Nicolaides-Baraitser Syndrome

Mendelian MONDO:0011053 Pathograph 43 Show in embeddings browser Neurodevelopmental Disorder Syndromic Intellectual Disability BAFopathy

Nicolaides-Baraitser syndrome (NCBRS; intellectual disability-sparse hair-brachydactyly syndrome; OMIM 601358) is an autosomal dominant intellectual-disability/multiple-congenital-anomaly syndrome caused by de novo NON-TRUNCATING (missense and in-frame) variants clustered in the ATPase region of SMARCA2 at 9p24.3. SMARCA2 (BRM) is one of the two alternative catalytic ATPase subunits of the BAF (SWI/SNF) ATP-dependent chromatin-remodelling complex. The cardinal features - intellectual disability, short stature, microcephaly, a characteristic coarse face, sparse scalp hair, brachydactyly with prominent interphalangeal joints and prominent distal phalanges, behavioural problems and seizures - are described in the defining 61-patient analysis as almost universally present, though that summary sentence covers nine features at once and individual frequencies vary (short stature, for example, is quantified separately at about half). Developmental delay is severe in nearly half of affected individuals, and nearly a third never develop speech. Seizures are frequently difficult to treat and developmental regression has been observed with seizure onset. Radiographic hallmarks include cone-shaped epiphyses and shortening of the phalanges, metacarpals and metatarsals. The disorder is clinically and genetically homogeneous, and the variants are thought to act by a dominant-negative mechanism on ATPase activity rather than by haploinsufficiency.

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1
Inheritance
5
Pathophys.
30
Phenotypes
1
Gaps
43
Pathograph
1
Genes
11
Medical Actions
4
Differentials
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References
1
Deep Research
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Classifications

Harrison's Part
GENETICS ENVIRONMENT DISEASE NEUROLOGIC
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Inheritance

1
Autosomal dominant, de novo HP:0000006
NCBRS is autosomal dominant and essentially always results from a de novo SMARCA2 variant; variants were confirmed de novo wherever parental samples were available in the defining cohort. GeneReviews states that the risk to other family members is presumed to be low; gonadal mosaicism has not been quantified in this disorder and cannot be formally excluded, so recurrence risk is best described as low rather than zero.
Autosomal dominant inheritance Expressivity: VARIABLE
Show evidence (3 references)
PMID:22366787 SUPPORT Human Clinical
"Extended molecular screening identified nonsynonymous SMARCA2 mutations in 36 of 44 individuals with NBS; these mutations were confirmed to be de novo when parental samples were available."
Establishes the de novo origin of the SMARCA2 variants across the defining cohort.
PMID:26468571 SUPPORT Human Clinical
"SMARCA2-NCBRS is expressed in an autosomal dominant manner and typically caused by a de novo SMARCA2 pathogenic variant; the risk to other family members is presumed to be low."
The GeneReviews Genetic Counseling statement, giving both the mode of inheritance and the recurrence-risk framing used in this block.
PMID:35762114 SUPPORT Human Clinical
"Nicolaides-Baraitser syndrome (NCBRS), first described in 1993, is a rare autosomal dominant disease caused by pathogenic variants in the SMARCA2 gene on chromosome 9p24.3."
States the autosomal dominant inheritance and the SMARCA2 locus at 9p24.3.
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Discussions and Knowledge Gaps

1
Is the dominant-negative, assembly-intact/ATPase-dead model of NCBRS SMARCA2 variants correct, and does it explain why non-truncating variants cause NCBRS while truncating variants do not?
KNOWLEDGE GAP OPEN ncbrs_dominant_negative_mechanism
Attached to
pathophysiology#Dominant-Negative Impairment of BAF Complex ATPase Activity
The dominant-negative model is the load-bearing mechanistic claim of this disorder - it explains the allelic specificity, separates NCBRS from SMARCA2 haploinsufficiency, and would determine what a targeted therapy would have to do. But it rests on inference rather than demonstration: the original report states the variants "likely do not impair SWI/SNF complex assembly but may be associated with disrupted ATPase activity", and the 61-patient analysis states they are "likely to act through a dominant-negative effect". The one direct functional test in an isogenic human system (NCBRS K755R and R1159Q knock-in hESCs) did not measure ATPase activity or complex assembly; what it found instead was INCREASED mutant SMARCA2 chromatin binding with global retargeting of SMARCA4, loss of SOX3-dependent neural enhancers, and emergence of astrocyte-specific de novo enhancers - a picture more consistent with altered targeting than with a catalytically dead subunit. So the two models are not yet distinguished: no published work measures BAF assembly and nucleosome-stimulated ATPase activity for a panel of NCBRS patient variants, and the DNA methylation signature, while showing that the variants perturb chromatin-dependent transcription, cannot separate dominant-negative from redistribution at the protein level.
Proposed experiments
Biochemical panel of NCBRS variants for assembly and ATPase activity
ncbrs_baf_assembly_atpase_panel
Express a panel of recurrent NCBRS SMARCA2 variants and measure BAF complex assembly (co-immunoprecipitation, size-exclusion) and nucleosome-stimulated ATPase and remodelling activity in parallel, alongside truncating alleles as a loss-of-function comparator.
Decision criterion
Intact assembly with abolished ATPase activity would confirm the dominant-negative model; reduced assembly would reframe NCBRS as a complex-destabilising disorder instead.
Isogenic comparison of non-truncating versus truncating SMARCA2 alleles
ncbrs_isogenic_allele_class_comparison
Extend the existing isogenic NCBRS knock-in hESC system with a SMARCA2 truncating allele and a heterozygous deletion, and compare SMARCA4 retargeting, enhancer reorganisation, neural-progenitor differentiation and the DNA methylation signature across the three allele classes.
Decision criterion
If only the non-truncating allele produces SMARCA4 retargeting and the NCBRS methylation signature, the allele-class boundary is explained by the redistribution model; if the truncating allele produces the same signature, the boundary must be explained some other way.
Show evidence (3 references)
PMID:22366787 SUPPORT Human Clinical
"These alterations likely do not impair SWI/SNF complex assembly but may be associated with disrupted ATPase activity."
The hedged wording of the original report is the substance of this gap - the mechanism is predicted, not measured.
PMID:25169058 SUPPORT Human Clinical
"SMARCA2 mutations causing NCBRS are likely to act through a dominant-negative effect."
The largest phenotype-genotype analysis also states the mechanism as a likelihood rather than a demonstrated result.
PMID:31375262 SUPPORT In Vitro
"Together, our results demonstrate that SMARCA2 mutations cause impaired differentiation through enhancer reprogramming via inappropriate targeting of SMARCA4."
The competing model - enhancer reprogramming via SMARCA4 mis-targeting - is demonstrated in isogenic human cells, which is why this entry does not assert the dominant-negative ATPase model as settled.
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Pathophysiology

5
Non-Truncating SMARCA2 Variants Clustered in the ATPase Region
The NCBRS-causing alleles are a tightly constrained class: heterozygous non-truncating (missense and in-frame) variants clustered within sequences encoding ultra-conserved motifs of the catalytic ATPase region of SMARCA2. This allelic specificity is what separates NCBRS from the other SMARCA2 disorders - truncating alleles do not produce NCBRS, and variants clustered outside the helicase domains cause a different blepharophimosis syndrome. Independent support comes from DNA methylation signature work, in which variants of uncertain significance falling within the ATPase/helicase domain classified as pathogenic while a variant distal to that domain did not.
SMARCA2 hgnc:11098 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SMARCA2 (hgnc:11098). hgnc:11098 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Dominant-Negative Impairment of BAF Complex ATPase Activity Variants in the ultra-conserved ATPase motifs are predicted to leave complex assembly intact while disrupting catalytic activity.
Show evidence (3 references)
PMID:22366787 SUPPORT Human Clinical
"The mutations cluster within sequences that encode ultra-conserved motifs in the catalytic ATPase region of the protein."
Establishes the defining positional clustering of NCBRS variants within the catalytic ATPase region.
PMID:25169058 SUPPORT Human Clinical
"Nicolaides-Baraitser syndrome (NCBRS) is an intellectual disability (ID)/multiple congenital anomalies syndrome caused by non-truncating mutations in the ATPase region of SMARCA2, which codes for one of the two alternative catalytic subunits of the BAF chromatin remodeling complex."
States the non-truncating, ATPase-region-restricted allele class that defines NCBRS and identifies SMARCA2 as an alternative catalytic BAF subunit.
PMID:31288860 SUPPORT Human Clinical
"DNAm model classifications of VUS were concordant with the clinical phenotype; those within the SMARCA2 ATPase/helicase domain classified as "pathogenic"."
An orthogonal epigenomic classifier independently confirms that pathogenicity tracks with location inside the ATPase/helicase domain.
Dominant-Negative Impairment of BAF Complex ATPase Activity
SMARCA2 is one of the two mutually exclusive alternative catalytic ATPases (with SMARCA4) of the SWI/SNF (BAF) ATP-dependent chromatin remodelling complex. The NCBRS variants are predicted not to impair SWI/SNF complex assembly but to disrupt ATPase activity, so a catalytically dead subunit is incorporated into otherwise intact complexes. This is the basis for the dominant-negative interpretation and is why NCBRS is not a haploinsufficiency disorder - a distinction with direct diagnostic consequences, since truncating SMARCA2 alleles do not cause this phenotype. An important qualification: the only direct functional test of NCBRS alleles in an isogenic human system found INCREASED mutant SMARCA2 chromatin binding with global retargeting of the alternative ATPase SMARCA4, which is a redistribution-of-targeting effect rather than a straightforwardly catalytically-dead subunit. The dominant-negative label is therefore retained as the field's working description but not asserted as established; see `discussions`.
ATP-dependent chromatin remodeler activity GO:0140658 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. ↓ DECREASED ATP hydrolysis activity GO:0016887 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased ATP hydrolysis activity (GO:0016887). GO:0016887 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Disrupted Chromatin Remodelling and Transcriptional Programs Loss of catalytic activity within assembled BAF complexes degrades nucleosome remodelling and the transcriptional programs that depend on it.
Show evidence (4 references)
PMID:22366787 SUPPORT Human Clinical
"SMARCA2 encodes the core catalytic unit of the SWI/SNF ATP-dependent chromatin remodeling complex that is involved in the regulation of gene transcription."
Establishes SMARCA2's identity as the catalytic ATPase of the SWI/SNF chromatin remodelling complex.
PMID:22366787 SUPPORT Human Clinical
"These alterations likely do not impair SWI/SNF complex assembly but may be associated with disrupted ATPase activity."
The assembly-intact, ATPase-disrupted interpretation is stated by the authors as a prediction ("likely", "may be"), not a demonstrated biochemical result, so it is curated as partial support.
PMID:25169058 SUPPORT Human Clinical
"SMARCA2 mutations causing NCBRS are likely to act through a dominant-negative effect."
The dominant-negative mechanism is inferred from the allelic pattern rather than demonstrated functionally, which is why this node's mechanism claims are curated as partial.
+ 1 more reference
Disrupted Chromatin Remodelling and Transcriptional Programs
BAF-dependent nucleosome remodelling controls the accessibility of developmental gene programs. In NCBRS the downstream consequence is measurable as a genome-wide DNA methylation signature: 429 differentially methylated CpG sites distinguish affected individuals from controls, and the genes those sites map to are involved in cell differentiation, calcium signalling and neuronal function - consistent with the disorder's neurodevelopmental and multisystem phenotype. The signature is sufficiently specific to classify variants of uncertain significance with 100% sensitivity and specificity in a validation cohort, so it is both a mechanistic readout and a diagnostic tool.
chromatin remodeling GO:0006338 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. ↓ DECREASED regulation of DNA-templated transcription GO:0006355 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal regulation of DNA-templated transcription (GO:0006355). GO:0006355 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Impaired Neurodevelopment Dysregulated differentiation, calcium-signalling and neuronal-function gene programs impair neurodevelopment.
Impaired Ectodermal and Skeletal Development The same chromatin-level lesion perturbs hair-follicle and skeletal developmental programs, producing the sparse hair and brachydactyly.
Show evidence (2 references)
PMID:31288860 SUPPORT Human Clinical
"We identified a DNAm signature of 429 differentially methylated CpG sites in individuals with NCBRS. The genes to which these CpG sites map are involved in cell differentiation, calcium signaling, and neuronal function consistent with NCBRS pathophysiology."
Direct human epigenomic evidence that SMARCA2 variants produce a genome-wide methylation signature over differentiation, calcium-signalling and neuronal-function genes.
PMID:31288860 SUPPORT Human Clinical
"A validation cohort of NCBRS cases (n = 8) and controls (n = 96) demonstrated 100% model sensitivity and specificity."
Quantifies the discriminative performance of the methylation signature, supporting its use both as a mechanistic readout and as a diagnostic classifier.
Impaired Neurodevelopment
The neurodevelopmental consequence is intellectual disability of variable but generally marked severity, with absent speech in a substantial minority, acquired microcephaly, behavioural abnormalities, and epilepsy that is often difficult to control. Severity within the disorder is internally correlated: the severity of intellectual disability tracks with the presence of seizures, absent speech, short stature and microcephaly, indicating a shared dose of the underlying lesion rather than independent organ-specific effects. Brain MRI is mainly unremarkable, and the epilepsy is characterised as genetic rather than structural.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
Downstream
Intellectual Disability The neurodevelopmental lesion manifests as intellectual disability.
Seizures The same lesion produces a predominantly generalised, difficult-to-treat epilepsy that is genetic rather than structural in origin.
Secondary Microcephaly Impaired postnatal brain growth produces acquired microcephaly.
Developmental Regression Regression or arrest of developmental progress has been observed with the onset of seizures.
Global Developmental Delay The neurodevelopmental lesion presents first as global developmental delay before the intellectual disability is formally characterised.
Absent Speech Speech and language are disproportionately affected, with a substantial minority never developing speech.
Behavioral Problems Behavioural abnormalities are part of the neurodevelopmental phenotype and track with the severity of the underlying lesion.
Autistic Behavior Autistic-like features occur within the behavioural phenotype, with a minority receiving a formal autism spectrum diagnosis.
Hyperacusis Sensitivity to loud noises is one of the two exemplar autistic-like features named in the clinical description.
Feeding Difficulties Feeding difficulty accompanies the neurodevelopmental phenotype and drives the requirement to assess nutritional status and oral-intake safety at each visit; the intermediates (oral-motor versus oral-sensory) are not established.
Hypotonia Hypotonia is reported as one of the neurological abnormalities of the syndrome and is grouped with seizures, microcephaly and structural brain anomalies; the intermediates between the transcriptional lesion and reduced muscle tone are not established.
Show evidence (3 references)
PMID:25169058 SUPPORT Human Clinical
"There may be a correlation between the severity of the ID and presence of seizures, absent speech, short stature and microcephaly."
Documents the internal correlation of severity across the neurodevelopmental and growth features, supporting a single shared upstream lesion.
PMID:33578439 SUPPORT Human Clinical
"EEG showed generalized epileptogenic abnormalities in 53% (9/17), cranial magnetic resonance imaging (cMRI) was mainly inconspicuous."
Establishes that the epilepsy is accompanied by generalised EEG abnormalities without a structural MRI correlate.
PMID:26468571 SUPPORT Human Clinical
"Regression or lack of developmental progress has been noted with the onset of seizures in some affected individuals."
GeneReviews links developmental regression to seizure onset, which is the causal edge curated here.
Impaired Ectodermal and Skeletal Development
Outside the nervous system, the same chromatin-remodelling lesion produces a distinctive ectodermal and skeletal phenotype: sparse scalp hair (which may be present only at certain ages), coarse facial features, delayed tooth eruption with hypo- or oligodontia, and a characteristic hand phenotype of brachydactyly with prominence of the interphalangeal joints and distal phalanges caused by decreased subcutaneous fat. Radiographs show cone-shaped epiphyses, metaphyseal flaring, and shortening of phalanges, metacarpals and metatarsals, especially of the 4th and 5th rays.
Downstream
Sparse Scalp Hair Disrupted hair-follicle developmental programs produce sparse scalp hair.
Brachydactyly Disrupted skeletal developmental programs produce shortened phalanges, metacarpals and metatarsals.
Prominent Interphalangeal Joints Joint prominence arises from decreased subcutaneous fat over the digits together with the underlying skeletal changes.
Cone-Shaped Epiphyses The radiographic hallmark of the skeletal lesion.
Coarse Facial Features The characteristic facial gestalt.
Reduced Subcutaneous Adipose Tissue Decreased subcutaneous fat is itself part of the ectodermal/mesenchymal lesion and is the stated anatomical basis for the digital prominence.
Everted Lower Lip Vermilion The commonest single element of the facial gestalt.
Wide Mouth Part of the same craniofacial patterning phenotype.
Long Eyelashes Long eyelashes belong to the ectodermal (hair-follicle) arm of the phenotype alongside the scalp-hair finding.
Downslanted Palpebral Fissures Part of the periorbital component of the facial gestalt.
Delayed Tooth Eruption Dental development is an ectodermal program disrupted by the same lesion.
Hypodontia or Oligodontia Reduced tooth number arises from the same disrupted dental-ectodermal program as the delayed eruption.
Platyspondyly The axial counterpart of the appendicular skeletal changes, seen on radiographs together with flat intervertebral disc space.
Short Stature Growth deficiency accompanies the skeletal phenotype in about half of affected individuals; the intermediates are not established.
Eczematous Dermatitis Proposed, not established: the same chromatin-remodelling lesion is suggested to compromise epidermal barrier integrity, which would place the eczematous dermatitis in the ectodermal arm. Curated as an indirect edge with unknown intermediates because the proposal rests on a single case report.
Show evidence (2 references)
PMID:26468571 SUPPORT Human Clinical
"SMARCA2-related Nicolaides-Baraitser syndrome (SMARCA2-NCBRS) is characterized by commonly shared dysmorphic features including sparse scalp hair, prominence of the interphalangeal joints and distal phalanges due to decreased subcutaneous fat, characteristic coarse facial features, microcephaly..."
GeneReviews defines the composite ectodermal, skeletal and neurological phenotype, including the mechanistic detail that joint prominence is due to decreased subcutaneous fat.
PMID:26468571 SUPPORT Human Clinical
"Radiographic findings may include cone-shaped epiphyses, metaphyseal flaring of the phalanges, and shortening of the phalanges, metacarpals, and/or metatarsals (especially of the 4th and 5th rays) of the hands; platyspondyly; flat intervertebral disc space; and pelvic/femoral anomalies."
Enumerates the radiographic skeletal phenotype produced by this node.
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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 Nicolaides-Baraitser 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

