 LP records; F010); de novo occurrence (PS2), absence from gnomAD (PM2), and conserved functional-domain location support pathogenicity.
  • Imaging: fetal/neonatal cranial ultrasound and brain MRI demonstrate ventriculomegaly, aqueductal stenosis, and callosal anomalies; echocardiography for cardiac defects.
  • Laboratory biomarkers / metabolomics / proteomics / liquid biopsy: no specific biochemical biomarker exists; diagnosis is molecular/radiological.
  • Clinical criteria: no formal consensus criteria yet (newly defined).
  • Differential diagnosis: other BAFopathies — Coffin-Siris syndrome (ARID1B, ARID1A, SMARCB1, SMARCA4, SMARCA2, SMARCE1, ARID2) and Nicolaides-Baraitser syndrome — which share BAF-subunit etiology but are distinguished by coarse facial features, sparse scalp hair, hypertrichosis, and fifth-digit nail/phalanx hypoplasia rather than the prominent congenital hydrocephalus/aqueductal stenosis of SMARCC1 disease (F008; PMID: 34906496, PMID: 35813374, PMID: 27264197). Also consider other monogenic congenital-hydrocephalus genes (e.g., TRIM71, CCDC88C, MPDZ; PMID: 29983323).
  • Screening: no population or newborn screening exists; cascade testing is generally uninformative given de novo origin.

11. Outcome / Prognosis

Prognostic data specific to SMARCC1 disease are limited/not formally reported. Outcome is driven by the severity of hydrocephalus and associated brain/cardiac malformations and by developmental delay. By analogy to genetic congenital hydrocephalus, morbidity relates to neurodevelopmental impairment and shunt-dependence complications (pediatric VP-shunt 30-day failure ~13.8%; PMID: 42829386). Survival, mortality, 5/10-year outcomes, QoL measures, and validated prognostic biomarkers are not available for this specific entity. Disease course is chronic/lifelong with stable (non-degenerative) neurodevelopmental impairment.

12. Treatment

No disease-specific or targeted therapy exists. Management is supportive and symptomatic, following general congenital-hydrocephalus and neurodevelopmental care:

  • Neurosurgical CSF diversion for hydrocephalus — ventriculoperitoneal shunting (NCIT: Ventriculoperitoneal Shunt) or endoscopic third ventriculostomy (ETV), particularly for obstructive/aqueductal-stenosis physiology (supporting surgical literature: PMID: 42886343, PMID: 42829386).
  • Cardiac management for structural defects (cardiology/surgical as indicated).
  • Developmental support — physical, occupational, and speech therapy; early intervention (NCIT: Rehabilitation Therapy).
  • Pharmacotherapy / pharmacogenomics / gene / cell / RNA / targeted / immunotherapy: none established or applicable.
  • Experimental: no disease-specific trials (no NCT identifiers) target SMARCC1 disease. Mechanistically, the epigenetic link (↑H3K27me3 via EZH2/demethylase axis) is of conceptual interest — EZH2 inhibition (GSK126) rescued a Baf155-CKO myeloid phenotype in mice (PMID: 33207205) — but this is not a validated therapy and the prenatal critical window likely limits translational feasibility.

13. Prevention

  • Primary prevention: none available (de novo mutation; not preventable by risk-factor modification or immunization).
  • Secondary prevention: prenatal detection of ventriculomegaly on ultrasound/MRI can prompt genetic evaluation and delivery/neurosurgical planning.
  • Genetic counseling: recurrence risk for parents of a child with a confirmed de novo variant is low but non-zero due to possible gonadal mosaicism; prenatal/preimplantation testing is feasible if a familial variant is identified. Counseling per NSGC/ACMG principles is recommended.
  • Public health / behavioral / environmental / prophylaxis: not applicable.

14. Other Species / Natural Disease

  • Orthologs: Smarcc1 is conserved across mammals (mouse Smarcc1), zebrafish (smarcc1a/b), Xenopus tropicalis (smarcc1), and other vertebrates. BAF-complex function is deeply evolutionarily conserved.
  • Natural disease in other species: no naturally occurring companion-animal or wildlife disease specifically attributed to SMARCC1 is catalogued (no established OMIA entry). Veterinary relevance is currently limited to experimental models.
  • Comparative biology: BAF/SMARCC1 roles in embryonic development, lineage specification, and neural progenitor regulation are conserved from frog to human (PMID: 26952987, PMID: 29779894); a zebrafish study linked BBS6 to Smarcc1a in congenital heart disease (PMID: 28753627).
  • Transmission / zoonosis: not applicable (genetic disorder).

