Intellectual disability-sparse hair-brachydactyly syndrome

Summary

Intellectual disability-sparse hair-brachydactyly syndrome (MONDO:0011053) is a disease caused by SMARCA2 (GenCC Definitive), with 3 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SMARCA2 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 262
• Phenotypes (HPO): 50
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		61	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

50 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000154	Wide mouth	Very frequent (80-99%)
HP:0000232	Everted lower lip vermilion	Very frequent (80-99%)
HP:0000233	Thin vermilion border	Very frequent (80-99%)
HP:0000252	Microcephaly	Very frequent (80-99%)
HP:0000319	Smooth philtrum	Very frequent (80-99%)
HP:0000325	Triangular face	Very frequent (80-99%)
HP:0000343	Long philtrum	Very frequent (80-99%)
HP:0000463	Anteverted nares	Very frequent (80-99%)
HP:0001156	Brachydactyly	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001328	Specific learning disability	Very frequent (80-99%)
HP:0001373	Joint dislocation	Very frequent (80-99%)
HP:0001596	Alopecia	Very frequent (80-99%)
HP:0002300	Mutism	Very frequent (80-99%)
HP:0002381	Aphasia	Very frequent (80-99%)
HP:0002705	High, narrow palate	Very frequent (80-99%)
HP:0004279	Short palm	Very frequent (80-99%)
HP:0008070	Sparse hair	Very frequent (80-99%)
HP:0009928	Thick nasal alae	Very frequent (80-99%)
HP:0010529	Echolalia	Very frequent (80-99%)
HP:0005916	Abnormal metacarpal morphology	Very frequent (80-99%)
HP:0000028	Cryptorchidism	Frequent (30-79%)
HP:0000035	Abnormal testis morphology	Frequent (30-79%)
HP:0000446	Narrow nasal bridge	Frequent (30-79%)
HP:0000527	Long eyelashes	Frequent (30-79%)
HP:0000581	Blepharophimosis	Frequent (30-79%)
HP:0000964	Eczematoid dermatitis	Frequent (30-79%)
HP:0001167	Abnormality of finger	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001852	Sandal gap	Frequent (30-79%)
HP:0002121	Generalized non-motor (absence) seizure	Frequent (30-79%)
HP:0002133	Status epilepticus	Frequent (30-79%)
HP:0002553	Highly arched eyebrow	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0003510	Severe short stature	Frequent (30-79%)
HP:0006610	Wide intermamillary distance	Frequent (30-79%)
HP:0007392	Excessive wrinkled skin	Frequent (30-79%)
HP:0007665	Curly eyelashes	Frequent (30-79%)
HP:0009836	Broad distal phalanx of finger	Frequent (30-79%)
HP:0010720	Abnormal hair pattern	Frequent (30-79%)
HP:0011097	Epileptic spasm	Frequent (30-79%)
HP:0012745	Short palpebral fissure	Frequent (30-79%)
HP:0100760	Clubbing of toes	Frequent (30-79%)
HP:0000494	Downslanted palpebral fissures	Occasional (5-29%)
HP:0002750	Delayed skeletal maturation	Occasional (5-29%)
HP:0005616	Accelerated skeletal maturation	Occasional (5-29%)
HP:0005930	Abnormality of epiphysis morphology	Occasional (5-29%)
HP:0030680	Abnormal cardiovascular system morphology	Occasional (5-29%)
HP:0100790	Hernia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability-sparse hair-brachydactyly syndrome
Mondo ID	MONDO:0011053
MeSH	C536116
OMIM	601358
Orphanet	3051
DOID	DOID:0081441
SNOMED CT	401046009
UMLS	C1303073
MedGen	220983
GARD	0000270
Is cancer (heuristic)	no

Also known as: intellectual disability-sparse hair-brachydactyly syndrome · NCBRS · NICOLAIDES-Baraitser syndrome · Nicolaides-Baraitser syndrome · SMARCA2-related BAFopathy · sparse hair and mental retardation

Data availability: 262 ClinVar variants · 5 GenCC gene-disease records · 2 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › intellectual disability-sparse hair-brachydactyly syndrome