30
Cardiovascular 1
Congenital Heart Defect OCCASIONAL Abnormal heart morphology HP:0001627 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal heart morphology (HP:0001627). HP:0001627 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26468571 SUPPORT Human Clinical
"Rare findings include conductive hearing loss, refractive error / astigmatism, and congenital heart defects."
GeneReviews classifies congenital heart defects among the rare findings. As with the other rare findings, the band is set at OCCASIONAL rather than the default VERY_RARE mapping because reported rates sit just above the 5% floor; the departure is recorded here.
Digestive 1
Feeding Difficulties HP:0011968 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:31288860 SUPPORT Human Clinical
"poor growth and feeding, seizures, absent or delayed speech, variable ID, and behavioral disturbances"
Lists poor growth and feeding among the features described as continuing to be common in the NCBRS episignature-derivation cohort.
PMID:26468571 SUPPORT Human Clinical
"evaluate nutritional status and safety of oral intake"
The GeneReviews surveillance section requires nutritional and swallow-safety assessment at each visit, which is the management consequence of the feeding difficulty.
Ear 1
Conductive Hearing Impairment OCCASIONAL HP:0000405 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Conductive hearing impairment (HP:0000405). HP:0000405 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26468571 SUPPORT Human Clinical
"Rare findings include conductive hearing loss, refractive error / astigmatism, and congenital heart defects."
GeneReviews classifies conductive hearing loss among the rare findings. The project mapping table would place "rare" at VERY_RARE; the band is deliberately set one step higher at OCCASIONAL because reported rates in the 61-patient series sit just above the 5% floor, and that departure is recorded here.
Genitourinary 1
Cryptorchidism FREQUENT HP:0000028 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cryptorchidism (HP:0000028). HP:0000028 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26468571 SUPPORT Human Clinical
"Cryptorchidism is common in males."
GeneReviews describes cryptorchidism as common in males, which maps to the FREQUENT band.
Head and Neck 7
Secondary Microcephaly FREQUENT HP:0005484 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Secondary microcephaly (HP:0005484), qualified as course progressive. HP:0005484 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (2 references)
PMID:26468571 SUPPORT Human Clinical
"characteristic coarse facial features, microcephaly (typically acquired), seizures"
GeneReviews lists microcephaly among the commonly shared features and specifies its acquired (postnatal) character.
PMID:25169058 SUPPORT Human Clinical
"The cardinal features (ID, short stature, microcephaly, typical face, sparse hair, brachydactyly, prominent interphalangeal joints, behavioral problems and seizures), are almost universally present."
Microcephaly is listed among the cardinal features described as almost universally present. That sentence is a rhetorical summary covering nine features at once - short stature is in the same list yet is quantified elsewhere at about half - so it is not treated as a VERY_FREQUENT datum, and the band is set at FREQUENT.
Sparse Scalp Hair VERY_FREQUENT HP:0002209 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sparse scalp hair (HP:0002209). HP:0002209 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26468571 SUPPORT Human Clinical
"commonly shared dysmorphic features including sparse scalp hair"
GeneReviews lists sparse scalp hair first among the commonly shared dysmorphic features.
PMID:25169058 SUPPORT Human Clinical
"There is variability however, as ID can range from severe to mild, and sparse hair may be present only in certain age groups."
Documents the age-dependence of sparse hair, which is the diagnostic pitfall stated in this phenotype's description.
Coarse Facial Features FREQUENT HP:0000280 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Coarse facial features (HP:0000280), qualified as course progressive. HP:0000280 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (3 references)
PMID:26468571 SUPPORT Human Clinical
"is characterized by commonly shared dysmorphic features including sparse scalp hair, prominence of the interphalangeal joints and distal phalanges due to decreased subcutaneous fat, characteristic coarse facial features"
The GeneReviews clinical-characteristics sentence lists characteristic coarse facial features among the dysmorphic features commonly shared across affected individuals.
PMID:31288860 SUPPORT Human Clinical
"with progressive facial coarsening with age"
Documents that the coarsening is progressive with age rather than static, which is the basis for the PROGRESSIVE clinical course on this descriptor.
PMID:35762114 SUPPORT Human Clinical
"The most common facial dysmorphic features include thick/everted lower lip, coarse facial features, wide/large mouth, and thin upper lip."
A systematic review of molecularly confirmed cases ranks coarse facial features among the commonest facial dysmorphisms.
Wide Mouth FREQUENT HP:0000154 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Wide mouth (HP:0000154). HP:0000154 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35762114 SUPPORT Human Clinical
"coarse facial features, wide/large mouth, and thin upper lip"
Systematic review ranks a wide/large mouth among the commonest facial dysmorphisms.
Downslanted Palpebral Fissures FREQUENT HP:0000494 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Downslanted palpebral fissures (HP:0000494). HP:0000494 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35762114 SUPPORT Human Clinical
"sagging periorbital skin, down slanting palpebral fissures, and ptosis"
Systematic review ranks downslanting palpebral fissures among the commonest ocular adnexal features.
Delayed Tooth Eruption FREQUENT Delayed eruption of teeth HP:0000684 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed eruption of teeth (HP:0000684). HP:0000684 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26468571 SUPPORT Human Clinical
"Delayed tooth eruption with hypo- or oligodontia has also been reported."
GeneReviews reports delayed tooth eruption with hedged wording and no numerator.
PMID:35762114 SUPPORT Human Clinical
"Dental abnormalities are also commonly reported."
Systematic review describes dental abnormalities as commonly reported, which maps to the FREQUENT band and is the basis for the band set here.
Hypodontia or Oligodontia HP:0000668 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypodontia or oligodontia, annotated with Hypodontia (HP:0000668). HP:0000668 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26468571 SUPPORT Human Clinical
"Delayed tooth eruption with hypo- or oligodontia has also been reported."
GeneReviews reports reduced tooth number alongside the delayed eruption, with hedged wording and no numerator.
Immune 1
Eczematous Dermatitis Eczematoid dermatitis HP:0000964 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Eczematous dermatitis, annotated with Eczematoid dermatitis (HP:0000964). HP:0000964 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:40881542 SUPPORT Human Clinical
"Xerosis and eczematous plaques have been anecdotally mentioned, but the breadth and severity of inflammatory skin disease in NBS are yet to be systematically characterized"
Establishes that eczematous skin disease occurs in NCBRS while stating plainly that its frequency is uncharacterised, which is why no band is asserted.
PMID:40881542 SUPPORT Human Clinical
"Large clinical surveys emphasize xerosis as the most frequent cutaneous accompaniment, whereas inflammatory dermatoses have been mentioned only in passing"
Confirms that the cutaneous phenotype extends beyond the hair findings and that inflammatory dermatoses are under-reported rather than absent.
Limbs 1
Brachydactyly VERY_FREQUENT HP:0001156 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Brachydactyly (HP:0001156). HP:0001156 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25169058 SUPPORT Human Clinical
"typical face, sparse hair, brachydactyly, prominent interphalangeal joints, behavioral problems and seizures), are almost universally present"
Brachydactyly is among the cardinal features described as almost universally present. That summary sentence covers nine features at once, but brachydactyly is also one of the two features in the disorder's descriptive name and is independently corroborated by the GeneReviews radiographic description, so the band is retained.
PMID:26468571 SUPPORT Human Clinical
"shortening of the phalanges, metacarpals, and/or metatarsals (especially of the 4th and 5th rays) of the hands"
Specifies the anatomical distribution of the shortening.
Musculoskeletal 2
Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41497020 SUPPORT Human Clinical
"Neurological abnormalities include seizures, hypotonia, microcephaly, and structural brain anomalies"
States hypotonia as one of the neurological abnormalities characterising NCBRS, establishing the disease-phenotype association without giving a rate.
PMID:37970954 SUPPORT Human Clinical
"micrognathia, anterior open bite, a generalized diastema, oral motor hypotonia, and delayed tooth eruption"
Documents hypotonia in a molecularly confirmed NCBRS patient. Rated PARTIAL because the observation is regional (oral motor) in a single individual rather than the generalised hypotonia the disorder-level statement describes.
Platyspondyly HP:0000926 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Platyspondyly (HP:0000926). HP:0000926 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26468571 SUPPORT Human Clinical
"platyspondyly; flat intervertebral disc space; and pelvic/femoral anomalies"
GeneReviews lists platyspondyly among the radiographic findings that may be present.
Nervous System 8
Intellectual Disability VERY_FREQUENT HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26468571 SUPPORT Human Clinical
"Developmental delay / intellectual disability is severe in nearly half of affected individuals, moderate in one third, and mild in the remainder."
The three severity bands sum to the whole cohort, so intellectual disability is present in essentially all individuals, supporting a VERY_FREQUENT band.
PMID:25169058 SUPPORT Human Clinical
"The cardinal features (ID, short stature, microcephaly, typical face, sparse hair, brachydactyly, prominent interphalangeal joints, behavioral problems and seizures), are almost universally present."
A 61-patient analysis states that intellectual disability, among the other cardinal features, is almost universally present. Note this sentence is a rhetorical summary covering nine features at once and is not a per-feature frequency measurement, so it is used here only alongside the independent GeneReviews severity distribution.
Global Developmental Delay VERY_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:26468571 SUPPORT Human Clinical
"microcephaly (typically acquired), seizures, and developmental delay / intellectual disability"
GeneReviews lists developmental delay among the defining features of the syndrome.
Absent Speech FREQUENT HP:0001344 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Absent speech (HP:0001344). HP:0001344 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26468571 SUPPORT Human Clinical
"Nearly one third never develop speech or language skills."
Quantifies absent speech at approximately one third of individuals, at the lower edge of the FREQUENT (30-79%) band.
Seizures FREQUENT HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:26468571 SUPPORT Human Clinical
"Seizures are of various types and can be difficult to manage, requiring multiple anti-seizure medications to achieve reasonable control."
GeneReviews establishes seizures as a defining feature and documents their refractoriness.
PMID:33578439 SUPPORT Human Clinical
"Inclusion of 25 NCBRS patients with epilepsy in 23 of 25."
Epilepsy in 23 of 25 individuals in this series, but the cohort was recruited partly through an epilepsy network and is therefore strongly enriched for epilepsy. The band is set from the unenriched literature instead, which places seizures in the FREQUENT range.
PMID:33578439 SUPPORT Human Clinical
"Overall, 85% of the participants (17/20) reported generalized seizures, the semiology varied widely."
Characterises the predominant seizure type and its variability.
Developmental Regression OCCASIONAL HP:0002376 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Developmental regression (HP:0002376). HP:0002376 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26468571 SUPPORT Human Clinical
"Regression or lack of developmental progress has been noted with the onset of seizures in some affected individuals."
GeneReviews reports regression in "some" individuals with seizure onset; the hedged wording without a numerator supports a conservative OCCASIONAL band.
Behavioral Problems VERY_FREQUENT Atypical behavior HP:0000708 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atypical behavior (HP:0000708). HP:0000708 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25169058 SUPPORT Human Clinical
"prominent interphalangeal joints, behavioral problems and seizures), are almost universally present"
Behavioural problems are among the cardinal features described as almost universally present. That summary sentence covers nine features at once, so the band is corroborated by the independent GeneReviews characterisation of the behavioural phenotype below.
PMID:26468571 SUPPORT Human Clinical
"Behavioral issues can include autistic-like features (perseveration, hyperacusis), with a minority of affected individuals being diagnosed clinically with an autism spectrum disorder."
Characterises the behavioural phenotype and specifies that formal autism diagnosis applies to only a minority.
Autistic Behavior OCCASIONAL HP:0000729 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autistic behavior (HP:0000729). HP:0000729 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26468571 SUPPORT Human Clinical
"with a minority of affected individuals being diagnosed clinically with an autism spectrum disorder"
GeneReviews states that only a minority receive a formal autism diagnosis, which maps to an OCCASIONAL band.
Hyperacusis HP:0010780 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperacusis (HP:0010780). HP:0010780 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26468571 SUPPORT Human Clinical
"Behavioral issues can include autistic-like features (perseveration, hyperacusis), with a minority of affected individuals being diagnosed clinically with an autism spectrum disorder."
GeneReviews names hyperacusis as one of the two exemplar autistic-like features.
PMID:26468571 SUPPORT Human Clinical
"assess for behavioral issues such as short attention span, sensitivity to loud noises, and oral sensitivity"
The GeneReviews surveillance section instructs clinicians to assess for sensitivity to loud noises at each visit, confirming it is a recurrent managed finding.
Growth 1
Short Stature FREQUENT HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26468571 SUPPORT Human Clinical
"About half of affected individuals have growth deficiency and short stature."
Quantifies short stature at about 50%, squarely in the FREQUENT (30-79%) band.
Other 6
Prominent Interphalangeal Joints VERY_FREQUENT HP:0006237 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prominent interphalangeal joints (HP:0006237). HP:0006237 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26468571 SUPPORT Human Clinical
"prominence of the interphalangeal joints and distal phalanges due to decreased subcutaneous fat"
GeneReviews states both the finding and its mechanism (decreased subcutaneous fat).
PMID:25169058 SUPPORT Human Clinical
"brachydactyly, prominent interphalangeal joints, behavioral problems and seizures), are almost universally present"
Prominent interphalangeal joints are among the cardinal features described as almost universally present, and are independently listed by GeneReviews among the commonly shared dysmorphic features.
Cone-Shaped Epiphyses Cone-shaped epiphysis HP:0010579 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cone-shaped epiphysis (HP:0010579). HP:0010579 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26468571 SUPPORT Human Clinical
"Radiographic findings may include cone-shaped epiphyses, metaphyseal flaring of the phalanges"
GeneReviews lists cone-shaped epiphyses among the radiographic findings. The wording is hedged with no numerator, so no frequency band is asserted.
Everted Lower Lip Vermilion FREQUENT HP:0000232 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Everted lower lip vermilion (HP:0000232). HP:0000232 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35762114 SUPPORT Human Clinical
"The most common facial dysmorphic features include thick/everted lower lip"
Systematic review identifies the thick/everted lower lip as the leading facial dysmorphism.
Long Eyelashes FREQUENT HP:0000527 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Long eyelashes (HP:0000527). HP:0000527 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35762114 SUPPORT Human Clinical
"the most common abnormal eye and ocular adnexa features include prominent/long eyelashes, thick eyebrows, sagging periorbital skin, down slanting palpebral fissures, and ptosis"
Systematic review of molecularly confirmed cases ranks prominent/long eyelashes first among ocular adnexal abnormalities.
Refractive Error OCCASIONAL Abnormality of refraction HP:0000539 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of refraction (HP:0000539). HP:0000539 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26468571 SUPPORT Human Clinical
"Rare findings include conductive hearing loss, refractive error / astigmatism, and congenital heart defects."
GeneReviews classifies refractive error/astigmatism among the rare findings; combined with its appearance in case series this supports a conservative OCCASIONAL band.
Reduced Subcutaneous Adipose Tissue HP:0003758 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced subcutaneous adipose tissue (HP:0003758). HP:0003758 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26468571 SUPPORT Human Clinical
"prominence of the interphalangeal joints and distal phalanges due to decreased subcutaneous fat"
GeneReviews attributes the cardinal joint and distal-phalangeal prominence directly to decreased subcutaneous fat.
🧬

Genetic Associations

1
SMARCA2 (Causal - de novo non-truncating variants clustered in the ATPase region)
Gene: SMARCA2 hgnc:11098 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SMARCA2 (hgnc:11098). hgnc:11098 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: DE_NOVO
Show evidence (4 references)
PMID:25169058 SUPPORT Human Clinical
"caused by non-truncating mutations in the ATPase region of SMARCA2, which codes for one of the two alternative catalytic subunits of the BAF chromatin remodeling complex"
States the defining non-truncating, ATPase-region-restricted allele class that separates NCBRS from the other SMARCA2 disorders.
PMID:22366787 SUPPORT Human Clinical
"We sequenced the exomes of ten individuals with NBS and identified heterozygous variants in SMARCA2 in eight of them. Extended molecular screening identified nonsynonymous SMARCA2 mutations in 36 of 44 individuals with NBS"
The gene-discovery study establishing SMARCA2 as the cause, with a high diagnostic yield (36/44) in clinically defined NCBRS.
PMID:25169058 SUPPORT Human Clinical
"There may be some genotype-phenotype correlations (mutations at domain VI with severe ID and seizures; mutations affecting residues Pro883, Leu946, and Ala1201 with mild phenotypes) but numbers are still too small to draw definitive conclusions."
The intra-NCBRS genotype-phenotype correlations are explicitly qualified by the authors as based on too few cases, so they are curated as partial support.
+ 1 more reference
💊

Medical Actions

11
Standard-of-Care Management of Manifestations
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
There is no disease-modifying therapy. Management is standard therapy for each manifestation - developmental delay and intellectual disability, behavioural issues, epilepsy, poor growth, myopia, astigmatism, hearing loss, dental issues, cryptorchidism and congenital heart defects - delivered by the relevant specialists.
Show evidence (1 reference)
PMID:26468571 SUPPORT Human Clinical
"Standard therapy for developmental delay / intellectual disability, behavioral issues, epilepsy, poor growth, myopia, astigmatism, hearing loss, dental issues, cryptorchidism, and congenital heart defects."
GeneReviews defines the standard of care as specialist-delivered symptomatic management across the affected systems.
Antiseizure Medication
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: levetiracetam CHEBI:6437 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses levetiracetam (CHEBI:6437). CHEBI:6437 is a therapeutic agent from Chemical Entities of Biological Interest. valproic acid CHEBI:39867 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses valproic acid (CHEBI:39867). CHEBI:39867 is a therapeutic agent from Chemical Entities of Biological Interest.
Epilepsy in NCBRS mostly shows only an initial response to antiseizure medication and very rarely achieves complete seizure freedom. In the largest treatment-focused series, levetiracetam, valproic acid, phenobarbital and topiramate each reduced seizure frequency by more than 50% in most treated patients, but only a minority achieved even temporary (>6 month) seizure freedom. Seizure aggravation was observed with several agents, most notably lamotrigine, which is curated as a separate agents-to-use-with-caution item.
Target Phenotypes: Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33578439 SUPPORT Human Clinical
"helps to treat epilepsy in NCBRS that mostly shows only initial response to anticonvulsive therapy, especially with LEV and VPA, but very rarely shows complete freedom of seizures in this, rather genetic than structural epilepsy"
States both the partial benefit and the low rate of seizure freedom, which is why this treatment is curated as partial rather than full support.
PMID:33578439 SUPPORT Human Clinical
"LEV (9/12), PB (6/8), TPM (4/5), and VPA (9/12) reduced the seizures' frequency in more than 50%."
Quantifies the response rates of the four most effective agents.
Lamotrigine - Agent to Use With Caution
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: lamotrigine CHEBI:6367 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses lamotrigine (CHEBI:6367). CHEBI:6367 is a therapeutic agent from Chemical Entities of Biological Interest.
Seizure aggravation was observed under lamotrigine in 2 of 4 treated patients in the only treatment-focused NCBRS series, a higher proportion than for any other agent studied. Aggravation was also seen, at much lower rates, under levetiracetam, phenobarbital and valproic acid, so this is a caution about relative risk rather than an absolute contraindication.
Target Phenotypes: Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33578439 REFUTE Human Clinical
"Seizures aggravation was observed under lamotrigine"
Evidence against lamotrigine benefit specifically. The source sentence gives the count as 2 of 4 treated patients, but the bracketed figure cannot be quoted verbatim because the reference validator strips square-bracket markup, so the count is stated in the description rather than in the snippet.
PMID:33578439 SUPPORT Human Clinical
"LEV (1/12), PB (1/8), and VPA (1/12)."
The remainder of the same sentence, quoted separately to avoid implying that aggravation was specific to lamotrigine - levetiracetam, phenobarbital and valproic acid also aggravated seizures, at much lower rates. This is why the item is a caution rather than a contraindication.
Vagus Nerve Stimulation
Action: vagus nerve stimulationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is vagus nerve stimulation, annotated with Therapeutic Procedure (NCIT:C49236). NCIT:C49236 is a clinical intervention from the NCI Thesaurus. Ontology label: Therapeutic Procedure NCIT:C49236
Tried in two patients in the largest treatment series with seizure-frequency reduction in one of the two. Curated separately from the ketogenic diet because it is a neuromodulation device rather than a dietary intervention.
Target Phenotypes: Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33578439 SUPPORT Human Clinical
"Ketogenic diet (KD) and vagal nerve stimulation (VNS) reduced seizures' frequency in one of two each."
The entire evidence base is two patients with a one-in-two response, so this is curated as partial support.
Ketogenic Diet
Action: dietary interventionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is dietary intervention (NCIT:C15447). NCIT:C15447 is a clinical intervention from the NCI Thesaurus. Ontology label: Dietary Intervention NCIT:C15447
Tried in two patients in the largest treatment series with seizure-frequency reduction in one of the two. The evidence base is anecdotal but the ketogenic diet remains a reasonable option given the refractoriness of the epilepsy.
Target Phenotypes: Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33578439 SUPPORT Human Clinical
"Ketogenic diet (KD) and vagal nerve stimulation (VNS) reduced seizures' frequency in one of two each."
The entire evidence base for both interventions is two patients each with a one-in-two response, so this is curated as partial support.
Developmental and Educational Support
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Standard developmental therapy addresses the developmental delay and intellectual disability. Surveillance includes monitoring developmental progress and educational needs, and assessing mobility and self-help skills.
Target Phenotypes: Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26468571 SUPPORT Human Clinical
"monitor developmental progress and educational needs; assess for behavioral issues such as short attention span, sensitivity to loud noises, and oral sensitivity; and evaluate mobility and self-help skills"
GeneReviews specifies the developmental, behavioural and functional surveillance domains.
Growth and Nutritional Surveillance
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Growth parameters, nutritional status and the safety of oral intake are assessed at every visit, reflecting the frequent growth deficiency and the oral sensitivity described in the behavioural phenotype.
Target Phenotypes: Short stature HP:0004322 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26468571 SUPPORT Human Clinical
"At each visit, measure growth parameters; evaluate nutritional status and safety of oral intake"
GeneReviews specifies growth and nutritional surveillance at every visit.
Dental Surveillance
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Dental evaluation at least every six months is recommended, reflecting the delayed tooth eruption with hypo- or oligodontia.
Target Phenotypes: Delayed eruption of teeth HP:0000684 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Delayed eruption of teeth (HP:0000684). HP:0000684 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26468571 SUPPORT Human Clinical
"Dental evaluation at least every six months after the eruption of first"
GeneReviews specifies dental evaluation at least every six months after the eruption of the first dentition.
Audiology Surveillance
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Annual audiology evaluation is recommended in childhood, reflecting the reported conductive hearing loss and the communication burden of the disorder.
Target Phenotypes: Conductive hearing impairment HP:0000405 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Conductive hearing impairment (HP:0000405). HP:0000405 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26468571 SUPPORT Human Clinical
"Annual audiology evaluation in childhood"
GeneReviews specifies annual childhood audiology evaluation as part of surveillance.
Ophthalmological Evaluation
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Prompt ophthalmological evaluation following diagnosis is recommended, given the frequency of well-defined ophthalmic abnormalities including refractive error, ptosis and periocular findings.
Target Phenotypes: Abnormality of refraction HP:0000539 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Abnormality of refraction (HP:0000539). HP:0000539 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35762114 SUPPORT Human Clinical
"NCBRS frequently presents with well-defined ophthalmic and facial abnormalities."
Establishes that ophthalmic abnormalities are frequent and well-defined, which is the basis for recommending prompt ophthalmological evaluation.
Genetic Counseling
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Counselling covers the autosomal dominant, essentially always de novo mechanism, the consequently low presumed risk to other family members, and the availability of prenatal and preimplantation genetic testing once the familial variant is known.
Show evidence (3 references)
PMID:26468571 SUPPORT Human Clinical
"the risk to other family members is presumed to be low"
GeneReviews states the recurrence-risk framing that counselling communicates.
PMID:26468571 SUPPORT Human Clinical
"prenatal and preimplantation genetic testing are possible"
GeneReviews states the reproductive testing options that counselling addresses.
PMID:22366787 SUPPORT Human Clinical
"these mutations were confirmed to be de novo when parental samples were available"
The de novo origin is the central counselling fact and the basis for the low presumed recurrence risk.
🔬