15. Model Organisms

Model Type Manipulation Phenotype recapitulation Reference
Xenopus tropicalis Vertebrate (amphibian) smarcc1 knockdown; WT vs variant rescue Recapitulated aqueductal stenosis AND cardiac defects; rescued by WT but not patient-variant SMARCC1; shared NEUROD2/MAB21L2 dysregulation with human fetal brain PMID: 38128548 (F007)
Mouse (Mus musculus) Mammalian Baf155/Baf170 conditional KO (forebrain); Baf155 CKO ↑H3K27me3, impaired forebrain development; de-repressed Wnt, ↑NSC proliferation, impaired neuronal differentiation PMID: 26986003, PMID: 29779894 (F003, F005)
Mouse blastocyst/embryo Mammalian BAF155 up/down-regulation Lineage-specification defects (pluripotency-marker dysregulation) PMID: 26952987
Zebrafish (Danio rerio) Vertebrate smarcc1a/bbs6 manipulation Congenital-heart-disease-relevant transcriptional changes PMID: 28753627

Strengths: The Xenopus model is the strongest disease-specific validation — it reproduces both the neural (aqueductal stenosis) and cardiac arms of the human phenotype and provides variant-level loss-of-function proof via rescue. Mouse BAF155-loss models illuminate the upstream epigenetic (H3K27me3/Wnt) mechanism. Limitations: mouse studies use conditional/compound knockouts rather than the human heterozygous de novo state; no reported germline heterozygous Smarcc1 mouse that fully mirrors the human syndrome; iPSC/organoid models of patient variants are not yet published.

Mechanistic Model / Interpretation

The evidence converges on a single coherent model: SMARCC1 disease is a chromatinopathy of fetal neurogenesis. A de novo hit reduces functional BAF155 below the dose the developing brain tolerates (haploinsufficiency, pLI≈1). Because BAF155 is the scaffold that holds the BAF complex together, its loss has an outsized, complex-wide effect — explaining why a single damaging allele is pathogenic. The destabilized complex loses grip on the H3K27-methylation machinery, tipping progenitors toward Wnt-driven over-proliferation and away from neuronal differentiation, and derailing the NEUROD2/MAB21L2 neurogenic program during the narrow midgestational window. The resulting malformed neural tube/ventricular system manifests as aqueductal stenosis and ventriculomegaly, with a parallel branch in cardiac progenitors producing heart defects. Crucially, the hydrocephalus is a downstream developmental consequence, not a primary plumbing failure — reframing a "neurosurgical" phenotype as a chromatin-remodeling disorder (F002).

This model cleanly separates the germline developmental context (haploinsufficiency → malformation) from the somatic oncogenic context (SMARCC1 as a tumor suppressor whose loss drives cancer), unifying them under the theme that SMARCC1 dosage is critical across distinct cellular programs.

Evidence Base

PMID Role How it supports the findings
38128548 Defining study Names the syndrome; genome-wide-significant de novo SMARCC1 variants in 2,697 trios; Xenopus rescue; NEUROD2/MAB21L2 (F001, F006, F007)
34906496 Independent cohort De novo/LoF SMARCC1 in clinical-exome BAFopathy cohort; genotype-first constraint approach (F001, F004, F008)
33077954 Mechanistic framing Genetic disruption of neuro-gliogenesis, not CSF dynamics, is the primary CH pathomechanism (F002)
31020615 Protein function BAF155 as core/scaffold regulating BAF stability (F003)
26986003 Epigenetic mechanism BAF controls H3K27me2/3 via UTX/JMJD3; forebrain development (F003, F005)
29779894 Mechanism BAF loss → Wnt de-repression → ↑NSC proliferation, impaired differentiation (F005)
33953332 Structure N-terminal MarR/chromo/BRCT module architecture (F011)
28438634 Structure SWIRM domain binds BAF47/SMARCB1 (F011)
26934577 / 24916674 / 35158202 Somatic contrast SMARCC1 as tumor suppressor; SWI/SNF in >20% cancers (F009)
25249037 Epidemiologic context BAFopathy/CSS ~1% of intellectual disability (F008)

Constraint metrics (pLI, LOEUF) were retrieved directly from the gnomAD GraphQL API; ClinVar counts from NCBI E-utilities; MONDO parentage/gene link from the Monarch Initiative API and EBI OLS4.