Related subtypes (216): polymicrogyria, congenital myasthenic syndrome with tubular aggregates, prenatal-onset spinal muscular atrophy with congenital bone fractures, anencephaly, cerebral cavernous malformation, meningocele, progressive external ophthalmoplegia, congenital nystagmus, congenital toxoplasmosis, congenital contractural arachnodactyly, congenital trigeminal anesthesia, familial congenital palsy of trochlear nerve, Myhre syndrome, Aase-Smith syndrome, KBG syndrome, autosomal dominant primary microcephaly, Mobius syndrome, MYH7-related skeletal myopathy, congenital stationary night blindness autosomal dominant 2, Prader-Willi syndrome, congenital myopathy 7A, myosin storage, autosomal dominant, Smith-Magenis syndrome, spina bifida, Freeman-Sheldon syndrome, isolated cerebellar hypoplasia/agenesis, Chediak-Higashi syndrome, Cohen syndrome, multiple pterygium-malignant hyperthermia syndrome, corpus callosum, agenesis of, congenital lactic acidosis, Saguenay-Lac-Saint-Jean type, facial dysmorphism-macrocephaly-myopia-Dandy-Walker malformation syndrome, diastematomyelia, EEM syndrome, Mowat-Wilson syndrome, Johanson-Blizzard syndrome, intellectual disability, Buenos-Aires type, myasthenia, congenital, refractory to acetylcholinesterase inhibitors, congenital myasthenic syndrome 6, Bailey-Bloch congenital myopathy, congenital stationary night blindness 1B, radioulnar synostosis-developmental delay-hypotonia syndrome, Schinzel-Giedion syndrome, schizencephaly, intellectual disability, Wolff type, X-linked intellectual disability-plagiocephaly syndrome, X-linked adrenal hypoplasia congenita, syndromic X-linked intellectual disability 7, syndromic X-linked intellectual disability Shashi type, syndromic X-linked intellectual disability Lubs type, syndromic X-linked intellectual disability Abidi type, syndromic X-linked intellectual disability Siderius type, X-linked intellectual disability, Cabezas type, X-linked intellectual disability-cubitus valgus-dysmorphism syndrome, syndromic X-linked intellectual disability Claes-Jensen type, moyamoya angiopathy-short stature-facial dysmorphism-hypergonadotropic hypogonadism syndrome, multiple congenital anomalies-hypotonia-seizures syndrome 2, developmental and epileptic encephalopathy, 36, blepharophimosis - intellectual disability syndrome, MKB type, X-linked intellectual disability-short stature-overweight syndrome, intellectual disability, X-linked, syndromic 33, syndromic X-linked intellectual disability 34, infantile-onset X-linked spinal muscular atrophy, syndromic X-linked intellectual disability 5, holoprosencephaly-hypokinesia-congenital contractures syndrome, X-linked intellectual disability with marfanoid habitus, Wieacker-Wolff syndrome, MERRF syndrome, macrocephaly-spastic paraplegia-dysmorphism syndrome, myofibrillar myopathy 1, isolated hereditary congenital facial paralysis, fibrosis of extraocular muscles, congenital, 2, Pierpont syndrome, congenital cataracts-facial dysmorphism-neuropathy syndrome, Bohring-Opitz syndrome, PHACE syndrome, B4GALT1-congenital disorder of glycosylation, developmental malformations-deafness-dystonia syndrome, sensory ataxic neuropathy, dysarthria, and ophthalmoparesis, AICA-ribosiduria, myofibrillar myopathy 3, fibrosis of extraocular muscles, congenital, 3c, myofibrillar myopathy 4, myofibrillar myopathy 5, cone-rod synaptic disorder, congenital nonprogressive, congenital stationary night blindness autosomal dominant 3, congenital stationary night blindness autosomal dominant 1, intellectual disability, autosomal recessive 12, progressive myoclonic epilepsy type 3, chromosome 15q13.3 microdeletion syndrome, combined pituitary hormone deficiencies, genetic form, congenital stationary night blindness 1D, DYRK1A-related intellectual disability syndrome, Pitt-Hopkins-like syndrome 2, developmental and epileptic encephalopathy, 15, Schuurs-Hoeijmakers syndrome, severe intellectual disability-poor language-strabismus-grimacing face-long fingers syndrome, severe intellectual disability-progressive spastic diplegia syndrome, hypotonia, infantile, with psychomotor retardation and characteristic facies, developmental and epileptic encephalopathy, 18, CTCF-related neurodevelopmental disorder, autism spectrum disorder due to AUTS2 deficiency, developmental and epileptic encephalopathy, 23, ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder, Bardet-Biedl syndrome 11, cerebellar-facial-dental syndrome, fibrosis of extraocular muscles, congenital, 5, congenital myasthenic syndrome 15, lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome, autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome, congenital myasthenic syndrome 18, autosomal recessive spinocerebellar ataxia 20, Houge-Janssens syndrome 1, intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome, congenital stationary night blindness 1G, hypomyelinating leukodystrophy 10, developmental and epileptic encephalopathy, 50, congenital insensitivity to pain-hypohidrosis syndrome, macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome, SLC39A8-CDG, spastic paraplegia-severe developmental delay-epilepsy syndrome, cardiac anomalies - developmental delay - facial dysmorphism syndrome, severe intellectual disability-corpus callosum agenesis-facial dysmorphism-cerebellar ataxia syndrome, intellectual disability, autosomal recessive 53, TELO2-related intellectual disability-neurodevelopmental disorder, micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome, autosomal recessive limb-girdle muscular dystrophy type 2Y, myofibrillar myopathy 7, short stature-brachydactyly-obesity-global developmental delay syndrome, autosomal recessive limb-girdle muscular dystrophy type 2R1, severe microbrachycephaly-intellectual disability-athetoid cerebral palsy syndrome, congenital laryngeal palsy, congenital or early infantile CACH syndrome, congenital epulis, severe congenital nemaline myopathy, intermediate nemaline myopathy, typical nemaline myopathy, childhood-onset nemaline myopathy, adult-onset nemaline myopathy, qualitative or quantitative defects of protein involved in O-glycosylation of alpha-dystroglycan, holoprosencephaly, congenital insensitivity to pain with hyperhidrosis, congenital hydrocephalus, familial congenital mirror movements, macrocephaly-short stature-paraplegia syndrome, cephalocele, mitochondrial neurogastrointestinal encephalomyopathy, X-linked intellectual disability-hypogonadism-ichthyosis-obesity-short stature syndrome, 7p22.1 microduplication syndrome, congenital achiasma, congenital retinal arteriovenous communication, 3q27.3 microdeletion syndrome, Prader-Willi-like syndrome, 9q31.1q31.3 microdeletion syndrome, congenital oculomotor nerve palsy, congenital abducens nerve palsy, neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-hip dysplasia syndrome, congenital insensitivity to pain with severe intellectual disability, X-linked intellectual disability-cerebellar hypoplasia-spondylo-epiphyseal dysplasia syndrome, global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome, lissencephaly spectrum disorders, hyaline body myopathy, 22q11.2 deletion syndrome, craniorachischisis, Leber congenital amaurosis, Ritscher-Schinzel syndrome, Rubinstein-Taybi syndrome, X-linked intellectual disability-hypogammaglobulinemia-progressive neurological deterioration syndrome, X-linked intellectual disability-epilepsy-progressive joint contractures-dysmorphism syndrome, X-linked intellectual disability, Pai type, X-linked intellectual disability, Stevenson type, X-linked intellectual disability, Stoll type, congenital muscular dystrophy, congenital vitreoretinal dysplasia, periventricular nodular heterotopia, postsynaptic congenital myasthenic syndrome, subcortical band heterotopia, congenital fibrosis of extraocular muscles type 1, Al Gazali Khidr Prem Chandran syndrome, distal arthrogryposis Moore weaver type, congenital myotonic dystrophy, myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive, intellectual disability, autosomal dominant 47, intellectual disability, autosomal dominant 48, spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and leber congenital amaurosis, myasthenic syndrome, congenital, 23, presynaptic, myasthenic syndrome, congenital, 24, presynaptic, myasthenic syndrome, congenital, 25, presynaptic, developmental and epileptic encephalopathy, 77, night blindness, congenital stationary, type1i, neuropathy, congenital hypomelinating, congenital axonal neuropathy with encephalopathy, developmental and epileptic encephalopathy, 73, PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome, isolated exencephaly, myasthenic syndrome, congenital, 22, intellectual developmental disorder with gastrointestinal difficulties and high pain threshold, intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies, 9q33.3q34.11 microdeletion syndrome, congenital labioscrotal agenesis-cerebellar malformation-corneal dystrophy-facial dysmorphism syndrome, early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, SIN3A-related intellectual disability syndrome, childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder, X-linked congenital stationary night blindness, neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies, FOXG1 disorder, alpha-actinopathy, TPM3-related myopathy, X-linked recessive mitochondrial myopathy, RYR1-related myopathy, TTN-related myopathy, TPM2-related myopathy, myopathy caused by variation in POMGNT1, central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease, segmental spinal dysgenesis, myopathy, myofibrillar, 13, with rimmed vacuoles, congenital neuronal ceroid lipofuscinosis 10