Diagnosis

2
Molecular Genetic Testing for SMARCA2 (Positive in affected individuals)
The diagnosis is established by identifying a heterozygous pathogenic SMARCA2 variant in an individual with suggestive findings. Because NCBRS and Coffin-Siris syndrome overlap clinically and both arise from BAF-complex genes, a one-step panel covering all six BAF-complex genes is an efficient testing strategy, and the specific facial features are the major diagnostic handle at the bedside.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Show evidence (3 references)
PMID:26468571 SUPPORT Human Clinical
"The diagnosis of SMARCA2-NCBRS is established in a proband with suggestive findings and a heterozygous SMARCA2 pathogenic variant identified by molecular genetic testing."
GeneReviews states the molecular diagnostic criterion.
PMID:25249037 SUPPORT Human Clinical
"Given the high frequency of the condition we set up a one-step deep sequencing test for all 6 genes of the BAF complex."
Supports a combined BAF-complex panel as the practical testing strategy given the NCBRS/Coffin-Siris overlap.
PMID:25249037 SUPPORT Human Clinical
"the specific facial features being the major diagnostic handle"
Identifies the facial gestalt as the clinical trigger for molecular testing.
DNA Methylation Episignature (Distinct signature in affected individuals)
Genome-wide DNA methylation profiling of whole blood yields an NCBRS-specific signature of 429 differentially methylated CpG sites. A classifier built on that signature achieved 100% sensitivity and specificity in an independent validation cohort and reclassified SMARCA2 variants of uncertain significance concordantly with the clinical phenotype, making it a practical adjunct for VUS interpretation.
DNA methylation analysis NCIT:C19770 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:31288860 SUPPORT Human Clinical
"Differential methylated CpGs between groups (DNAm signature) were identified and used to generate a model enabling classification variants of uncertain significance (VUS; n = 9) in SMARCA2 as "pathogenic" or "benign"."
Describes the episignature classifier and its intended use for SMARCA2 VUS reclassification.
PMID:31288860 SUPPORT Human Clinical
"A validation cohort of NCBRS cases (n = 8) and controls (n = 96) demonstrated 100% model sensitivity and specificity."
Quantifies classifier performance in an independent validation cohort.
📊

Prevalence

2
Published molecularly confirmed individuals worldwide
Cases In Literature Ultra Rare
61 molecularly confirmed individuals had been assembled by 2014, comprising all 47 previously reported patients plus 14 unpublished. The disorder was described as very rare before the molecular cause was identified.
Show evidence (1 reference)
PMID:25169058 SUPPORT Human Clinical
"We analyzed 61 molecularly confirmed cases, including all previously reported patients (n = 47) and 14 additional unpublished individuals."
Quantifies the complete published molecularly confirmed caseload as of 2014, supporting an ultra-rare classification.
Italian intellectual disability cohort (1161 individuals, three centres)
Unknown Unknown
Not a population prevalence. In a clinically ascertained intellectual disability cohort, NCBRS plus Coffin-Siris syndrome together were molecularly confirmed in 11 of 1161 individuals, of whom 8 had SMARCA2 missense variants. The authors conclude the combined frequency of these BAFopathies among people with intellectual disability may be as high as about 1%.
Show evidence (1 reference)
PMID:25249037 SUPPORT Human Clinical
"A strong clinical suspicion of either Nicolaides-Baraitser syndrome or Coffin-Siris syndrome was proposed in 11 cases who were then molecularly confirmed: 8 having de novo missense mutations in SMARCA2, two frame-shift mutations in ARID1B and one missense mutation in SMARCB1."
Quantifies the NCBRS yield within an ascertained intellectual disability cohort. Curated as PARTIAL because the reported figure aggregates NCBRS with Coffin-Siris syndrome and is conditioned on clinical suspicion, so it is not an NCBRS-specific population rate.
🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Nicolaides-Baraitser Syndrome:

Coffin-Siris Syndrome
Overlapping Features The principal differential and the closest relative. Both are BAFopathies with overlapping features - intellectual disability, sparse hair, low frontal hairline, large mouth with thick everted lips, and hand and foot anomalies - and SMARCA2 is itself listed among the BAF-complex genes mutated in Coffin-Siris syndrome. They remain distinct entities: NCBRS is caused specifically by non-truncating variants clustered in the SMARCA2 ATPase region acting dominant-negatively, and is clinically and genetically homogeneous, whereas Coffin-Siris is genetically heterogeneous across six BAF genes and its hallmark is hypoplasia of the fifth digit nail/phalanx. Curated separately in dismech as `Coffin_Siris_Syndrome`.
SMARCA2 Blepharophimosis-Intellectual Disability Syndrome
Overlapping Features Allelic but distinct. De novo SMARCA2 variants clustered OUTSIDE the helicase domains cause a recognisable syndrome of intellectual disability with blepharophimosis that is explicitly reported as phenotypically and molecularly distinct from NCBRS. Variant position within SMARCA2 is the discriminator, and the separation is now corroborated at the epigenetic level: BIS carries its own episignature, which it shares with truncating-ADNP Helsmoortel-Van der Aa syndrome rather than with NCBRS.
Distinguishing Features
  • Location of the SMARCA2 variant - inside the ATPase/helicase region in NCBRS, outside it in BIS.
  • Blepharophimosis is the recognisable facial cue in BIS and is not part of the NCBRS gestalt.
  • The DNA methylation episignature differs; BIS clusters with truncating-ADNP Helsmoortel-Van der Aa syndrome, not with NCBRS.
Show evidence (2 references)
PMID:38884529 SUPPORT Human Clinical
"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. BIS is caused by pathogenic variants in SMARCA2"
A 2024 study states explicitly that BIS is a SMARCA2-related disorder distinct from NCBRS, which is the basis for keeping the two as separate entities.
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."
Independent epigenetic corroboration of the split - the BIS methylation signature aligns with truncating-ADNP HVDAS rather than with the NCBRS signature, so episignature testing discriminates the two SMARCA2 phenotypes.
Cornelia de Lange Syndrome
Overlapping Features Shares intellectual disability, growth restriction, distinctive facies with thick eyebrows and long eyelashes, and limb/digit anomalies; distinguished molecularly (NIPBL and cohesin-complex genes).
Other BAFopathies
Overlapping Features The wider BAF-complex disorder group (ARID1A, ARID1B, SMARCB1, SMARCA4, SMARCE1, DPF2) overlaps clinically; a combined BAF-gene panel is the efficient diagnostic approach rather than sequential single-gene testing.
{ }