Limitations and Knowledge Gaps

  1. Newly defined, minimally curated entity: no OMIM phenotype MIM, Orphanet, ICD, or MeSH code; zero curated HPO annotations (F012). All phenotype frequencies are literature-derived from a single defining cohort.
  2. Small patient numbers: six de novo variants underpin the definition; penetrance, expressivity ranges, prevalence/incidence, sex ratio, and natural history are not quantified.
  3. Prognosis and treatment: no disease-specific outcome data, QoL measures, prognostic biomarkers, or targeted therapies; management is extrapolated from general congenital-hydrocephalus practice.
  4. Mechanistic inferences: the human causal chain from histone-methylation shift → Wnt → malformation is strongly supported in mouse/frog but partly inferred for human; the EZH2-inhibition rescue is from a non-neural mouse model and is not a validated therapy.
  5. ClinVar counts mix germline and somatic submissions, inflating the apparent germline pathogenic-variant pool.
  6. No patient-derived iPSC/organoid models or human methylation episignature yet.

Proposed Follow-up Experiments / Actions

  1. Curate HPO annotations for MONDO:0700123 from the Singh 2024 cohort and future cases, with explicit frequencies, to enable automated phenotype-driven diagnosis.
  2. Establish a patient registry / GeneMatcher recruitment to quantify prevalence, penetrance, expressivity, sex ratio, and natural history.
  3. Patient-specific iPSC-derived cerebral organoids carrying the de novo variants to test, in a human system, the predicted H3K27me3 increase, Wnt de-repression, and NEUROD2/MAB21L2 loss, and to screen candidate modulators (e.g., EZH2 inhibitors) for developmental-window rescue.
  4. Generate a heterozygous germline Smarcc1 mouse matching the human dosage state to test faithful recapitulation and therapeutic windows.
  5. Define a DNA-methylation episignature for clinical variant classification (reclassifying VUS).
  6. Cross-reference OMIM/Orphanet/ICD submissions to formalize identifiers and align the knowledge base.
  7. Structure-function mapping of each pathogenic variant onto Q92922 domains (MarR/chromo/BRCT module, SWIRM) to predict genotype–phenotype correlation and assembly impact.

Evidence source legend: human clinical/genetic (38128548, 34906496, 33077954, 29983323, 27385966, 25249037); model organism (38128548 Xenopus; 26986003, 29779894, 26952987, 33207205 mouse; 28753627 zebrafish); in vitro/structural (31020615, 33953332, 28438634, 35158202); somatic/computational constraint (26934577, 24916674, gnomAD/ClinVar APIs).

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.5.1.

Outcome Count
References checked 21
Resolved 21
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 1
Quoted claims found in source 1
Quoted claims not found in source 0
References weighed for topical relevance 21
On topic 5
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 24
Resolved 22
Unresolved (possible confabulation) 0
Obsolete 1
Unverifiable 1
Terms whose name was checked 12
Terms named correctly 7
Terms named as a different term 2
Terms whose name is worth a second look 3

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:0700123 (4 mentions) - the report calls it "MONDO"; MONDO calls it SMARCC1-associated developmental dysgenesis syndrome
  • UBERON:0000955 (1 mention) - the report calls it "Primary organ: brain"; UBERON calls it brain

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • GO:0070734 (obsolete histone H3-K27 methylation) (1 mention)

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • HP:0001273 (1 mention) - the report calls it "Abnormal corpus callosum"; HP calls it Abnormal corpus callosum morphology, and lists "Abnormal corpus callosum" among its other names
  • GO:0000785 (2 mentions) - the report calls it "Subcellular: nucleus / chromatin"; GO calls it chromatin**, and lists "nuclear chromatin" among its other names
  • UBERON:0000948 (1 mention) - the report calls it "Secondary / branch organ: heart"; UBERON calls it heart, and lists "branchial heart" among its other names