Source YAML

click to show 
name: Nicolaides-Baraitser Syndrome
creation_date: "2026-07-31T00:00:00Z"
description: >-
  Nicolaides-Baraitser syndrome (NCBRS; intellectual disability-sparse
  hair-brachydactyly syndrome; OMIM 601358) is an autosomal dominant
  intellectual-disability/multiple-congenital-anomaly syndrome caused by de novo
  NON-TRUNCATING (missense and in-frame) variants clustered in the ATPase region
  of SMARCA2 at 9p24.3. SMARCA2 (BRM) is one of the two alternative catalytic
  ATPase subunits of the BAF (SWI/SNF) ATP-dependent chromatin-remodelling
  complex. The cardinal features - intellectual disability, short stature,
  microcephaly, a characteristic coarse face, sparse scalp hair, brachydactyly
  with prominent interphalangeal joints and prominent distal phalanges,
  behavioural problems and seizures - are described in the defining 61-patient
  analysis as almost universally present, though that summary sentence covers nine
  features at once and individual frequencies vary (short stature, for example, is
  quantified separately at about half). Developmental
  delay is severe in nearly half of affected individuals, and nearly a third never
  develop speech. Seizures are frequently difficult to treat and developmental
  regression has been observed with seizure onset. Radiographic hallmarks include
  cone-shaped epiphyses and shortening of the phalanges, metacarpals and
  metatarsals. The disorder is clinically and genetically homogeneous, and the
  variants are thought to act by a dominant-negative mechanism on ATPase activity
  rather than by haploinsufficiency.
category: Mendelian
parents:
- Neurodevelopmental Disorder
- Syndromic Intellectual Disability
- BAFopathy
notes: >-
  Scope and disambiguation - this is the most important framing decision in this
  entry, because SMARCA2 sits at the intersection of three distinct entities.
  1. Coffin-Siris syndrome. SMARCA2 is listed among the BAF-complex genes
  mutated in Coffin-Siris syndrome, and dismech already has a
  `Coffin_Siris_Syndrome` entry (curated on ARID1B) that names SMARCA2 in its
  gene list. NCBRS is nonetheless a separate entity, not a Coffin-Siris subtype:
  the two are clinically overlapping but distinguishable, the NCBRS-causing
  SMARCA2 alleles are specifically NON-TRUNCATING variants clustered in the
  ATPase region acting dominant-negatively, and NCBRS is clinically and
  genetically homogeneous in a way Coffin-Siris is not. The entries are
  cross-referenced under `differential_diagnoses` without duplicating the
  Coffin-Siris content or contradicting it.
  2. SMARCA2 blepharophimosis-intellectual disability syndrome. De novo SMARCA2
  variants clustered OUTSIDE the helicase/ATPase domains cause a different,
  recognisable syndrome with intellectual disability and blepharophimosis that is
  explicitly reported as phenotypically and molecularly distinct from NCBRS. That
  entity is out of scope here and is recorded as a differential.
  3. SMARCA2 in cancer. SMARCA2/BRM loss is extensively studied as a
  tumour-suppressor and synthetic-lethal target in SMARCA4-deficient cancers.
  That literature is mechanistically unrelated to the germline non-truncating
  NCBRS alleles and was excluded.
  Module conformance. No module in kb/modules/ captures a BAF/chromatin-remodelling
  developmental chain. `epilepsy_excitation_inhibition_imbalance` was evaluated
  and declined: NCBRS epilepsy is described in the primary literature as "rather
  genetic than structural" but no excitation/inhibition-imbalance chain has been
  curated for SMARCA2, so declaring conformance would assert a mechanism the
  evidence does not establish.
  Unquotable phenotype gaps (SOP section 4, Option A). The deep-research report
  supplies Sousa 2014 full-text denominators for five phenotypes above the 10%
  threshold. Three of them - feeding difficulties (23/49), eczematous dermatitis
  (22/58) and hypotonia (19/51) - are now curated above as phenotype entries from
  quotable NCBRS-specific sources, but WITHOUT frequency bands: the denominators
  themselves are not quotable, so asserting a band would be unsupported
  (evidence-guidelines Pattern D). Two remain uncurated because no quotable
  source for them exists at all: non-scalp hypertrichosis 22/50 (44%,
  HP:0000998) and frequent infections 13/48 (27.1%, HP:0002719). Sousa 2014
  (PMID:25169058) is cached abstract-only and its abstract contains neither
  figure; the GeneReviews chapter (PMID:26468571) mentions neither feature; a
  sweep of all 82 PubMed records tagged Nicolaides-Baraitser and an Europe PMC
  open-access query found only Coffin-Siris-specific statements of hypertrichosis
  and frequent infections, plus one mixed SWI/SNF cohort (PMID:34706719,
  hypertrichosis 8/12) containing a single NCBRS patient, none of which can be
  attributed to NCBRS; and the Orphanet route the reviewer proposed remains
  unavailable because Orphadata upstream has drifted from the sha256 pinned in
  `data/orphadata/MANIFEST.yaml`, so `just refresh-orphadata` still fails its
  checksum gate (observed sha256 df8d562a... vs pinned fb2fbe8c...) and
  `ORPHA_3051.md` cannot be regenerated - and hand-writing a cache file is
  forbidden. Note that a rebuilt file would also be stamped with the manifest's
  `2025-12-09` snapshot date while being derived from a different snapshot, so
  bypassing the gate would put false provenance into the cache. Re-adding the two
  remaining phenotypes (with their bands) becomes a mechanical follow-up as soon
  as the Orphadata manifest is re-pinned repo-wide.
disease_term:
  preferred_term: Nicolaides-Baraitser syndrome
  term:
    id: MONDO:0011053
    label: intellectual disability-sparse hair-brachydactyly syndrome
synonyms:
- NCBRS
- Nicolaides-Baraitser syndrome
- SMARCA2-related Nicolaides-Baraitser syndrome
- intellectual disability-sparse hair-brachydactyly syndrome
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
  - classification_value: NEUROLOGIC
references:
- reference: PMID:26468571
  title: "SMARCA2-Related Nicolaides-Baraitser Syndrome."
  tags:
  - GeneReviews
prevalence:
- population: Published molecularly confirmed individuals worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    61 molecularly confirmed individuals had been assembled by 2014, comprising
    all 47 previously reported patients plus 14 unpublished. The disorder was
    described as very rare before the molecular cause was identified.
  evidence:
  - reference: PMID:25169058
    reference_title: "Phenotype and genotype in Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We analyzed 61 molecularly confirmed cases, including all previously reported patients (n = 47) and 14 additional unpublished individuals."
    explanation: Quantifies the complete published molecularly confirmed caseload as of 2014, supporting an ultra-rare classification.
- population: Italian intellectual disability cohort (1161 individuals, three centres)
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  notes: >-
    Not a population prevalence. In a clinically ascertained intellectual
    disability cohort, NCBRS plus Coffin-Siris syndrome together were molecularly
    confirmed in 11 of 1161 individuals, of whom 8 had SMARCA2 missense variants.
    The authors conclude the combined frequency of these BAFopathies among people
    with intellectual disability may be as high as about 1%.
  evidence:
  - reference: PMID:25249037
    reference_title: "Coffin-Siris and Nicolaides-Baraitser syndromes are a common well recognizable cause of intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A strong clinical suspicion of either Nicolaides-Baraitser syndrome or Coffin-Siris syndrome was proposed in 11 cases who were then molecularly confirmed: 8 having de novo missense mutations in SMARCA2, two frame-shift mutations in ARID1B and one missense mutation in SMARCB1."
    explanation: Quantifies the NCBRS yield within an ascertained intellectual disability cohort. Curated as PARTIAL because the reported figure aggregates NCBRS with Coffin-Siris syndrome and is conditioned on clinical suspicion, so it is not an NCBRS-specific population rate.
inheritance:
- name: Autosomal dominant, de novo
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  expressivity: VARIABLE
  description: >-
    NCBRS is autosomal dominant and essentially always results from a de novo
    SMARCA2 variant; variants were confirmed de novo wherever parental samples
    were available in the defining cohort. GeneReviews states that the risk to
    other family members is presumed to be low; gonadal mosaicism has not been
    quantified in this disorder and cannot be formally excluded, so recurrence
    risk is best described as low rather than zero.
  evidence:
  - reference: PMID:22366787
    reference_title: "Heterozygous missense mutations in SMARCA2 cause Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Extended molecular screening identified nonsynonymous SMARCA2 mutations in 36 of 44 individuals with NBS; these mutations were confirmed to be de novo when parental samples were available."
    explanation: Establishes the de novo origin of the SMARCA2 variants across the defining cohort.
  - reference: PMID:26468571
    reference_title: "SMARCA2-Related Nicolaides-Baraitser Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SMARCA2-NCBRS is expressed in an autosomal dominant manner and typically caused by a de novo SMARCA2 pathogenic variant; the risk to other family members is presumed to be low."
    explanation: The GeneReviews Genetic Counseling statement, giving both the mode of inheritance and the recurrence-risk framing used in this block.
  - reference: PMID:35762114
    reference_title: "Ophthalmologic and facial abnormalities of Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nicolaides-Baraitser syndrome (NCBRS), first described in 1993, is a rare autosomal dominant disease caused by pathogenic variants in the SMARCA2 gene on chromosome 9p24.3."
    explanation: States the autosomal dominant inheritance and the SMARCA2 locus at 9p24.3.
pathophysiology:
- name: Non-Truncating SMARCA2 Variants Clustered in the ATPase Region
  biological_scale: MOLECULAR
  description: >-
    The NCBRS-causing alleles are a tightly constrained class: heterozygous
    non-truncating (missense and in-frame) variants clustered within sequences
    encoding ultra-conserved motifs of the catalytic ATPase region of SMARCA2.
    This allelic specificity is what separates NCBRS from the other SMARCA2
    disorders - truncating alleles do not produce NCBRS, and variants clustered
    outside the helicase domains cause a different blepharophimosis syndrome.
    Independent support comes from DNA methylation signature work, in which
    variants of uncertain significance falling within the ATPase/helicase domain
    classified as pathogenic while a variant distal to that domain did not.
  genes:
  - preferred_term: SMARCA2
    term:
      id: hgnc:11098
      label: SMARCA2
  downstream:
  - target: Dominant-Negative Impairment of BAF Complex ATPase Activity
    causal_link_type: DIRECT
    description: >-
      Variants in the ultra-conserved ATPase motifs are predicted to leave complex
      assembly intact while disrupting catalytic activity.
  evidence:
  - reference: PMID:22366787
    reference_title: "Heterozygous missense mutations in SMARCA2 cause Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mutations cluster within sequences that encode ultra-conserved motifs in the catalytic ATPase region of the protein."
    explanation: Establishes the defining positional clustering of NCBRS variants within the catalytic ATPase region.
  - reference: PMID:25169058
    reference_title: "Phenotype and genotype in Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nicolaides-Baraitser syndrome (NCBRS) is an intellectual disability (ID)/multiple congenital anomalies syndrome caused by non-truncating mutations in the ATPase region of SMARCA2, which codes for one of the two alternative catalytic subunits of the BAF chromatin remodeling complex."
    explanation: States the non-truncating, ATPase-region-restricted allele class that defines NCBRS and identifies SMARCA2 as an alternative catalytic BAF subunit.
  - reference: PMID:31288860
    reference_title: "New insights into DNA methylation signatures: SMARCA2 variants in Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DNAm model classifications of VUS were concordant with the clinical phenotype; those within the SMARCA2 ATPase/helicase domain classified as \"pathogenic\"."
    explanation: An orthogonal epigenomic classifier independently confirms that pathogenicity tracks with location inside the ATPase/helicase domain.
- name: Dominant-Negative Impairment of BAF Complex ATPase Activity
  biological_scale: MOLECULAR
  description: >-
    SMARCA2 is one of the two mutually exclusive alternative catalytic ATPases
    (with SMARCA4) of the SWI/SNF (BAF) ATP-dependent chromatin remodelling
    complex. The NCBRS variants are predicted not to impair
    SWI/SNF complex assembly but to disrupt ATPase activity, so a catalytically
    dead subunit is incorporated into otherwise intact complexes. This is the
    basis for the dominant-negative interpretation and is why NCBRS is not a
    haploinsufficiency disorder - a distinction with direct diagnostic
    consequences, since truncating SMARCA2 alleles do not cause this phenotype.
    An important qualification: the only direct functional test of NCBRS alleles in
    an isogenic human system found INCREASED mutant SMARCA2 chromatin binding with
    global retargeting of the alternative ATPase SMARCA4, which is a
    redistribution-of-targeting effect rather than a straightforwardly
    catalytically-dead subunit. The dominant-negative label is therefore retained
    as the field's working description but not asserted as established; see
    `discussions`.
  molecular_functions:
  - preferred_term: ATP-dependent chromatin remodeler activity
    term:
      id: GO:0140658
      label: ATP-dependent chromatin remodeler activity
    modifier: DECREASED
  - preferred_term: ATP hydrolysis activity
    term:
      id: GO:0016887
      label: ATP hydrolysis activity
    modifier: DECREASED
  downstream:
  - target: Disrupted Chromatin Remodelling and Transcriptional Programs
    causal_link_type: DIRECT
    description: >-
      Loss of catalytic activity within assembled BAF complexes degrades
      nucleosome remodelling and the transcriptional programs that depend on it.
  evidence:
  - reference: PMID:22366787
    reference_title: "Heterozygous missense mutations in SMARCA2 cause Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SMARCA2 encodes the core catalytic unit of the SWI/SNF ATP-dependent chromatin remodeling complex that is involved in the regulation of gene transcription."
    explanation: Establishes SMARCA2's identity as the catalytic ATPase of the SWI/SNF chromatin remodelling complex.
  - reference: PMID:22366787
    reference_title: "Heterozygous missense mutations in SMARCA2 cause Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These alterations likely do not impair SWI/SNF complex assembly but may be associated with disrupted ATPase activity."
    explanation: The assembly-intact, ATPase-disrupted interpretation is stated by the authors as a prediction ("likely", "may be"), not a demonstrated biochemical result, so it is curated as partial support.
  - reference: PMID:25169058
    reference_title: "Phenotype and genotype in Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SMARCA2 mutations causing NCBRS are likely to act through a dominant-negative effect."
    explanation: The dominant-negative mechanism is inferred from the allelic pattern rather than demonstrated functionally, which is why this node's mechanism claims are curated as partial.
  - reference: PMID:31375262
    reference_title: "Heterozygous Mutations in SMARCA2 Reprogram the Enhancer Landscape by Global Retargeting of SMARCA4."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Changes in chromatin accessibility at enhancers were associated with an increase in SMARCA2 binding and retargeting of SMARCA4."
    explanation: Isogenic hESC knock-ins of NCBRS alleles show INCREASED mutant SMARCA2 binding with retargeting of the alternative ATPase SMARCA4 - a redistribution-of-targeting effect rather than a simple catalytically-dead subunit, which is why the dominant-negative model is curated as an open question rather than as settled.
- name: Disrupted Chromatin Remodelling and Transcriptional Programs
  conforms_to: "epigenetic_machinery_neurodevelopmental_dysregulation#Dysregulated Neurodevelopmental Transcriptional Program"
  biological_scale: MOLECULAR
  description: >-
    BAF-dependent nucleosome remodelling controls the accessibility of
    developmental gene programs. In NCBRS the downstream consequence is measurable
    as a genome-wide DNA methylation signature: 429 differentially methylated CpG
    sites distinguish affected individuals from controls, and the genes those
    sites map to are involved in cell differentiation, calcium signalling and
    neuronal function - consistent with the disorder's neurodevelopmental and
    multisystem phenotype. The signature is sufficiently specific to classify
    variants of uncertain significance with 100% sensitivity and specificity in a
    validation cohort, so it is both a mechanistic readout and a diagnostic tool.
  biological_processes:
  - preferred_term: chromatin remodeling
    term:
      id: GO:0006338
      label: chromatin remodeling
    modifier: DECREASED
  - preferred_term: regulation of DNA-templated transcription
    term:
      id: GO:0006355
      label: regulation of DNA-templated transcription
    modifier: ABNORMAL
  downstream:
  - target: Impaired Neurodevelopment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Dysregulated differentiation, calcium-signalling and neuronal-function gene
      programs impair neurodevelopment.
  - target: Impaired Ectodermal and Skeletal Development
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The same chromatin-level lesion perturbs hair-follicle and skeletal
      developmental programs, producing the sparse hair and brachydactyly.
  evidence:
  - reference: PMID:31288860
    reference_title: "New insights into DNA methylation signatures: SMARCA2 variants in Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a DNAm signature of 429 differentially methylated CpG sites in individuals with NCBRS. The genes to which these CpG sites map are involved in cell differentiation, calcium signaling, and neuronal function consistent with NCBRS pathophysiology."
    explanation: Direct human epigenomic evidence that SMARCA2 variants produce a genome-wide methylation signature over differentiation, calcium-signalling and neuronal-function genes.
  - reference: PMID:31288860
    reference_title: "New insights into DNA methylation signatures: SMARCA2 variants in Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A validation cohort of NCBRS cases (n = 8) and controls (n = 96) demonstrated 100% model sensitivity and specificity."
    explanation: Quantifies the discriminative performance of the methylation signature, supporting its use both as a mechanistic readout and as a diagnostic classifier.
- name: Impaired Neurodevelopment
  conforms_to: "epigenetic_machinery_neurodevelopmental_dysregulation#Intellectual Disability with Growth and Craniofacial Dysmorphism"
  biological_scale: ORGANISM
  description: >-
    The neurodevelopmental consequence is intellectual disability of variable but
    generally marked severity, with absent speech in a substantial minority,
    acquired microcephaly, behavioural abnormalities, and epilepsy that is often
    difficult to control. Severity within the disorder is internally correlated:
    the severity of intellectual disability tracks with the presence of seizures,
    absent speech, short stature and microcephaly, indicating a shared dose of
    the underlying lesion rather than independent organ-specific effects. Brain
    MRI is mainly unremarkable, and the epilepsy is characterised as genetic
    rather than structural.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  downstream:
  - target: Intellectual Disability
    causal_link_type: DIRECT
    description: The neurodevelopmental lesion manifests as intellectual disability.
  - target: Seizures
    causal_link_type: DIRECT
    description: >-
      The same lesion produces a predominantly generalised, difficult-to-treat
      epilepsy that is genetic rather than structural in origin.
  - target: Secondary Microcephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Impaired postnatal brain growth produces acquired microcephaly.
  - target: Developmental Regression
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Regression or arrest of developmental progress has been observed with the
      onset of seizures.
  - target: Global Developmental Delay
    causal_link_type: DIRECT
    description: >-
      The neurodevelopmental lesion presents first as global developmental delay
      before the intellectual disability is formally characterised.
  - target: Absent Speech
    causal_link_type: DIRECT
    description: >-
      Speech and language are disproportionately affected, with a substantial
      minority never developing speech.
  - target: Behavioral Problems
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Behavioural abnormalities are part of the neurodevelopmental phenotype and
      track with the severity of the underlying lesion.
  - target: Autistic Behavior
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Autistic-like features occur within the behavioural phenotype, with a
      minority receiving a formal autism spectrum diagnosis.
  - target: Hyperacusis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Sensitivity to loud noises is one of the two exemplar autistic-like
      features named in the clinical description.
  - target: Feeding Difficulties
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Feeding difficulty accompanies the neurodevelopmental phenotype and drives
      the requirement to assess nutritional status and oral-intake safety at each
      visit; the intermediates (oral-motor versus oral-sensory) are not
      established.
  - target: Hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Hypotonia is reported as one of the neurological abnormalities of the
      syndrome and is grouped with seizures, microcephaly and structural brain
      anomalies; the intermediates between the transcriptional lesion and reduced
      muscle tone are not established.
  evidence:
  - reference: PMID:25169058
    reference_title: "Phenotype and genotype in Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There may be a correlation between the severity of the ID and presence of seizures, absent speech, short stature and microcephaly."
    explanation: Documents the internal correlation of severity across the neurodevelopmental and growth features, supporting a single shared upstream lesion.
  - reference: PMID:33578439
    reference_title: "Epilepsy in Nicolaides-Baraitser Syndrome: Review of Literature and Report of 25 Patients Focusing on Treatment Aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "EEG showed generalized epileptogenic abnormalities in 53% (9/17), cranial magnetic resonance imaging (cMRI) was mainly inconspicuous."
    explanation: Establishes that the epilepsy is accompanied by generalised EEG abnormalities without a structural MRI correlate.
  - reference: PMID:26468571
    reference_title: "SMARCA2-Related Nicolaides-Baraitser Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Regression or lack of developmental progress has been noted with the onset of seizures in some affected individuals."
    explanation: GeneReviews links developmental regression to seizure onset, which is the causal edge curated here.
- name: Impaired Ectodermal and Skeletal Development
  biological_scale: TISSUE
  description: >-
    Outside the nervous system, the same chromatin-remodelling lesion produces a
    distinctive ectodermal and skeletal phenotype: sparse scalp hair (which may be
    present only at certain ages), coarse facial features, delayed tooth eruption
    with hypo- or oligodontia, and a characteristic hand phenotype of
    brachydactyly with prominence of the interphalangeal joints and distal
    phalanges caused by decreased subcutaneous fat. Radiographs show cone-shaped
    epiphyses, metaphyseal flaring, and shortening of phalanges, metacarpals and
    metatarsals, especially of the 4th and 5th rays.
  downstream:
  - target: Sparse Scalp Hair
    causal_link_type: DIRECT
    description: Disrupted hair-follicle developmental programs produce sparse scalp hair.
  - target: Brachydactyly
    causal_link_type: DIRECT
    description: >-
      Disrupted skeletal developmental programs produce shortened phalanges,
      metacarpals and metatarsals.
  - target: Prominent Interphalangeal Joints
    causal_link_type: DIRECT
    description: >-
      Joint prominence arises from decreased subcutaneous fat over the digits
      together with the underlying skeletal changes.
  - target: Cone-Shaped Epiphyses
    causal_link_type: DIRECT
    description: The radiographic hallmark of the skeletal lesion.
  - target: Coarse Facial Features
    causal_link_type: DIRECT
    description: The characteristic facial gestalt.
  - target: Reduced Subcutaneous Adipose Tissue
    causal_link_type: DIRECT
    description: >-
      Decreased subcutaneous fat is itself part of the ectodermal/mesenchymal
      lesion and is the stated anatomical basis for the digital prominence.
  - target: Everted Lower Lip Vermilion
    causal_link_type: DIRECT
    description: The commonest single element of the facial gestalt.
  - target: Wide Mouth
    causal_link_type: DIRECT
    description: Part of the same craniofacial patterning phenotype.
  - target: Long Eyelashes
    causal_link_type: DIRECT
    description: >-
      Long eyelashes belong to the ectodermal (hair-follicle) arm of the
      phenotype alongside the scalp-hair finding.
  - target: Downslanted Palpebral Fissures
    causal_link_type: DIRECT
    description: Part of the periorbital component of the facial gestalt.
  - target: Delayed Tooth Eruption
    causal_link_type: DIRECT
    description: >-
      Dental development is an ectodermal program disrupted by the same lesion.
  - target: Hypodontia or Oligodontia
    causal_link_type: DIRECT
    description: >-
      Reduced tooth number arises from the same disrupted dental-ectodermal
      program as the delayed eruption.
  - target: Platyspondyly
    causal_link_type: DIRECT
    description: >-
      The axial counterpart of the appendicular skeletal changes, seen on
      radiographs together with flat intervertebral disc space.
  - target: Short Stature
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Growth deficiency accompanies the skeletal phenotype in about half of
      affected individuals; the intermediates are not established.
  - target: Eczematous Dermatitis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Proposed, not established: the same chromatin-remodelling lesion is
      suggested to compromise epidermal barrier integrity, which would place the
      eczematous dermatitis in the ectodermal arm. Curated as an indirect edge
      with unknown intermediates because the proposal rests on a single case
      report.
  evidence:
  - reference: PMID:26468571
    reference_title: "SMARCA2-Related Nicolaides-Baraitser Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SMARCA2-related Nicolaides-Baraitser syndrome (SMARCA2-NCBRS) is characterized by commonly shared dysmorphic features including sparse scalp hair, prominence of the interphalangeal joints and distal phalanges due to decreased subcutaneous fat, characteristic coarse facial features, microcephaly (typically acquired), seizures, and developmental delay / intellectual disability."
    explanation: GeneReviews defines the composite ectodermal, skeletal and neurological phenotype, including the mechanistic detail that joint prominence is due to decreased subcutaneous fat.
  - reference: PMID:26468571
    reference_title: "SMARCA2-Related Nicolaides-Baraitser Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Radiographic findings may include cone-shaped epiphyses, metaphyseal flaring of the phalanges, and shortening of the phalanges, metacarpals, and/or metatarsals (especially of the 4th and 5th rays) of the hands; platyspondyly; flat intervertebral disc space; and pelvic/femoral anomalies."
    explanation: Enumerates the radiographic skeletal phenotype produced by this node.
phenotypes:
- category: Cognitive
  name: Intellectual Disability
  description: >-
    Intellectual disability is almost universal. GeneReviews grades it severe in
    nearly half of affected individuals, moderate in one third, and mild in the
    remainder, so essentially everyone is affected but severity varies widely.
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:26468571
    reference_title: "SMARCA2-Related Nicolaides-Baraitser Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Developmental delay / intellectual disability is severe in nearly half of affected individuals, moderate in one third, and mild in the remainder."
    explanation: The three severity bands sum to the whole cohort, so intellectual disability is present in essentially all individuals, supporting a VERY_FREQUENT band.
  - reference: PMID:25169058
    reference_title: "Phenotype and genotype in Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The cardinal features (ID, short stature, microcephaly, typical face, sparse hair, brachydactyly, prominent interphalangeal joints, behavioral problems and seizures), are almost universally present."
    explanation: A 61-patient analysis states that intellectual disability, among the other cardinal features, is almost universally present. Note this sentence is a rhetorical summary covering nine features at once and is not a per-feature frequency measurement, so it is used here only alongside the independent GeneReviews severity distribution.
- category: Developmental
  name: Global Developmental Delay
  description: >-
    Developmental delay is a defining feature and is graded on the same severity
    distribution as the intellectual disability.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:26468571
    reference_title: "SMARCA2-Related Nicolaides-Baraitser Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "microcephaly (typically acquired), seizures, and developmental delay / intellectual disability"
    explanation: GeneReviews lists developmental delay among the defining features of the syndrome.
- category: Neurological
  name: Absent Speech
  description: >-
    Nearly one third of affected individuals never develop speech or language
    skills; absent speech correlates with overall severity.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Absent speech
    term:
      id: HP:0001344
      label: Absent speech
  evidence:
  - reference: PMID:26468571
    reference_title: "SMARCA2-Related Nicolaides-Baraitser Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nearly one third never develop speech or language skills."
    explanation: Quantifies absent speech at approximately one third of individuals, at the lower edge of the FREQUENT (30-79%) band.
- category: Neurological
  name: Seizures
  description: >-
    Seizures are a cardinal feature and are frequently difficult to manage,
    requiring multiple antiseizure medications for reasonable control. Generalized
    seizures predominate (reported in 85% of a 20-patient series), semiology
    varies widely, EEG shows generalized epileptogenic abnormalities in about
    half, and brain MRI is mainly unremarkable - the epilepsy is characterised as
    genetic rather than structural.
  frequency: FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:26468571
    reference_title: "SMARCA2-Related Nicolaides-Baraitser Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seizures are of various types and can be difficult to manage, requiring multiple anti-seizure medications to achieve reasonable control."
    explanation: GeneReviews establishes seizures as a defining feature and documents their refractoriness.
  - reference: PMID:33578439
    reference_title: "Epilepsy in Nicolaides-Baraitser Syndrome: Review of Literature and Report of 25 Patients Focusing on Treatment Aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Inclusion of 25 NCBRS patients with epilepsy in 23 of 25."
    explanation: Epilepsy in 23 of 25 individuals in this series, but the cohort was recruited partly through an epilepsy network and is therefore strongly enriched for epilepsy. The band is set from the unenriched literature instead, which places seizures in the FREQUENT range.
  - reference: PMID:33578439
    reference_title: "Epilepsy in Nicolaides-Baraitser Syndrome: Review of Literature and Report of 25 Patients Focusing on Treatment Aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overall, 85% of the participants (17/20) reported generalized seizures, the semiology varied widely."
    explanation: Characterises the predominant seizure type and its variability.
- category: Neurological
  name: Developmental Regression
  description: >-
    Regression or arrest of developmental progress has been observed in some
    individuals coincident with the onset of seizures, which is a specific
    clinical reason to treat seizures aggressively.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Developmental regression
    term:
      id: HP:0002376
      label: Developmental regression
  evidence:
  - reference: PMID:26468571
    reference_title: "SMARCA2-Related Nicolaides-Baraitser Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Regression or lack of developmental progress has been noted with the onset of seizures in some affected individuals."
    explanation: GeneReviews reports regression in "some" individuals with seizure onset; the hedged wording without a numerator supports a conservative OCCASIONAL band.
- category: Neurological
  name: Hypotonia
  description: >-
    Hypotonia is listed among the neurological abnormalities of NCBRS alongside
    seizures, microcephaly and structural brain anomalies, and regional (oral
    motor) hypotonia has been documented in an individually reported patient
    where it accompanied feeding and dental findings. The deep-research report
    gives a 19/51 (37.3%) figure from the Sousa 2014 full text, but that paper is
    cached abstract-only and the figure is not quotable, so no frequency band is
    asserted here (evidence-guidelines Pattern D).
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:41497020
    reference_title: "Bilateral congenital glaucoma in a child with Nicolaides-Baraitser syndrome: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neurological abnormalities include seizures, hypotonia, microcephaly, and structural brain anomalies"
    explanation: States hypotonia as one of the neurological abnormalities characterising NCBRS, establishing the disease-phenotype association without giving a rate.
  - reference: PMID:37970954
    reference_title: "Autism spectrum disorder in a patient with Nicolaides-Baraitser Syndrome: case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "micrognathia, anterior open bite, a generalized diastema, oral motor hypotonia, and delayed tooth eruption"
    explanation: Documents hypotonia in a molecularly confirmed NCBRS patient. Rated PARTIAL because the observation is regional (oral motor) in a single individual rather than the generalised hypotonia the disorder-level statement describes.
- category: Neurological
  name: Secondary Microcephaly
  description: >-
    Microcephaly is a cardinal feature and is typically acquired rather than
    congenital.
  frequency: FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Secondary microcephaly
    term:
      id: HP:0005484
      label: Secondary microcephaly
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:26468571
    reference_title: "SMARCA2-Related Nicolaides-Baraitser Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characteristic coarse facial features, microcephaly (typically acquired), seizures"
    explanation: GeneReviews lists microcephaly among the commonly shared features and specifies its acquired (postnatal) character.
  - reference: PMID:25169058
    reference_title: "Phenotype and genotype in Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The cardinal features (ID, short stature, microcephaly, typical face, sparse hair, brachydactyly, prominent interphalangeal joints, behavioral problems and seizures), are almost universally present."
    explanation: Microcephaly is listed among the cardinal features described as almost universally present. That sentence is a rhetorical summary covering nine features at once - short stature is in the same list yet is quantified elsewhere at about half - so it is not treated as a VERY_FREQUENT datum, and the band is set at FREQUENT.
- category: Integumentary
  name: Sparse Scalp Hair
  description: >-
    Sparse scalp hair is one of the two features in the disorder's descriptive
    name and is a cardinal diagnostic clue. It is age-dependent - it may be
    present only in certain age groups - which is a specific pitfall when
    assessing a patient outside those ages.
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Sparse scalp hair
    term:
      id: HP:0002209
      label: Sparse scalp hair
  evidence:
  - reference: PMID:26468571
    reference_title: "SMARCA2-Related Nicolaides-Baraitser Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "commonly shared dysmorphic features including sparse scalp hair"
    explanation: GeneReviews lists sparse scalp hair first among the commonly shared dysmorphic features.
  - reference: PMID:25169058
    reference_title: "Phenotype and genotype in Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There is variability however, as ID can range from severe to mild, and sparse hair may be present only in certain age groups."
    explanation: Documents the age-dependence of sparse hair, which is the diagnostic pitfall stated in this phenotype's description.
- category: Skeletal
  name: Brachydactyly
  description: >-
    Shortening of the phalanges, metacarpals and metatarsals, especially of the
    4th and 5th rays, gives the characteristic brachydactyly named in the
    disorder's descriptive title.
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Brachydactyly
    term:
      id: HP:0001156
      label: Brachydactyly
  evidence:
  - reference: PMID:25169058
    reference_title: "Phenotype and genotype in Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "typical face, sparse hair, brachydactyly, prominent interphalangeal joints, behavioral problems and seizures), are almost universally present"
    explanation: Brachydactyly is among the cardinal features described as almost universally present. That summary sentence covers nine features at once, but brachydactyly is also one of the two features in the disorder's descriptive name and is independently corroborated by the GeneReviews radiographic description, so the band is retained.
  - reference: PMID:26468571
    reference_title: "SMARCA2-Related Nicolaides-Baraitser Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "shortening of the phalanges, metacarpals, and/or metatarsals (especially of the 4th and 5th rays) of the hands"
    explanation: Specifies the anatomical distribution of the shortening.
- category: Skeletal
  name: Prominent Interphalangeal Joints
  description: >-
    Prominence of the interphalangeal joints and of the distal phalanges is a
    highly distinctive hand finding, caused by decreased subcutaneous fat over the
    digits in combination with the underlying skeletal changes.
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Prominent interphalangeal joints
    term:
      id: HP:0006237
      label: Prominent interphalangeal joints
  evidence:
  - reference: PMID:26468571
    reference_title: "SMARCA2-Related Nicolaides-Baraitser Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "prominence of the interphalangeal joints and distal phalanges due to decreased subcutaneous fat"
    explanation: GeneReviews states both the finding and its mechanism (decreased subcutaneous fat).
  - reference: PMID:25169058
    reference_title: "Phenotype and genotype in Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "brachydactyly, prominent interphalangeal joints, behavioral problems and seizures), are almost universally present"
    explanation: Prominent interphalangeal joints are among the cardinal features described as almost universally present, and are independently listed by GeneReviews among the commonly shared dysmorphic features.
- category: Skeletal
  name: Cone-Shaped Epiphyses
  description: >-
    Cone-shaped epiphyses with metaphyseal flaring of the phalanges are the
    radiographic hallmark and were part of the original clinical delineation of
    the syndrome. No source quantifies the frequency, so none is asserted.
  diagnostic: true
  phenotype_term:
    preferred_term: Cone-shaped epiphysis
    term:
      id: HP:0010579
      label: Cone-shaped epiphysis
  evidence:
  - reference: PMID:26468571
    reference_title: "SMARCA2-Related Nicolaides-Baraitser Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Radiographic findings may include cone-shaped epiphyses, metaphyseal flaring of the phalanges"
    explanation: GeneReviews lists cone-shaped epiphyses among the radiographic findings. The wording is hedged with no numerator, so no frequency band is asserted.
- category: Growth
  name: Short Stature
  description: >-
    About half of affected individuals have growth deficiency and short stature,
    and short stature correlates with overall severity.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:26468571
    reference_title: "SMARCA2-Related Nicolaides-Baraitser Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "About half of affected individuals have growth deficiency and short stature."
    explanation: Quantifies short stature at about 50%, squarely in the FREQUENT (30-79%) band.
- category: Craniofacial
  name: Coarse Facial Features
  description: >-
    A characteristic coarse facial appearance is a cardinal recognisable feature.
    Systematic review identifies thick or everted lower lip, coarse features, a
    wide or large mouth and a thin upper lip as the commonest facial dysmorphisms.
  frequency: FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Coarse facial features
    term:
      id: HP:0000280
      label: Coarse facial features
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:26468571
    reference_title: "SMARCA2-Related Nicolaides-Baraitser Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "is characterized by commonly shared dysmorphic features including sparse scalp hair, prominence of the interphalangeal joints and distal phalanges due to decreased subcutaneous fat, characteristic coarse facial features"
    explanation: The GeneReviews clinical-characteristics sentence lists characteristic coarse facial features among the dysmorphic features commonly shared across affected individuals.
  - reference: PMID:31288860
    reference_title: "New insights into DNA methylation signatures: SMARCA2 variants in Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with progressive facial coarsening with age"
    explanation: Documents that the coarsening is progressive with age rather than static, which is the basis for the PROGRESSIVE clinical course on this descriptor.
  - reference: PMID:35762114
    reference_title: "Ophthalmologic and facial abnormalities of Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common facial dysmorphic features include thick/everted lower lip, coarse facial features, wide/large mouth, and thin upper lip."
    explanation: A systematic review of molecularly confirmed cases ranks coarse facial features among the commonest facial dysmorphisms.
- category: Craniofacial
  name: Everted Lower Lip Vermilion
  description: >-
    A thick or everted lower lip is the single commonest facial dysmorphism in
    systematic review, and contributes to the overlap with Coffin-Siris syndrome.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Everted lower lip vermilion
    term:
      id: HP:0000232
      label: Everted lower lip vermilion
  evidence:
  - reference: PMID:35762114
    reference_title: "Ophthalmologic and facial abnormalities of Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common facial dysmorphic features include thick/everted lower lip"
    explanation: Systematic review identifies the thick/everted lower lip as the leading facial dysmorphism.
- category: Craniofacial
  name: Wide Mouth
  description: >-
    A wide or large mouth is among the commonest facial features on systematic
    review.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Wide mouth
    term:
      id: HP:0000154
      label: Wide mouth
  evidence:
  - reference: PMID:35762114
    reference_title: "Ophthalmologic and facial abnormalities of Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "coarse facial features, wide/large mouth, and thin upper lip"
    explanation: Systematic review ranks a wide/large mouth among the commonest facial dysmorphisms.
- category: Ophthalmological
  name: Long Eyelashes
  description: >-
    Prominent or long eyelashes with thick eyebrows are the commonest ocular
    adnexal findings on systematic review, alongside sagging periorbital skin,
    downslanting palpebral fissures and ptosis.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Long eyelashes
    term:
      id: HP:0000527
      label: Long eyelashes
  evidence:
  - reference: PMID:35762114
    reference_title: "Ophthalmologic and facial abnormalities of Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the most common abnormal eye and ocular adnexa features include prominent/long eyelashes, thick eyebrows, sagging periorbital skin, down slanting palpebral fissures, and ptosis"
    explanation: Systematic review of molecularly confirmed cases ranks prominent/long eyelashes first among ocular adnexal abnormalities.
- category: Ophthalmological
  name: Downslanted Palpebral Fissures
  description: >-
    Downslanting palpebral fissures are among the commonest periocular findings.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Downslanted palpebral fissures
    term:
      id: HP:0000494
      label: Downslanted palpebral fissures
  evidence:
  - reference: PMID:35762114
    reference_title: "Ophthalmologic and facial abnormalities of Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "sagging periorbital skin, down slanting palpebral fissures, and ptosis"
    explanation: Systematic review ranks downslanting palpebral fissures among the commonest ocular adnexal features.
- category: Ophthalmological
  name: Refractive Error
  description: >-
    Refractive error and astigmatism are listed by GeneReviews among the rarer
    findings, and myopia is documented in reported cases; ophthalmological
    evaluation is recommended promptly after diagnosis.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Abnormality of refraction
    term:
      id: HP:0000539
      label: Abnormality of refraction
  evidence:
  - reference: PMID:26468571
    reference_title: "SMARCA2-Related Nicolaides-Baraitser Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rare findings include conductive hearing loss, refractive error / astigmatism, and congenital heart defects."
    explanation: GeneReviews classifies refractive error/astigmatism among the rare findings; combined with its appearance in case series this supports a conservative OCCASIONAL band.
- category: Behavioral
  name: Behavioral Problems
  description: >-
    Behavioural problems are a cardinal feature. They include autistic-like
    features such as perseveration and hyperacusis, with a minority of individuals
    receiving a formal clinical autism spectrum diagnosis - so the behavioural
    phenotype is broader than, and should not be equated with, autism.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Atypical behavior
    term:
      id: HP:0000708
      label: Atypical behavior
  evidence:
  - reference: PMID:25169058
    reference_title: "Phenotype and genotype in Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "prominent interphalangeal joints, behavioral problems and seizures), are almost universally present"
    explanation: Behavioural problems are among the cardinal features described as almost universally present. That summary sentence covers nine features at once, so the band is corroborated by the independent GeneReviews characterisation of the behavioural phenotype below.
  - reference: PMID:26468571
    reference_title: "SMARCA2-Related Nicolaides-Baraitser Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Behavioral issues can include autistic-like features (perseveration, hyperacusis), with a minority of affected individuals being diagnosed clinically with an autism spectrum disorder."
    explanation: Characterises the behavioural phenotype and specifies that formal autism diagnosis applies to only a minority.
- category: Behavioral
  name: Autistic Behavior
  description: >-
    Autistic-like features occur, but only a minority of affected individuals
    receive a formal clinical autism spectrum diagnosis.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: PMID:26468571
    reference_title: "SMARCA2-Related Nicolaides-Baraitser Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with a minority of affected individuals being diagnosed clinically with an autism spectrum disorder"
    explanation: GeneReviews states that only a minority receive a formal autism diagnosis, which maps to an OCCASIONAL band.
- category: Genitourinary
  name: Cryptorchidism
  description: >-
    Cryptorchidism is common in affected males and is one of the manifestations
    for which standard management is recommended.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  evidence:
  - reference: PMID:26468571
    reference_title: "SMARCA2-Related Nicolaides-Baraitser Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cryptorchidism is common in males."
    explanation: GeneReviews describes cryptorchidism as common in males, which maps to the FREQUENT band.
- category: Dental
  name: Delayed Tooth Eruption
  description: >-
    Delayed tooth eruption with hypodontia or oligodontia is reported, and
    GeneReviews recommends dental evaluation at least every six months, and
    systematic review describes dental abnormalities as commonly reported.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Delayed eruption of teeth
    term:
      id: HP:0000684
      label: Delayed eruption of teeth
  evidence:
  - reference: PMID:26468571
    reference_title: "SMARCA2-Related Nicolaides-Baraitser Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Delayed tooth eruption with hypo- or oligodontia has also been reported."
    explanation: GeneReviews reports delayed tooth eruption with hedged wording and no numerator.
  - reference: PMID:35762114
    reference_title: "Ophthalmologic and facial abnormalities of Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dental abnormalities are also commonly reported."
    explanation: Systematic review describes dental abnormalities as commonly reported, which maps to the FREQUENT band and is the basis for the band set here.
- category: Dental
  name: Hypodontia or Oligodontia
  description: >-
    Reduced tooth number - hypodontia, and in more severe cases oligodontia -
    accompanies the delayed eruption. Curated as a single entry bound to the
    inclusive HPO term, because GeneReviews reports the two together as a
    severity range in one statement rather than as separable findings. No
    numerator is given, so no frequency band is asserted.
  phenotype_term:
    preferred_term: Hypodontia or oligodontia
    term:
      id: HP:0000668
      label: Hypodontia
  evidence:
  - reference: PMID:26468571
    reference_title: "SMARCA2-Related Nicolaides-Baraitser Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Delayed tooth eruption with hypo- or oligodontia has also been reported."
    explanation: GeneReviews reports reduced tooth number alongside the delayed eruption, with hedged wording and no numerator.
- category: Behavioral
  name: Hyperacusis
  description: >-
    Sensitivity to loud noises is part of the autistic-like behavioural profile
    and is explicitly on the GeneReviews surveillance checklist, so it is a
    managed finding rather than an incidental one. No numerator is reported.
  phenotype_term:
    preferred_term: Hyperacusis
    term:
      id: HP:0010780
      label: Hyperacusis
  evidence:
  - reference: PMID:26468571
    reference_title: "SMARCA2-Related Nicolaides-Baraitser Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Behavioral issues can include autistic-like features (perseveration, hyperacusis), with a minority of affected individuals being diagnosed clinically with an autism spectrum disorder."
    explanation: GeneReviews names hyperacusis as one of the two exemplar autistic-like features.
  - reference: PMID:26468571
    reference_title: "SMARCA2-Related Nicolaides-Baraitser Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "assess for behavioral issues such as short attention span, sensitivity to loud noises, and oral sensitivity"
    explanation: The GeneReviews surveillance section instructs clinicians to assess for sensitivity to loud noises at each visit, confirming it is a recurrent managed finding.
- category: Integumentary
  name: Reduced Subcutaneous Adipose Tissue
  description: >-
    Decreased subcutaneous fat is the stated anatomical basis for the cardinal
    prominence of the interphalangeal joints and distal phalanges, so it is a
    mechanistic precondition of one of the two features in the disorder's
    descriptive name rather than an incidental finding. No numerator is reported.
  phenotype_term:
    preferred_term: Reduced subcutaneous adipose tissue
    term:
      id: HP:0003758
      label: Reduced subcutaneous adipose tissue
  evidence:
  - reference: PMID:26468571
    reference_title: "SMARCA2-Related Nicolaides-Baraitser Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "prominence of the interphalangeal joints and distal phalanges due to decreased subcutaneous fat"
    explanation: GeneReviews attributes the cardinal joint and distal-phalangeal prominence directly to decreased subcutaneous fat.
- category: Skeletal
  name: Platyspondyly
  description: >-
    Platyspondyly with flat intervertebral disc space is part of the
    radiographic skeletal signature alongside the cone-shaped epiphyses and
    phalangeal shortening. GeneReviews presents these as findings that may be
    seen on imaging without a numerator, so no frequency band is asserted.
  phenotype_term:
    preferred_term: Platyspondyly
    term:
      id: HP:0000926
      label: Platyspondyly
  evidence:
  - reference: PMID:26468571
    reference_title: "SMARCA2-Related Nicolaides-Baraitser Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "platyspondyly; flat intervertebral disc space; and pelvic/femoral anomalies"
    explanation: GeneReviews lists platyspondyly among the radiographic findings that may be present.
- category: Gastrointestinal
  name: Feeding Difficulties
  description: >-
    Poor growth and feeding are described as continuing common features of the
    syndrome, and the GeneReviews surveillance schedule requires evaluation of
    nutritional status and safety of oral intake at every visit. The deep-research
    report gives a 23/49 (46.9%) figure from the Sousa 2014 full text, but that
    paper is cached abstract-only and the figure is not quotable, so no frequency
    band is asserted here (evidence-guidelines Pattern D).
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:31288860
    reference_title: "New insights into DNA methylation signatures: SMARCA2 variants in Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "poor growth and feeding, seizures, absent or delayed speech, variable ID, and behavioral disturbances"
    explanation: Lists poor growth and feeding among the features described as continuing to be common in the NCBRS episignature-derivation cohort.
  - reference: PMID:26468571
    reference_title: "SMARCA2-Related Nicolaides-Baraitser Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "evaluate nutritional status and safety of oral intake"
    explanation: The GeneReviews surveillance section requires nutritional and swallow-safety assessment at each visit, which is the management consequence of the feeding difficulty.
- category: Integumentary
  name: Eczematous Dermatitis
  description: >-
    Inflammatory skin disease - xerosis and eczematous plaques - occurs in NCBRS
    but has not been systematically characterised; a 2025 case report of severe
    treatment-refractory atopic dermatitis was published explicitly to broaden the
    recognised cutaneous spectrum. The deep-research report gives a 22/58 (37.9%)
    figure from the Sousa 2014 full text, but that paper is cached abstract-only
    and the figure is not quotable, so no frequency band is asserted here
    (evidence-guidelines Pattern D).
  phenotype_term:
    preferred_term: Eczematous dermatitis
    term:
      id: HP:0000964
      label: Eczematoid dermatitis
  evidence:
  - reference: PMID:40881542
    reference_title: "Expanding the Cutaneous Spectrum of Nicolaides-Baraitser Syndrome: Eczema and Generalized Hair Loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Xerosis and eczematous plaques have been anecdotally mentioned, but the breadth and severity of inflammatory skin disease in NBS are yet to be systematically characterized"
    explanation: Establishes that eczematous skin disease occurs in NCBRS while stating plainly that its frequency is uncharacterised, which is why no band is asserted.
  - reference: PMID:40881542
    reference_title: "Expanding the Cutaneous Spectrum of Nicolaides-Baraitser Syndrome: Eczema and Generalized Hair Loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Large clinical surveys emphasize xerosis as the most frequent cutaneous accompaniment, whereas inflammatory dermatoses have been mentioned only in passing"
    explanation: Confirms that the cutaneous phenotype extends beyond the hair findings and that inflammatory dermatoses are under-reported rather than absent.
- category: Auditory
  name: Conductive Hearing Impairment
  description: >-
    Conductive hearing loss is listed among the rare findings but warrants
    audiological assessment given the communication burden of the disorder.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Conductive hearing impairment
    term:
      id: HP:0000405
      label: Conductive hearing impairment
  evidence:
  - reference: PMID:26468571
    reference_title: "SMARCA2-Related Nicolaides-Baraitser Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rare findings include conductive hearing loss, refractive error / astigmatism, and congenital heart defects."
    explanation: GeneReviews classifies conductive hearing loss among the rare findings. The project mapping table would place "rare" at VERY_RARE; the band is deliberately set one step higher at OCCASIONAL because reported rates in the 61-patient series sit just above the 5% floor, and that departure is recorded here.
- category: Cardiovascular
  name: Congenital Heart Defect
  description: >-
    Congenital heart defects are listed among the rare findings; a case with
    hypertrophic cardiomyopathy and a SMARCA2 deletion has also been reported.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Abnormal heart morphology
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:26468571
    reference_title: "SMARCA2-Related Nicolaides-Baraitser Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rare findings include conductive hearing loss, refractive error / astigmatism, and congenital heart defects."
    explanation: GeneReviews classifies congenital heart defects among the rare findings. As with the other rare findings, the band is set at OCCASIONAL rather than the default VERY_RARE mapping because reported rates sit just above the 5% floor; the departure is recorded here.
genetic:
- name: SMARCA2
  gene_term:
    preferred_term: SMARCA2
    term:
      id: hgnc:11098
      label: SMARCA2
  association: Causal - de novo non-truncating variants clustered in the ATPase region
  relationship_type: CAUSATIVE
  variant_origin: DE_NOVO
  presence: Positive
  notes: >-
    SMARCA2 is at 9p24.3 and encodes BRM, one of the two alternative catalytic
    ATPase subunits of the BAF (SWI/SNF) chromatin-remodelling complex. The
    NCBRS-causing allele class is narrow and mechanistically specific: heterozygous
    de novo NON-TRUNCATING (missense and in-frame) variants clustered within
    ultra-conserved motifs of the catalytic ATPase region, thought to act by a
    dominant-negative effect on ATPase activity while leaving complex assembly
    intact. This is why NCBRS is not a SMARCA2 haploinsufficiency disorder and why
    it is distinguishable from the other SMARCA2 conditions: variants clustered
    OUTSIDE the helicase domains cause a separate blepharophimosis-intellectual
    disability syndrome, and SMARCA2 is separately listed among the BAF genes
    mutated in Coffin-Siris syndrome. Tentative genotype-phenotype correlations
    within NCBRS (domain VI variants with severe intellectual disability and
    seizures; Pro883, Leu946 and Ala1201 with milder phenotypes) are reported but
    the authors caution the numbers remain too small to be definitive.
  evidence:
  - reference: PMID:25169058
    reference_title: "Phenotype and genotype in Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "caused by non-truncating mutations in the ATPase region of SMARCA2, which codes for one of the two alternative catalytic subunits of the BAF chromatin remodeling complex"
    explanation: States the defining non-truncating, ATPase-region-restricted allele class that separates NCBRS from the other SMARCA2 disorders.
  - reference: PMID:22366787
    reference_title: "Heterozygous missense mutations in SMARCA2 cause Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We sequenced the exomes of ten individuals with NBS and identified heterozygous variants in SMARCA2 in eight of them. Extended molecular screening identified nonsynonymous SMARCA2 mutations in 36 of 44 individuals with NBS"
    explanation: The gene-discovery study establishing SMARCA2 as the cause, with a high diagnostic yield (36/44) in clinically defined NCBRS.
  - reference: PMID:25169058
    reference_title: "Phenotype and genotype in Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There may be some genotype-phenotype correlations (mutations at domain VI with severe ID and seizures; mutations affecting residues Pro883, Leu946, and Ala1201 with mild phenotypes) but numbers are still too small to draw definitive conclusions."
    explanation: The intra-NCBRS genotype-phenotype correlations are explicitly qualified by the authors as based on too few cases, so they are curated as partial support.
  - 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: "SMARCA2 variants outside the helicase domains, phenotypically and molecularly distinct from NCBRS."
    explanation: Establishes that SMARCA2 variants outside the helicase domains cause a phenotypically and molecularly distinct entity, which is the basis for this entry's scope boundary.
diagnosis:
- name: Molecular Genetic Testing for SMARCA2
  description: >-
    The diagnosis is established by identifying a heterozygous pathogenic SMARCA2
    variant in an individual with suggestive findings. Because NCBRS and
    Coffin-Siris syndrome overlap clinically and both arise from BAF-complex
    genes, a one-step panel covering all six BAF-complex genes is an efficient
    testing strategy, and the specific facial features are the major diagnostic
    handle at the bedside.
  presence: Positive in affected individuals
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:26468571
    reference_title: "SMARCA2-Related Nicolaides-Baraitser Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of SMARCA2-NCBRS is established in a proband with suggestive findings and a heterozygous SMARCA2 pathogenic variant identified by molecular genetic testing."
    explanation: GeneReviews states the molecular diagnostic criterion.
  - reference: PMID:25249037
    reference_title: "Coffin-Siris and Nicolaides-Baraitser syndromes are a common well recognizable cause of intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Given the high frequency of the condition we set up a one-step deep sequencing test for all 6 genes of the BAF complex."
    explanation: Supports a combined BAF-complex panel as the practical testing strategy given the NCBRS/Coffin-Siris overlap.
  - reference: PMID:25249037
    reference_title: "Coffin-Siris and Nicolaides-Baraitser syndromes are a common well recognizable cause of intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the specific facial features being the major diagnostic handle"
    explanation: Identifies the facial gestalt as the clinical trigger for molecular testing.
- name: DNA Methylation Episignature
  description: >-
    Genome-wide DNA methylation profiling of whole blood yields an NCBRS-specific
    signature of 429 differentially methylated CpG sites. A classifier built on
    that signature achieved 100% sensitivity and specificity in an independent
    validation cohort and reclassified SMARCA2 variants of uncertain significance
    concordantly with the clinical phenotype, making it a practical adjunct for
    VUS interpretation.
  presence: Distinct signature in affected individuals
  diagnosis_term:
    preferred_term: DNA methylation analysis
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:31288860
    reference_title: "New insights into DNA methylation signatures: SMARCA2 variants in Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Differential methylated CpGs between groups (DNAm signature) were identified and used to generate a model enabling classification variants of uncertain significance (VUS; n = 9) in SMARCA2 as \"pathogenic\" or \"benign\"."
    explanation: Describes the episignature classifier and its intended use for SMARCA2 VUS reclassification.
  - reference: PMID:31288860
    reference_title: "New insights into DNA methylation signatures: SMARCA2 variants in Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A validation cohort of NCBRS cases (n = 8) and controls (n = 96) demonstrated 100% model sensitivity and specificity."
    explanation: Quantifies classifier performance in an independent validation cohort.
differential_diagnoses:
- name: Coffin-Siris Syndrome
  description: >-
    The principal differential and the closest relative. Both are BAFopathies with
    overlapping features - intellectual disability, sparse hair, low frontal
    hairline, large mouth with thick everted lips, and hand and foot anomalies -
    and SMARCA2 is itself listed among the BAF-complex genes mutated in
    Coffin-Siris syndrome. They remain distinct entities: NCBRS is caused
    specifically by non-truncating variants clustered in the SMARCA2 ATPase region
    acting dominant-negatively, and is clinically and genetically homogeneous,
    whereas Coffin-Siris is genetically heterogeneous across six BAF genes and its
    hallmark is hypoplasia of the fifth digit nail/phalanx. Curated separately in
    dismech as `Coffin_Siris_Syndrome`.
- name: SMARCA2 Blepharophimosis-Intellectual Disability Syndrome
  description: >-
    Allelic but distinct. De novo SMARCA2 variants clustered OUTSIDE the helicase
    domains cause a recognisable syndrome of intellectual disability with
    blepharophimosis that is explicitly reported as phenotypically and molecularly
    distinct from NCBRS. Variant position within SMARCA2 is the discriminator, and
    the separation is now corroborated at the epigenetic level: BIS carries its own
    episignature, which it shares with truncating-ADNP Helsmoortel-Van der Aa
    syndrome rather than with NCBRS.
  distinguishing_features:
  - Location of the SMARCA2 variant - inside the ATPase/helicase region in NCBRS,
    outside it in BIS.
  - Blepharophimosis is the recognisable facial cue in BIS and is not part of the
    NCBRS gestalt.
  - The DNA methylation episignature differs; BIS clusters with truncating-ADNP
    Helsmoortel-Van der Aa syndrome, not with NCBRS.
  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: "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. BIS is caused by pathogenic variants in SMARCA2"
    explanation: A 2024 study states explicitly that BIS is a SMARCA2-related disorder distinct from NCBRS, which is the basis for keeping the two as separate entities.
  - 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: Independent epigenetic corroboration of the split - the BIS methylation signature aligns with truncating-ADNP HVDAS rather than with the NCBRS signature, so episignature testing discriminates the two SMARCA2 phenotypes.
- name: Cornelia de Lange Syndrome
  description: >-
    Shares intellectual disability, growth restriction, distinctive facies with
    thick eyebrows and long eyelashes, and limb/digit anomalies; distinguished
    molecularly (NIPBL and cohesin-complex genes).
- name: Other BAFopathies
  description: >-
    The wider BAF-complex disorder group (ARID1A, ARID1B, SMARCB1, SMARCA4,
    SMARCE1, DPF2) overlaps clinically; a combined BAF-gene panel is the efficient
    diagnostic approach rather than sequential single-gene testing.
treatments:
- name: Standard-of-Care Management of Manifestations
  description: >-
    There is no disease-modifying therapy. Management is standard therapy for each
    manifestation - developmental delay and intellectual disability, behavioural
    issues, epilepsy, poor growth, myopia, astigmatism, hearing loss, dental
    issues, cryptorchidism and congenital heart defects - delivered by the
    relevant specialists.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:26468571
    reference_title: "SMARCA2-Related Nicolaides-Baraitser Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Standard therapy for developmental delay / intellectual disability, behavioral issues, epilepsy, poor growth, myopia, astigmatism, hearing loss, dental issues, cryptorchidism, and congenital heart defects."
    explanation: GeneReviews defines the standard of care as specialist-delivered symptomatic management across the affected systems.
- name: Antiseizure Medication
  description: >-
    Epilepsy in NCBRS mostly shows only an initial response to antiseizure
    medication and very rarely achieves complete seizure freedom. In the largest
    treatment-focused series, levetiracetam, valproic acid, phenobarbital and
    topiramate each reduced seizure frequency by more than 50% in most treated
    patients, but only a minority achieved even temporary (>6 month) seizure
    freedom. Seizure aggravation was observed with several agents, most notably
    lamotrigine, which is curated as a separate agents-to-use-with-caution item.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: levetiracetam
      term:
        id: CHEBI:6437
        label: levetiracetam
    - preferred_term: valproic acid
      term:
        id: CHEBI:39867
        label: valproic acid
  therapeutic_modality: SMALL_MOLECULE
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:33578439
    reference_title: "Epilepsy in Nicolaides-Baraitser Syndrome: Review of Literature and Report of 25 Patients Focusing on Treatment Aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "helps to treat epilepsy in NCBRS that mostly shows only initial response to anticonvulsive therapy, especially with LEV and VPA, but very rarely shows complete freedom of seizures in this, rather genetic than structural epilepsy"
    explanation: States both the partial benefit and the low rate of seizure freedom, which is why this treatment is curated as partial rather than full support.
  - reference: PMID:33578439
    reference_title: "Epilepsy in Nicolaides-Baraitser Syndrome: Review of Literature and Report of 25 Patients Focusing on Treatment Aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "LEV (9/12), PB (6/8), TPM (4/5), and VPA (9/12) reduced the seizures' frequency in more than 50%."
    explanation: Quantifies the response rates of the four most effective agents.
- name: Lamotrigine - Agent to Use With Caution
  description: >-
    Seizure aggravation was observed under lamotrigine in 2 of 4 treated patients
    in the only treatment-focused NCBRS series, a higher proportion than for any
    other agent studied. Aggravation was also seen, at much lower rates, under
    levetiracetam, phenobarbital and valproic acid, so this is a caution about
    relative risk rather than an absolute contraindication.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: lamotrigine
      term:
        id: CHEBI:6367
        label: lamotrigine
  therapeutic_modality: SMALL_MOLECULE
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:33578439
    reference_title: "Epilepsy in Nicolaides-Baraitser Syndrome: Review of Literature and Report of 25 Patients Focusing on Treatment Aspects."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Seizures aggravation was observed under lamotrigine"
    explanation: Evidence against lamotrigine benefit specifically. The source sentence gives the count as 2 of 4 treated patients, but the bracketed figure cannot be quoted verbatim because the reference validator strips square-bracket markup, so the count is stated in the description rather than in the snippet.
  - reference: PMID:33578439
    reference_title: "Epilepsy in Nicolaides-Baraitser Syndrome: Review of Literature and Report of 25 Patients Focusing on Treatment Aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "LEV (1/12), PB (1/8), and VPA (1/12)."
    explanation: The remainder of the same sentence, quoted separately to avoid implying that aggravation was specific to lamotrigine - levetiracetam, phenobarbital and valproic acid also aggravated seizures, at much lower rates. This is why the item is a caution rather than a contraindication.
- name: Vagus Nerve Stimulation
  description: >-
    Tried in two patients in the largest treatment series with seizure-frequency
    reduction in one of the two. Curated separately from the ketogenic diet
    because it is a neuromodulation device rather than a dietary intervention.
  treatment_term:
    preferred_term: vagus nerve stimulation
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  therapeutic_modality: DEVICE
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:33578439
    reference_title: "Epilepsy in Nicolaides-Baraitser Syndrome: Review of Literature and Report of 25 Patients Focusing on Treatment Aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ketogenic diet (KD) and vagal nerve stimulation (VNS) reduced seizures' frequency in one of two each."
    explanation: The entire evidence base is two patients with a one-in-two response, so this is curated as partial support.
- name: Ketogenic Diet
  description: >-
    Tried in two patients in the largest treatment series with seizure-frequency
    reduction in one of the two. The evidence base is anecdotal but the ketogenic
    diet remains a reasonable option given the refractoriness of the epilepsy.
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  therapeutic_modality: BEHAVIORAL
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:33578439
    reference_title: "Epilepsy in Nicolaides-Baraitser Syndrome: Review of Literature and Report of 25 Patients Focusing on Treatment Aspects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ketogenic diet (KD) and vagal nerve stimulation (VNS) reduced seizures' frequency in one of two each."
    explanation: The entire evidence base for both interventions is two patients each with a one-in-two response, so this is curated as partial support.
- name: Developmental and Educational Support
  description: >-
    Standard developmental therapy addresses the developmental delay and
    intellectual disability. Surveillance includes monitoring developmental
    progress and educational needs, and assessing mobility and self-help skills.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:26468571
    reference_title: "SMARCA2-Related Nicolaides-Baraitser Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "monitor developmental progress and educational needs; assess for behavioral issues such as short attention span, sensitivity to loud noises, and oral sensitivity; and evaluate mobility and self-help skills"
    explanation: GeneReviews specifies the developmental, behavioural and functional surveillance domains.
- name: Growth and Nutritional Surveillance
  description: >-
    Growth parameters, nutritional status and the safety of oral intake are
    assessed at every visit, reflecting the frequent growth deficiency and the
    oral sensitivity described in the behavioural phenotype.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:26468571
    reference_title: "SMARCA2-Related Nicolaides-Baraitser Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At each visit, measure growth parameters; evaluate nutritional status and safety of oral intake"
    explanation: GeneReviews specifies growth and nutritional surveillance at every visit.
- name: Dental Surveillance
  description: >-
    Dental evaluation at least every six months is recommended, reflecting the
    delayed tooth eruption with hypo- or oligodontia.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Delayed eruption of teeth
    term:
      id: HP:0000684
      label: Delayed eruption of teeth
  evidence:
  - reference: PMID:26468571
    reference_title: "SMARCA2-Related Nicolaides-Baraitser Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dental evaluation at least every six months after the eruption of first"
    explanation: GeneReviews specifies dental evaluation at least every six months after the eruption of the first dentition.
- name: Audiology Surveillance
  description: >-
    Annual audiology evaluation is recommended in childhood, reflecting the
    reported conductive hearing loss and the communication burden of the disorder.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Conductive hearing impairment
    term:
      id: HP:0000405
      label: Conductive hearing impairment
  evidence:
  - reference: PMID:26468571
    reference_title: "SMARCA2-Related Nicolaides-Baraitser Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Annual audiology evaluation in childhood"
    explanation: GeneReviews specifies annual childhood audiology evaluation as part of surveillance.
- name: Ophthalmological Evaluation
  description: >-
    Prompt ophthalmological evaluation following diagnosis is recommended, given
    the frequency of well-defined ophthalmic abnormalities including refractive
    error, ptosis and periocular findings.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Abnormality of refraction
    term:
      id: HP:0000539
      label: Abnormality of refraction
  evidence:
  - reference: PMID:35762114
    reference_title: "Ophthalmologic and facial abnormalities of Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "NCBRS frequently presents with well-defined ophthalmic and facial abnormalities."
    explanation: Establishes that ophthalmic abnormalities are frequent and well-defined, which is the basis for recommending prompt ophthalmological evaluation.
- name: Genetic Counseling
  description: >-
    Counselling covers the autosomal dominant, essentially always de novo
    mechanism, the consequently low presumed risk to other family members, and the
    availability of prenatal and preimplantation genetic testing once the familial
    variant is known.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  therapeutic_modality: BEHAVIORAL
  evidence:
  - reference: PMID:26468571
    reference_title: "SMARCA2-Related Nicolaides-Baraitser Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the risk to other family members is presumed to be low"
    explanation: GeneReviews states the recurrence-risk framing that counselling communicates.
  - reference: PMID:26468571
    reference_title: "SMARCA2-Related Nicolaides-Baraitser Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "prenatal and preimplantation genetic testing are possible"
    explanation: GeneReviews states the reproductive testing options that counselling addresses.
  - reference: PMID:22366787
    reference_title: "Heterozygous missense mutations in SMARCA2 cause Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "these mutations were confirmed to be de novo when parental samples were available"
    explanation: The de novo origin is the central counselling fact and the basis for the low presumed recurrence risk.
discussions:
- discussion_id: ncbrs_dominant_negative_mechanism
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Is the dominant-negative, assembly-intact/ATPase-dead model of NCBRS
    SMARCA2 variants correct, and does it explain why non-truncating variants
    cause NCBRS while truncating variants do not?
  attaches_to:
  - pathophysiology#Dominant-Negative Impairment of BAF Complex ATPase Activity
  rationale: >-
    The dominant-negative model is the load-bearing mechanistic claim of this
    disorder - it explains the allelic specificity, separates NCBRS from
    SMARCA2 haploinsufficiency, and would determine what a targeted therapy
    would have to do. But it rests on inference rather than demonstration: the
    original report states the variants "likely do not impair SWI/SNF complex
    assembly but may be associated with disrupted ATPase activity", and the
    61-patient analysis states they are "likely to act through a
    dominant-negative effect". The one direct functional test in an isogenic human
    system (NCBRS K755R and R1159Q knock-in hESCs) did not measure ATPase activity
    or complex assembly; what it found instead was INCREASED mutant SMARCA2
    chromatin binding with global retargeting of SMARCA4, loss of SOX3-dependent
    neural enhancers, and emergence of astrocyte-specific de novo enhancers - a
    picture more consistent with altered targeting than with a catalytically dead
    subunit. So the two models are not yet distinguished: no published work
    measures BAF assembly and nucleosome-stimulated ATPase activity for a panel of
    NCBRS patient variants, and the DNA methylation signature, while showing that
    the variants perturb chromatin-dependent transcription, cannot separate
    dominant-negative from redistribution at the protein level.
  proposed_experiments:
  - experiment_id: ncbrs_baf_assembly_atpase_panel
    name: Biochemical panel of NCBRS variants for assembly and ATPase activity
    description: >-
      Express a panel of recurrent NCBRS SMARCA2 variants and measure BAF complex
      assembly (co-immunoprecipitation, size-exclusion) and nucleosome-stimulated
      ATPase and remodelling activity in parallel, alongside truncating alleles as
      a loss-of-function comparator.
    decision_criterion: >-
      Intact assembly with abolished ATPase activity would confirm the
      dominant-negative model; reduced assembly would reframe NCBRS as a
      complex-destabilising disorder instead.
  - experiment_id: ncbrs_isogenic_allele_class_comparison
    name: Isogenic comparison of non-truncating versus truncating SMARCA2 alleles
    description: >-
      Extend the existing isogenic NCBRS knock-in hESC system with a SMARCA2
      truncating allele and a heterozygous deletion, and compare SMARCA4
      retargeting, enhancer reorganisation, neural-progenitor differentiation and
      the DNA methylation signature across the three allele classes.
    decision_criterion: >-
      If only the non-truncating allele produces SMARCA4 retargeting and the NCBRS
      methylation signature, the allele-class boundary is explained by the
      redistribution model; if the truncating allele produces the same signature,
      the boundary must be explained some other way.
  evidence:
  - reference: PMID:22366787
    reference_title: "Heterozygous missense mutations in SMARCA2 cause Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These alterations likely do not impair SWI/SNF complex assembly but may be associated with disrupted ATPase activity."
    explanation: The hedged wording of the original report is the substance of this gap - the mechanism is predicted, not measured.
  - reference: PMID:25169058
    reference_title: "Phenotype and genotype in Nicolaides-Baraitser syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SMARCA2 mutations causing NCBRS are likely to act through a dominant-negative effect."
    explanation: The largest phenotype-genotype analysis also states the mechanism as a likelihood rather than a demonstrated result.
  - reference: PMID:31375262
    reference_title: "Heterozygous Mutations in SMARCA2 Reprogram the Enhancer Landscape by Global Retargeting of SMARCA4."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Together, our results demonstrate that SMARCA2 mutations cause impaired differentiation through enhancer reprogramming via inappropriate targeting of SMARCA4."
    explanation: The competing model - enhancer reprogramming via SMARCA4 mis-targeting - is demonstrated in isogenic human cells, which is why this entry does not assert the dominant-negative ATPase model as settled.
📚

References & Deep Research

References

1
PMID:26468571
SMARCA2-Related Nicolaides-Baraitser Syndrome.
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
Nicolaides–Baraitser Syndrome: Comprehensive Disease-Characteristics Report
Edison Scientific Literature 24 citations 2026-07-31T18:36:39.660694

Nicolaides–Baraitser Syndrome: Comprehensive Disease-Characteristics Report

Executive summary

Nicolaides–Baraitser syndrome (NCBRS) is a rare, congenital, lifelong neurodevelopmental BAFopathy/chromatinopathy caused primarily by heterozygous, usually de novo, non-truncating pathogenic variants in the ATPase/helicase region of SMARCA2. Its characteristic combination is developmental delay/intellectual disability, severely impaired speech, epilepsy, postnatal microcephaly and short stature, sparse scalp hair, progressive facial coarsening, brachydactyly, and prominent interphalangeal joints. The largest deeply phenotyped molecular cohort available in the retrieved literature comprised only 61 individuals, so most frequency estimates remain imprecise and vulnerable to ascertainment bias. (sousa2014phenotypeandgenotype pages 2-2, sousa2014phenotypeandgenotype pages 1-2)

Recent work has shifted the mechanistic model from simple loss of SMARCA2 activity toward mutation-specific dysregulation of BAF-complex targeting and enhancer selection. The most clinically mature recent development is peripheral-blood DNA-methylation episignature testing, used as an adjunct for interpreting uncertain SMARCA2 variants. No disease-modifying therapy or NCBRS-specific interventional trial was identified; current care is multidisciplinary and symptom-directed. (chaterdiehl2019newinsightsinto pages 1-2, gao2019heterozygousmutationsin pages 1-3, trajkova2024dnamethylationanalysis pages 1-2, NCT01793168 chunk 4)

The following table summarizes the strongest quantitative evidence.

Domain Best-supported finding Quantitative evidence Evidence type/date
Identifiers Nicolaides-Baraitser syndrome is a Mendelian neurodevelopmental disorder; available disease identifiers include MONDO:0011053, OMIM 601358, Orphanet 3051 MONDO:0011053; OMIM 601358; Orphanet 3051 (OpenTargets Search: Nicolaides-Baraitser syndrome-SMARCA2, pretegiani2016nicolaides–baraitsersyndromedefining pages 1-2) Disease-resource association/Open Targets and human clinical letter, 2016
Cause / inheritance Core cause is de novo heterozygous non-truncating SMARCA2 variation, usually in the ATPase/helicase region, consistent with autosomal-dominant sporadic disease 61/61 analyzed cases sporadic; SMARCA2 mutations in 34/37 clinically typical patients and 2/7 less typical patients in early grouped analyses; >50% (36/61, 59%) in C-terminal helicase region (sousa2014phenotypeandgenotype pages 2-2, sousa2014phenotypeandgenotype pages 10-10, sousa2014phenotypeandgenotype pages 1-2) Human cohort/review, 2014
Intellectual disability Intellectual disability is universal and often moderate-to-severe Mild 18.0%, moderate 36.1%, severe 45.9% among 61 cases (sousa2014phenotypeandgenotype pages 3-3) Molecularly confirmed 61-case cohort, 2014
Seizures Epilepsy is a major feature with usual onset in infancy/early childhood 39/61 (63.9%); median onset 18 months, range 0–168 months; review text also notes typical onset 1–2.5 years (sousa2014phenotypeandgenotype pages 10-11, sousa2014phenotypeandgenotype pages 3-3) Molecularly confirmed cohort/review, 2014
Speech Severe speech impairment is common, including absent speech and later decline Absent speech 19/60 (31.7%); speech decline 9/42 (21.4%); first words median 24 months, range 10–96 months (sousa2014phenotypeandgenotype pages 3-3) Molecularly confirmed 61-case cohort, 2014
Growth / stature Postnatal growth impairment is common Short stature 30/56 (53.6%); reduced weight 24/46 (52.2%); birth weight < -2 SD in 19/57 (33.3%); birth length < -2 SD in 8/38 (21.1%) (sousa2014phenotypeandgenotype pages 2-2, sousa2014phenotypeandgenotype pages 2-3, sousa2014phenotypeandgenotype pages 3-3) Molecularly confirmed cohort/review, 2014
Microcephaly Microcephaly often emerges or becomes more evident over time 34/52 (65.4%) later in life; 7/30 (23%) at birth (sousa2014phenotypeandgenotype pages 2-3, sousa2014phenotypeandgenotype pages 3-3) Molecularly confirmed cohort/review, 2014
Hypotonia / motor delay Hypotonia and delayed gross motor milestones are frequent Hypotonia 19/51 (37.3%); sitting median 8 months (range 6–20); walking median 18 months (range 10–60) (sousa2014phenotypeandgenotype pages 3-3) Molecularly confirmed 61-case cohort, 2014
Feeding / skin / organ findings Supportive morbidity includes feeding problems, eczema, and occasional cardiac/hearing involvement Feeding problems 23/49 (46.9%); eczema 22/58 (37.9%); cardiac defects 6/61 (9.8%); hearing loss 4/59 (6.8%) (sousa2014phenotypeandgenotype pages 4-4) Molecularly confirmed cohort table, 2014
Mechanism NCBRS is a BAFopathy caused by SMARCA2 dysfunction affecting chromatin remodeling and neural differentiation; engineered human stem-cell models support enhancer retargeting rather than simple haploinsufficiency In engineered hESC-derived neural progenitors with SMARCA2 K755R/+ or R1159Q/+ mutations, neural differentiation was severely impaired; ~97% of upregulated genes with increased accessibility were FRA2-bound (gao2019heterozygousmutationsin pages 1-3, gao2019heterozygousmutationsin pages 10-12, gao2019heterozygousmutationsin pages 12-14) Experimental human hESC/NPC study, 2019
Methylation diagnostics Peripheral-blood DNA methylation episignatures can aid SMARCA2 variant interpretation 429 differentially methylated CpGs in 8 NCBRS cases vs 23 controls; validation reported 100% sensitivity and 100% specificity with 8 cases and 96 controls; 9 SMARCA2 VUS assessed (chaterdiehl2019newinsightsinto pages 1-2) Epigenomic diagnostic study, 2019
Recent diagnostic development 2024 work supports episignatures as a practical adjunct for NDD/BAFopathy variant resolution but highlights interpretive limitations Validation cohort 59 and test cohort 38 in a broader NDD study; 90% expected episignature recovery; intermediate SMARCA2 classifications reported in familial/VUS contexts (trajkova2024dnamethylationanalysis pages 1-2, awamleh2024dnamethylationsignatures pages 3-6) Diagnostic/epigenomic studies and review, 2024
Trials / implementation No disease-modifying interventional trial was identified; current formal research implementation is observational registry participation NCT01793168 is observational, recruiting, prospective, case-only, target enrollment 20,000 across rare diseases including NCBRS; no syndrome-specific therapeutic intervention reported (NCT01793168 chunk 4) ClinicalTrials.gov registry entry, 2010–current

Table: This table condenses the strongest available evidence for Nicolaides-Baraitser syndrome across identifiers, genetics, phenotype frequencies, mechanism, diagnostics, and trial status. It is useful as a quick-reference artifact for disease knowledge-base population with denominated cohort data and recent diagnostic advances.

1. Disease information

Definition and classification

NCBRS is a Mendelian syndromic intellectual-developmental disorder caused by altered ATP-dependent chromatin remodeling. It belongs to the group of SWI/SNF-related intellectual-disability disorders, particularly the BAFopathies, which overlap clinically and molecularly with Coffin–Siris syndrome. Open Targets links the disease to SMARCA2, with the preferred gene name “SWI/SNF related BAF chromatin remodeling complex subunit ATPase 2.” (OpenTargets Search: Nicolaides-Baraitser syndrome-SMARCA2, pretegiani2016nicolaides–baraitsersyndromedefining pages 1-2)

Identifiers and synonyms

  • MONDO: MONDO:0011053
  • OMIM: 601358
  • Orphanet: ORPHA:3051
  • Causal-gene OMIM: SMARCA2, OMIM 600014
  • Common names: Nicolaides–Baraitser syndrome; NCBRS; intellectual disability–sparse hair–brachydactyly syndrome; intellectual disability–sparse hair–prominent distal phalanges syndrome.
  • ICD-10/ICD-11 and MeSH: no disease-specific code or dedicated MeSH descriptor was established in the retrieved evidence. In practice, nonspecific codes for congenital malformation syndromes, intellectual disability, developmental delay, or epilepsy may be used, but these should not be treated as exact NCBRS mappings.

The disease-level identifiers are aggregated ontology/resource assertions, whereas the clinical frequencies below derive from aggregated published patients, diagnostic-laboratory cases, and questionnaire-based phenotyping rather than longitudinal EHR surveillance. The principal 61-person analysis included 47 previously reported and 14 unpublished molecularly confirmed cases. (OpenTargets Search: Nicolaides-Baraitser syndrome-SMARCA2, sousa2014phenotypeandgenotype pages 1-2)

2. Etiology

Causal and genetic factors

The core cause is a heterozygous pathogenic SMARCA2 variant, most often a de novo missense change or small in-frame deletion affecting the conserved ATPase/helicase region. The 2012 discovery study is indexed as PMID 22366787. Open Targets independently associates SMARCA2 with MONDO:0011053 and cites that study. (OpenTargets Search: Nicolaides-Baraitser syndrome-SMARCA2)

Classic NCBRS variants are non-truncating and cluster within functional ATPase motifs rather than being distributed like ordinary haploinsufficient alleles. In the 61-case analysis, 36/61 (59%) involved the C-terminal helicase region. Motif VI, particularly Arg1159, was a hotspot; this residue participates in ATP-phosphate interaction and hydrolysis. Variants p.Pro883Leu, p.Leu946Ser/Phe, and p.Ala1201Val were associated with relatively milder presentations, whereas motif-VI variants were more often associated with severe intellectual disability and epilepsy. These correlations remain provisional because individual variant groups were small. (sousa2014phenotypeandgenotype pages 10-10, sousa2014phenotypeandgenotype pages 1-2)

Atypical variants outside the canonical region require caution. For example, a reported p.Gly1420Arg bromodomain-region variant produced partial phenotypic overlap but lacked some classic findings. Conversely, a de novo p.Gln1241Glu variant outside the usual ATPase cluster was reported with myoclonic–astatic epilepsy. Thus, location is strongly informative but not an absolute diagnostic rule. (sousa2014phenotypeandgenotype pages 10-11, sousa2014phenotypeandgenotype pages 11-11)

Risk, protective, and environmental factors

  • Established risk factor: conception of a child with a de novo pathogenic SMARCA2 allele.
  • Parental age: mean paternal and maternal ages in the 61-case cohort were 32.9 and 30.1 years, respectively, but no causal age effect was established. (sousa2014phenotypeandgenotype pages 2-2, sousa2014phenotypeandgenotype pages 1-2)
  • Environmental, infectious, occupational, dietary, lifestyle, or toxic causes: none established.
  • Protective variants or environmental protective factors: none established.
  • Modifier genes: no validated modifier gene was identified. Variation in residual BAF activity, paralogous SMARCA4 recruitment, developmental context, mosaicism, or epigenetic state are plausible modifiers but are not clinically validated.
  • Gene–environment interaction: no disease-specific interaction has been demonstrated. Environmental factors may influence seizure threshold, nutrition, and rehabilitation outcomes without causing the syndrome.

3. Phenotypes

Neurodevelopment, behavior, and epilepsy

All 61 molecularly confirmed individuals had intellectual disability: mild in 18.0%, moderate in 36.1%, and severe in 45.9%. Median independent sitting was 8 months (range 6–20) and walking 18 months (10–60); hypotonia occurred in 19/51 (37.3%). Suggested HPO terms include Intellectual disability (HP:0001249), Global developmental delay (HP:0001263), Delayed speech and language development (HP:0000750), Motor delay (HP:0001270), and Muscular hypotonia (HP:0001252). (sousa2014phenotypeandgenotype pages 3-3)

Speech is disproportionately impaired. First words occurred at a median of 24 months (range 10–96); 19/60 (31.7%) had no speech, and 9/42 (21.4%) had speech decline. Some lost speech around seizure onset. These deficits materially restrict communication, education, autonomy, and caregiver quality of life, although no NCBRS-specific EQ-5D, SF-36, PROMIS, or utility study was found. (sousa2014phenotypeandgenotype pages 10-11, sousa2014phenotypeandgenotype pages 3-3)

Seizures occurred in 39/61 (63.9%), with median onset at 18 months (range birth to 14 years); the typical onset window was approximately 1–2.5 years. Among seizure-affected cases, 23 had severe ID and only three had mild ID, although causality between epilepsy and developmental severity cannot be inferred. Suggested HPO: Seizure (HP:0001250) and, where clinically documented, specific seizure-type terms. EEG phenotype and antiseizure-drug response should be recorded at patient level because robust syndrome-wide response rates could not be verified from accessible full text. (sousa2014phenotypeandgenotype pages 10-11, sousa2014phenotypeandgenotype pages 3-3)

Behavioral problems are recognized but heterogeneous; reported manifestations include aggressive episodes, autism-like behavior, anxiety, and sleep disturbance. The retrieved evidence did not support reliable syndrome-wide percentages. A 35-year-old woman had occasional aggression associated with moderate hyperglycemia, but this is a single case and not evidence of a general metabolic-behavioral mechanism. (pretegiani2016nicolaides–baraitsersyndromedefining pages 1-2, sousa2014phenotypeandgenotype pages 1-2)

Growth and craniofacial phenotype

  • Small for gestational age/birth weight below −2 SD: 19/57 (33.3%).
  • Birth length below −2 SD: 8/38 (21.1%).
  • Reduced postnatal weight: 24/46 (52.2%); 36/46 (75%) were below the 50th centile and none were overweight.
  • Short stature: 30/56 (53.6%).
  • Microcephaly: 7/30 (23%) at birth and 34/52 (65.4%) later, demonstrating a predominantly postnatal or progressive pattern. (sousa2014phenotypeandgenotype pages 2-2, sousa2014phenotypeandgenotype pages 2-3, sousa2014phenotypeandgenotype pages 3-3)

Suggested HPO terms are Short stature (HP:0004322), Microcephaly (HP:0000252), Postnatal growth retardation, and Failure to thrive when individually documented.

Facial characteristics include a triangular facial shape in younger children, broad nasal base, thick alae, upturned nasal tip, rounded premaxilla, broad philtrum, thin upper vermilion, thick/everted lower vermilion, wide mouth, dense eyelashes, and increasingly coarse features. Coarse face occurred in 43/56 (76.6%), and progressive coarsening in 18/31 (58.0%). The gestalt can be subtle in infancy and becomes more recognizable with age. (sousa2014phenotypeandgenotype pages 4-4, sousa2014phenotypeandgenotype pages 3-3)

Hair, skin, limbs, and skeleton

Sparse scalp hair is cardinal but age dependent and may improve. Eyebrows can be initially dense and later become less prominent; eyelashes generally remain dense. Non-scalp hypertrichosis occurred in 22/50 (44%), and eczema in 22/58 (37.9%). Suggested HPO: Sparse scalp hair, Hypertrichosis (HP:0000998), and Eczema (HP:0000964). (sousa2014phenotypeandgenotype pages 4-4)

Brachydactyly, broad distal phalanges, prominent/swollen interphalangeal joints, and broad fingertips are characteristic. Radiographs may show shortened distal phalanges, cone-shaped or ivory epiphyses, tarsal fusions, and broad first metatarsals. These findings affect dexterity, footwear, and occupational function, although formal functional scores are unavailable. Suggested HPO terms include Brachydactyly (HP:0001156), Broad distal phalanges, Prominent interphalangeal joints, Cone-shaped epiphyses, and Tarsal synostosis. (mari2015coffin–sirisandnicolaides–baraitser pages 15-17)

Other systems

Feeding problems affected 23/49 (46.9%), frequent infections 13/48 (27.1%), congenital cardiac defects 6/61 (9.8%), hearing loss 4/59 (6.8%), and hypospadias 1/36 males (2.8%). Myopia and astigmatism were reported, but complete denominators were unavailable. No malignancy occurred among the 61 reported patients. Rare vascular malformations, insulin resistance, and hypertrophic cardiomyopathy are case-level observations and should remain “possible/uncertain,” not cardinal disease features. (pretegiani2016nicolaides–baraitsersyndromedefining pages 1-2, sousa2014phenotypeandgenotype pages 4-4)

4. Genetic and molecular information

Gene and variant interpretation

  • Gene: SMARCA2; approved name above; Ensembl target ENSG00000080503.
  • Origin: constitutional/germline; overwhelmingly de novo. Somatic SMARCA2 changes in cancer are biologically distinct and do not constitute NCBRS.
  • Variant classes: predominantly missense; less commonly small in-frame deletions. A 32-kb de novo in-frame deletion removing part of the C-terminal helicase domain established that domain’s importance.
  • Population frequency: causal variants are expected to be absent or exceptionally rare in gnomAD/other reference populations. Exact per-variant frequencies must be checked against the current genome build and database release.
  • ACMG/AMP: classification should integrate de novo status, absence from population databases, ATPase-domain clustering, phenotype specificity, computational/functional evidence, and—where available—the NCBRS methylation episignature. An episignature is supporting functional evidence, not an automatic stand-alone pathogenic classification.

The disease is not adequately explained by simple haploinsufficiency. Earlier clinical literature favored a dominant-negative mechanism; engineered-cell evidence instead indicates mutation-dependent gain or redistribution of remodeling activity and retargeting of the paralogous SMARCA4 complex. The safest current annotation is altered-function/dominant dysregulation of BAF chromatin remodeling, with mechanism potentially variant dependent. (sousa2014phenotypeandgenotype pages 1-2, gao2019heterozygousmutationsin pages 1-3, gao2019heterozygousmutationsin pages 12-14)

Epigenetics

Whole-blood methylation profiling identified 429 differentially methylated CpGs in eight NCBRS cases compared with 23 controls. A classifier tested in eight cases and 96 controls achieved reported 100% sensitivity and specificity and helped assess nine SMARCA2 VUS. This requires external validation because the development cohorts were small. (chaterdiehl2019newinsightsinto pages 1-2)

A broader 2024 study analyzed 97 neurodevelopmental-disorder cases—59 with known pathogenic/likely pathogenic variants and 38 test cases—and recovered the expected episignature in 90% of its validation cohort. It included a SMARCA2 p.Met856Val case and supported relationships between homologous SMARCA2/SMARCA4 residues. Current expert analysis warns that age, tissue/cell composition, mosaicism, hypomorphic alleles, intrafamilial variability, cohort size, and experimental design can yield intermediate or misleading scores. (trajkova2024dnamethylationanalysis pages 1-2, awamleh2024dnamethylationsignatures pages 3-6)

5. Environmental information

NCBRS is not caused by pollution, radiation, occupational exposure, smoking, alcohol, diet, exercise, or an infectious agent. No lifestyle factor is known to prevent the causal de novo variant. Standard health measures—adequate nutrition, vaccination, safe physical activity, sleep hygiene, and avoidance of seizure triggers—may reduce complications but do not alter the genetic cause. Zoonotic transmission and person-to-person transmission are not applicable.

6. Mechanism and pathophysiology

Upstream causal chain

  1. A de novo non-truncating SMARCA2 variant alters a conserved ATPase/helicase residue.
  2. Mutant SMARCA2 is incorporated into mammalian SWI/SNF/BAF chromatin-remodeling complexes.
  3. ATP-dependent nucleosome remodeling and, importantly, genomic targeting of BAF complexes become dysregulated.
  4. Enhancer accessibility and transcription-factor recruitment are reprogrammed during neurodevelopment.
  5. Neural progenitor differentiation and neuronal gene programs are impaired, producing developmental delay, intellectual disability, speech impairment, epilepsy, and altered craniofacial/skeletal development.

SMARCA2 normally couples ATP hydrolysis to nucleosome remodeling. In engineered human embryonic stem cells carrying heterozygous K755R or R1159Q NCBRS variants, stem-cell maintenance appeared relatively normal, but differentiation into neural progenitors was severely impaired. Neural SOX3-dependent enhancers lost accessibility, whereas FRA2/AP-1 pioneered de novo astrocytic enhancers and retargeted both SMARCA2- and SMARCA4-containing complexes; approximately 97% of upregulated genes with increased accessibility were FRA2 bound. Ectopically activated programs included CD44, F3, CLU, FSTL1, and NFI-family genes. This is direct in-vitro human evidence, not merely pathway inference. (gao2019heterozygousmutationsin pages 1-3, gao2019heterozygousmutationsin pages 10-12, gao2019heterozygousmutationsin pages 12-14)

A concise exact statement from the 2019 study’s title captures the central finding: “Heterozygous mutations in SMARCA2 reprogram the enhancer landscape by global retargeting of SMARCA4.” The experiment supports an altered enhancer-selection mechanism rather than global absence of chromatin remodeling. (gao2019heterozygousmutationsin pages 1-3)

Recent structural understanding

A 2023 Nature Genetics analysis placed neurodevelopmental variants across mSWI/SNF structures and found that non-truncating variants disproportionately affect cBAF and cluster at nucleosome interfaces, the ATPase-core/ARID-armadillo insertion site, Arp module, and DNA-binding domains. More than 70% of NDD-perturbed residues overlapped residues altered in cancer, although about 60% of the exact amino-acid substitutions were NDD specific. This is powerful structural/computational context, but it is not a disease-specific therapeutic study. DOI: https://doi.org/10.1038/s41588-023-01451-6; published July 2023.

Suggested ontology annotations

  • GO biological process: chromatin remodeling (GO:0006338); regulation of transcription by RNA polymerase II; neurogenesis; neural precursor-cell proliferation; neuron differentiation; regulation of chromatin accessibility.
  • GO molecular function: ATP hydrolysis activity; ATP-dependent chromatin-remodeler activity; chromatin binding; nucleosome binding.
  • GO cellular component: nucleus (GO:0005634); SWI/SNF superfamily-type complex; BAF complex; chromatin.
  • Cell Ontology: neural stem cell, neural progenitor cell, neuroblast, neuron, astrocyte, and cranial neural-crest cell. Neural progenitors are directly supported by the engineered-cell work; the other cell types are mechanistically plausible and should be annotated with lower evidence strength. (gao2019heterozygousmutationsin pages 1-3, gao2019heterozygousmutationsin pages 10-12)

No validated NCBRS-specific metabolomic, lipidomic, proteomic, immune, inflammatory, oxidative-stress, single-cell, spatial-transcriptomic, organoid, or in-vivo CRISPR-screen signature was identified.

7. Anatomical structures affected

The central nervous system is the primary functional target, with developmental effects on cerebral networks governing cognition, language, motor control, and seizure susceptibility. Secondary systems include craniofacial structures, scalp/hair follicles, skin, phalanges and interphalangeal joints, and growth-related musculoskeletal tissues. Cardiac, auditory, ocular, and genitourinary involvement occurs in minorities. (pretegiani2016nicolaides–baraitsersyndromedefining pages 1-2, mari2015coffin–sirisandnicolaides–baraitser pages 15-17, sousa2014phenotypeandgenotype pages 4-4)

Suggested UBERON mappings include brain, cerebral cortex, scalp, hair follicle, skin, hand digit, foot digit, interphalangeal joint, epiphyseal plate, heart, inner ear, and external male genitalia. No consistent lateralization is described. At the subcellular level, the relevant compartment is the nucleus/chromatin, not mitochondria, lysosome, or endoplasmic reticulum.

8. Temporal development

NCBRS is congenital in cause but often not recognizable morphologically in the neonatal period. Developmental delay emerges in infancy; epilepsy most commonly begins in the first few years, with median onset 18 months. Microcephaly, sparse hair, facial coarsening, and joint prominence can become more evident postnatally, although scalp-hair density may later improve. (sousa2014phenotypeandgenotype pages 2-3, sousa2014phenotypeandgenotype pages 10-11, sousa2014phenotypeandgenotype pages 4-4, sousa2014phenotypeandgenotype pages 3-3)

The course is chronic and lifelong rather than relapsing-remitting. Developmental skills may continue to accrue slowly, but speech can plateau or regress, especially around uncontrolled seizures. No formal stages, remission pattern, or end-stage phase are recognized. Early childhood is the principal intervention window for communication therapy, developmental rehabilitation, nutritional support, and seizure control.

9. Inheritance and population

NCBRS follows an autosomal-dominant mechanism but is usually sporadic because variants arise de novo. The 61-person cohort contained 35 males and 26 females, median age 10 years (range 2–33), with no ancestry-based pattern. No consanguinity, founder effect, or convincing familial recurrence was reported, apart from affected monozygotic twins. (sousa2014phenotypeandgenotype pages 2-2, sousa2014phenotypeandgenotype pages 1-2)

Penetrance for classic ATPase-domain pathogenic variants appears high, but expressivity is variable from borderline/mild intellectual impairment to severe disability and epilepsy. Anticipation is not expected. Gonadal mosaicism has not been quantified; therefore recurrence after an apparently de novo event is low but not zero. Carrier frequency is not meaningful for a predominantly de novo dominant disorder.

No reliable population prevalence or incidence per 100,000 was found. Orphanet classifies it as rare, and published cohorts are too selected to calculate prevalence. There is no established ethnic, geographic, or sex predilection.

10. Diagnostics

Clinical recognition

Clinical suspicion is strongest when developmental delay—especially severe speech impairment—is accompanied by seizures, postnatal microcephaly/short stature, sparse scalp hair, coarse or triangular facies, brachydactyly, and prominent interphalangeal joints. Clinical gestalt alone is insufficient because the phenotype evolves with age and overlaps Coffin–Siris and other chromatinopathies. (sousa2014phenotypeandgenotype pages 11-11, sousa2014phenotypeandgenotype pages 1-2)

Recommended molecular workflow

  1. Trio exome or genome sequencing is the preferred broad first-line strategy for an unexplained syndromic neurodevelopmental disorder; it detects de novo SMARCA2 SNVs/indels and alternative diagnoses.
  2. A neurodevelopmental/epilepsy or chromatinopathy panel should include SMARCA2 and relevant differential genes.
  3. If phenotype is classic and broad sequencing is unavailable, sequence SMARCA2, with particular attention to exons encoding the ATPase/helicase region; older guidance prioritized exons 15–25.
  4. Add exon-level deletion/duplication analysis, MLPA, read-depth CNV analysis, or genome sequencing to detect in-frame intragenic deletions.
  5. Confirm parental samples to establish de novo status and evaluate possible mosaicism.
  6. Use a validated peripheral-blood DNA-methylation episignature assay as an adjunct for a VUS or phenotypically ambiguous result. (sousa2014phenotypeandgenotype pages 11-11, chaterdiehl2019newinsightsinto pages 1-2, trajkova2024dnamethylationanalysis pages 1-2)

Chromosomal microarray can identify larger deletions but is not the most sensitive test for canonical missense NCBRS. Karyotype and FISH have low routine yield unless a structural rearrangement is suspected. Mitochondrial, repeat-expansion, liquid-biopsy, proteomic, and metabolomic testing are not disease-specific diagnostic methods.

Clinical evaluations after diagnosis

Recommended baseline assessments include growth and nutrition; developmental, speech-language, and behavioral evaluation; neurologic examination and EEG if seizures or concerning events occur; hearing and ophthalmologic testing; cardiac examination with echocardiography when clinically indicated; musculoskeletal/hand assessment; dermatologic and dental review; and renal/genitourinary assessment guided by findings. Brain MRI is appropriate for seizures, regression, abnormal examination, or concern for structural/vascular abnormalities, but no pathognomonic MRI biomarker is established.

Differential diagnosis

The closest differential is Coffin–Siris syndrome/ARID1B-related disorder. Other considerations include Wiedemann–Steiner, Coffin–Lowry, Cornelia de Lange, Kabuki, KBG, DOORS, Pitt–Hopkins, and other BAF/chromatin-remodeling disorders. NCBRS favors sparse hair, prominent interphalangeal joints and broad distal phalanges rather than classic fifth-digit hypoplasia. Exome sequencing is valuable because clinically suspected CSS/NCBRS cohorts contain unexpected molecular diagnoses. (sousa2014phenotypeandgenotype pages 11-11, mari2015coffin–sirisandnicolaides–baraitser pages 15-17)

No newborn biochemical screen or population screening program exists. Testing is phenotype-driven or familial after a molecular diagnosis.

11. Outcome and prognosis

No valid 5-year/10-year survival, mortality rate, or disease-specific life-expectancy estimate exists. Adults into at least their third and fourth decades have been reported, but the small, young cohorts preclude concluding that lifespan is normal. The largest cohort’s age range ended at 33 years, while a separate case was 35. (pretegiani2016nicolaides–baraitsersyndromedefining pages 1-2, sousa2014phenotypeandgenotype pages 1-2)

The main long-term burden is neurodevelopmental disability: limited speech, dependence in activities of daily living, epilepsy, feeding/growth difficulty, behavioral problems, and motor or hand-function limitations. Severe ID correlated with epilepsy, speech impairment, short stature, and microcephaly. Prognosis is variable; certain motif-VI variants appear more severe, whereas variants at Pro883, Leu946, or Ala1201 may be milder, but these associations are not sufficiently powered for individual prediction. (sousa2014phenotypeandgenotype pages 10-10, sousa2014phenotypeandgenotype pages 10-11)

No validated prognostic biomarker exists. The blood episignature is diagnostic/functional rather than proven prognostic. Recovery to typical development is not expected, although early communication support, rehabilitation, nutrition, and seizure control can improve function and participation.

12. Treatment and current applications

There is no approved therapy that corrects SMARCA2 or BAF-complex dysfunction. Treatment is individualized:

  • Epilepsy: standard antiseizure medication chosen by seizure type and EEG; rescue plans for prolonged seizures; specialist management for drug resistance. No genotype-specific drug or robust NCBRS response-rate hierarchy could be verified.
  • Development: early physical, occupational, speech-language, feeding, behavioral, and educational therapies; augmentative and alternative communication is particularly important when speech is absent.
  • Nutrition/GI: growth monitoring, dietetic assessment, swallow study when indicated, reflux/constipation management, and enteral feeding if oral intake is unsafe or inadequate.
  • Musculoskeletal: physiotherapy, orthotics, monitoring of joint limitations/contractures and spine; orthopedic intervention based on functional impairment.
  • Hearing/vision/dental/skin: hearing aids, refractive correction, preventive dental care, emollients/topical anti-inflammatory therapy for eczema, and routine specialty care.
  • Cardiac/genitourinary: lesion-specific surveillance or intervention rather than universal syndrome-specific surgery.

Suggested NCIT intervention concepts include anticonvulsant therapy, physical therapy, occupational therapy, speech and language therapy, behavioral therapy, nutritional support, enteral nutrition, hearing aid, corrective lenses, and genetic counseling. Exact NCIT identifiers should be resolved against the target NCIT release.

No gene replacement, CRISPR editing, ASO, siRNA, mRNA, cell therapy, immunotherapy, or targeted small-molecule therapy is clinically available. Although chromatin remodelers are drug targets in oncology, inhibiting a broadly essential developmental complex is not presently a validated NCBRS strategy.

The only directly relevant registered study found was NCT01793168, a recruiting, prospective, observational rare-disease registry that includes NCBRS, targets 20,000 participants across all included diseases, and offers online/Sanford Health enrollment. It is not an interventional treatment trial and has no NCBRS efficacy endpoint. ClinicalTrials.gov: https://clinicaltrials.gov/study/NCT01793168. (NCT01793168 chunk 4)

13. Prevention

Primary prevention by lifestyle or vaccination is not possible because the disorder usually results from a de novo constitutional variant. Secondary prevention consists of early molecular diagnosis, prompt seizure recognition, developmental intervention, and surveillance for feeding, hearing, visual, cardiac, and orthopedic complications. Tertiary prevention focuses on avoiding aspiration/malnutrition, seizure injury/status epilepticus, loss of mobility, communication deprivation, and preventable dental or skin disease.

After identifying the familial variant, genetic counseling should explain autosomal-dominant inheritance, high expected penetrance for classic pathogenic variants, low-but-nonzero recurrence from possible parental gonadal mosaicism, and a 50% transmission risk if an affected individual reproduces. Prenatal diagnosis and preimplantation genetic testing are technically possible when the causal variant is known. Routine population carrier or newborn screening is not justified.

14. Other species and natural disease

SMARCA2 and ATP-dependent SWI/SNF mechanisms are evolutionarily conserved across vertebrates and invertebrates, supporting comparative functional work. However, no well-established naturally occurring veterinary analogue of NCBRS, breed predisposition, cross-species transmission, or zoonotic potential was identified. NCBI Taxonomy examples relevant to experimental ortholog studies include human (Homo sapiens, 9606), mouse (Mus musculus, 10090), zebrafish (Danio rerio, 7955), and fruit fly (Drosophila melanogaster, 7227). Species-specific ortholog gene IDs should be retrieved from the current NCBI/Alliance release before database ingestion.

15. Model organisms and experimental systems

The strongest disease-specific model in the retrieved literature is engineered human embryonic stem cells differentiated into neural progenitor cells, carrying heterozygous K755R or R1159Q SMARCA2 variants. It reproduces impaired neural differentiation and reveals enhancer retargeting, altered SOX3/FRA2 programs, and SMARCA4 redistribution. Its principal limitation is that a two-dimensional developmental cell system cannot reproduce epilepsy, cognition, craniofacial morphogenesis, growth, or whole-organism pharmacology. (gao2019heterozygousmutationsin pages 1-3, gao2019heterozygousmutationsin pages 10-12, gao2019heterozygousmutationsin pages 12-14)

Generic Smarca2 knockout or perturbation models can elucidate BAF biology, but they should not automatically be labeled NCBRS models because canonical human disease is usually caused by specific non-truncating altered-function alleles rather than complete gene loss. No thoroughly validated NCBRS knock-in mouse, zebrafish, Drosophila, patient-iPSC organoid, or natural animal model with quantified recapitulation of the full human phenotype was established in the retrieved evidence. This is a major translational gap.

Recent developments and expert interpretation, 2023–2024

  1. Structural grouping of BAF variants (July 2023): mapping neurodevelopmental variants onto mSWI/SNF structures highlighted recurrent perturbation of nucleosome interfaces and ATPase structural hubs. This strengthens domain-aware variant interpretation but does not replace functional or clinical evidence. DOI: https://doi.org/10.1038/s41588-023-01451-6.
  2. Episignature implementation (April–July 2024): recent work supports blood methylation profiling as a practical second-line assay for uncertain chromatinopathy variants. In a broader NDD cohort, expected signatures were recovered in 90% of validation cases. Experts emphasize that intermediate scores can reflect mosaicism, hypomorphic alleles, age, tissue composition, or familial variability—not simply “positive” versus “negative.” DOI: https://doi.org/10.1016/j.xhgg.2024.100309, published July 2024; review DOI: https://doi.org/10.1007/s00439-023-02544-2, published April 2024. (trajkova2024dnamethylationanalysis pages 1-2, awamleh2024dnamethylationsignatures pages 3-6)
  3. Clinical reality: research has advanced mechanistic and diagnostic resolution, but there remains no disease-modifying intervention, validated molecular prognostic test, or NCBRS-specific interventional trial. (NCT01793168 chunk 4)

Key evidence quotations

  • The 2018 methylation study’s abstract stated that a machine-learning model could “resolve ambiguous clinical cases, reclassify those with variants of unknown significance, and identify previously undiagnosed subjects.” This supports diagnostic utility but not treatment or prognosis.
  • The 2024 chromatinopathy perspective states that DNA-methylation signatures “serve as both a research avenue for elucidating disease pathophysiology and a clinical diagnostic tool,” particularly for VUS classification. (awamleh2024dnamethylationsignatures pages 3-6)
  • The foundational clinical synthesis characterized NCBRS through progressive hair, facial, and joint findings and emphasized that its phenotypic spectrum is probably broader than initially recognized. (sousa2014phenotypeandgenotype pages 1-2)

Evidence limitations

The evidence base is constrained by rarity, referral bias, small cohorts, incomplete denominators, cross-sectional rather than longitudinal assessment, and limited adult follow-up. Many management recommendations are expert-practice extrapolations rather than trial-tested NCBRS guidelines. Rare cardiac, vascular, endocrine, or imaging findings should not be promoted to core associations without replication. Ontology terms above are suggested mappings and should be validated against current HPO, GO, CL, UBERON, NCIT, and MONDO releases before production ingestion.

References

  1. (sousa2014phenotypeandgenotype pages 2-2): Sérgio B. Sousa and Raoul C. Hennekam. Phenotype and genotype in nicolaides–baraitser syndrome. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 166:302-314, Sep 2014. URL: https://doi.org/10.1002/ajmg.c.31409, doi:10.1002/ajmg.c.31409. This article has 99 citations.

  2. (sousa2014phenotypeandgenotype pages 1-2): Sérgio B. Sousa and Raoul C. Hennekam. Phenotype and genotype in nicolaides–baraitser syndrome. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 166:302-314, Sep 2014. URL: https://doi.org/10.1002/ajmg.c.31409, doi:10.1002/ajmg.c.31409. This article has 99 citations.

  3. (chaterdiehl2019newinsightsinto pages 1-2): Eric Chater-Diehl, Resham Ejaz, Cheryl Cytrynbaum, Michelle T. Siu, Andrei Turinsky, Sanaa Choufani, Sarah J. Goodman, Omar Abdul-Rahman, Melanie Bedford, Naghmeh Dorrani, Kendra Engleman, Josue Flores-Daboub, David Genevieve, Roberto Mendoza-Londono, Wendy Meschino, Laurence Perrin, Nicole Safina, Sharron Townshend, Stephen W. Scherer, Evdokia Anagnostou, Amelie Piton, Matthew Deardorff, Michael Brudno, David Chitayat, and Rosanna Weksberg. New insights into dna methylation signatures: smarca2 variants in nicolaides-baraitser syndrome. BMC Medical Genomics, Jul 2019. URL: https://doi.org/10.1186/s12920-019-0555-y, doi:10.1186/s12920-019-0555-y. This article has 48 citations and is from a peer-reviewed journal.

  4. (gao2019heterozygousmutationsin pages 1-3): Fangjian Gao, Nicholas J. Elliott, Josephine Ho, Alexzander Sharp, Maxim N. Shokhirev, and Diana C. Hargreaves. Heterozygous mutations in smarca2 reprogram the enhancer landscape by global retargeting of smarca4. Molecular cell, 75:891-904.e7, Sep 2019. URL: https://doi.org/10.1016/j.molcel.2019.06.024, doi:10.1016/j.molcel.2019.06.024. This article has 72 citations and is from a highest quality peer-reviewed journal.

  5. (trajkova2024dnamethylationanalysis pages 1-2): Slavica Trajkova, Jennifer Kerkhof, Matteo Rossi Sebastiano, Lisa Pavinato, Enza Ferrero, Chiara Giovenino, Diana Carli, Eleonora Di Gregorio, Roberta Marinoni, Giorgia Mandrile, Flavia Palermo, Silvia Carestiato, Simona Cardaropoli, Verdiana Pullano, Antonina Rinninella, Elisa Giorgio, Tommaso Pippucci, Paola Dimartino, Jessica Rzasa, Kathleen Rooney, Haley McConkey, Aleksandar Petlichkovski, Barbara Pasini, Elena Sukarova-Angelovska, Christopher M. Campbell, Kay Metcalfe, Sarah Jenkinson, Siddharth Banka, Alessandro Mussa, Giovanni Battista Ferrero, Bekim Sadikovic, and Alfredo Brusco. Dna methylation analysis in patients with neurodevelopmental disorders improves variant interpretation and reveals complexity. Jul 2024. URL: https://doi.org/10.1016/j.xhgg.2024.100309, doi:10.1016/j.xhgg.2024.100309. This article has 23 citations and is from a peer-reviewed journal.

  6. (NCT01793168 chunk 4): Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford. Sanford Health. 2010. ClinicalTrials.gov Identifier: NCT01793168

  7. (OpenTargets Search: Nicolaides-Baraitser syndrome-SMARCA2): Open Targets Query (Nicolaides-Baraitser syndrome-SMARCA2, 2 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  8. (pretegiani2016nicolaides–baraitsersyndromedefining pages 1-2): Elena Pretegiani, Francesca Mari, Alessandra Renieri, Silvana Penco, and Maria Teresa Dotti. Nicolaides–baraitser syndrome: defining a phenotype. Journal of Neurology, 263:1659-1660, Jun 2016. URL: https://doi.org/10.1007/s00415-016-8194-0, doi:10.1007/s00415-016-8194-0. This article has 13 citations and is from a domain leading peer-reviewed journal.

  9. (sousa2014phenotypeandgenotype pages 10-10): Sérgio B. Sousa and Raoul C. Hennekam. Phenotype and genotype in nicolaides–baraitser syndrome. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 166:302-314, Sep 2014. URL: https://doi.org/10.1002/ajmg.c.31409, doi:10.1002/ajmg.c.31409. This article has 99 citations.

  10. (sousa2014phenotypeandgenotype pages 3-3): Sérgio B. Sousa and Raoul C. Hennekam. Phenotype and genotype in nicolaides–baraitser syndrome. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 166:302-314, Sep 2014. URL: https://doi.org/10.1002/ajmg.c.31409, doi:10.1002/ajmg.c.31409. This article has 99 citations.

  11. (sousa2014phenotypeandgenotype pages 10-11): Sérgio B. Sousa and Raoul C. Hennekam. Phenotype and genotype in nicolaides–baraitser syndrome. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 166:302-314, Sep 2014. URL: https://doi.org/10.1002/ajmg.c.31409, doi:10.1002/ajmg.c.31409. This article has 99 citations.

  12. (sousa2014phenotypeandgenotype pages 2-3): Sérgio B. Sousa and Raoul C. Hennekam. Phenotype and genotype in nicolaides–baraitser syndrome. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 166:302-314, Sep 2014. URL: https://doi.org/10.1002/ajmg.c.31409, doi:10.1002/ajmg.c.31409. This article has 99 citations.

  13. (sousa2014phenotypeandgenotype pages 4-4): Sérgio B. Sousa and Raoul C. Hennekam. Phenotype and genotype in nicolaides–baraitser syndrome. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 166:302-314, Sep 2014. URL: https://doi.org/10.1002/ajmg.c.31409, doi:10.1002/ajmg.c.31409. This article has 99 citations.

  14. (gao2019heterozygousmutationsin pages 10-12): Fangjian Gao, Nicholas J. Elliott, Josephine Ho, Alexzander Sharp, Maxim N. Shokhirev, and Diana C. Hargreaves. Heterozygous mutations in smarca2 reprogram the enhancer landscape by global retargeting of smarca4. Molecular cell, 75:891-904.e7, Sep 2019. URL: https://doi.org/10.1016/j.molcel.2019.06.024, doi:10.1016/j.molcel.2019.06.024. This article has 72 citations and is from a highest quality peer-reviewed journal.

  15. (gao2019heterozygousmutationsin pages 12-14): Fangjian Gao, Nicholas J. Elliott, Josephine Ho, Alexzander Sharp, Maxim N. Shokhirev, and Diana C. Hargreaves. Heterozygous mutations in smarca2 reprogram the enhancer landscape by global retargeting of smarca4. Molecular cell, 75:891-904.e7, Sep 2019. URL: https://doi.org/10.1016/j.molcel.2019.06.024, doi:10.1016/j.molcel.2019.06.024. This article has 72 citations and is from a highest quality peer-reviewed journal.

  16. (awamleh2024dnamethylationsignatures pages 3-6): Zain Awamleh, Sarah Goodman, Sanaa Choufani, and Rosanna Weksberg. Dna methylation signatures for chromatinopathies: current challenges and future applications. Human Genetics, 143:551-557, Apr 2024. URL: https://doi.org/10.1007/s00439-023-02544-2, doi:10.1007/s00439-023-02544-2. This article has 26 citations and is from a peer-reviewed journal.

  17. (sousa2014phenotypeandgenotype pages 11-11): Sérgio B. Sousa and Raoul C. Hennekam. Phenotype and genotype in nicolaides–baraitser syndrome. American Journal of Medical Genetics Part C: Seminars in Medical Genetics, 166:302-314, Sep 2014. URL: https://doi.org/10.1002/ajmg.c.31409, doi:10.1002/ajmg.c.31409. This article has 99 citations.

  18. (mari2015coffin–sirisandnicolaides–baraitser pages 15-17): Francesca Mari, Annabella Marozza, Maria Antonietta Mencarelli, Caterina Lo Rizzo, Chiara Fallerini, Laura Dosa, Chiara Di Marco, Giulia Carignani, Margherita Baldassarri, Paola Cianci, Rossella Vivarelli, Marina Vascotto, Salvatore Grosso, Pietro Rubegni, Carla Caffarelli, Elena Pretegiani, Michele Fimiani, Livia Garavelli, Francesca Cristofoli, Joris R. Vermeesch, Ranuccio Nuti, Maria Teresa Dotti, Paolo Balestri, Joussef Hayek, Angelo Selicorni, and Alessandra Renieri. Coffin–siris and nicolaides–baraitser syndromes are a common well recognizable cause of intellectual disability. Brain and Development, 37(5):527-536, May 2015. URL: https://doi.org/10.1016/j.braindev.2014.08.009, doi:10.1016/j.braindev.2014.08.009. This article has 54 citations and is from a peer-reviewed journal.

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