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

262 retrieved; paginated sample, class counts are floors:

85 uncertain significance, 41 benign/likely benign, 36 benign, 29 likely pathogenic, 29 pathogenic, 23 conflicting classifications of pathogenicity, 10 likely benign, 7 pathogenic/likely pathogenic, 2 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
397537	NM_001374828.1(ARID1B):c.1984C>T (p.Gln662Ter)	ARID1B	Pathogenic	criteria provided, multiple submitters, no conflicts
1320261	NM_003070.5(SMARCA2):c.3479C>G (p.Ala1160Gly)	SMARCA2	Pathogenic	criteria provided, multiple submitters, no conflicts
1686216	NM_003070.5(SMARCA2):c.2258T>A (p.Leu753His)	SMARCA2	Pathogenic	criteria provided, single submitter
1805414	NM_003070.5(SMARCA2):c.3292G>A (p.Gly1098Ser)	SMARCA2	Pathogenic	criteria provided, single submitter
1805420	NM_003070.5(SMARCA2):c.2838A>C (p.Leu946Phe)	SMARCA2	Pathogenic	criteria provided, single submitter
212225	NM_003070.5(SMARCA2):c.2486C>T (p.Thr829Ile)	SMARCA2	Pathogenic	criteria provided, single submitter
217002	NM_003070.5(SMARCA2):c.1600G>T (p.Asp534Tyr)	SMARCA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2580925	NM_003070.5(SMARCA2):c.3655G>C (p.Ala1219Pro)	SMARCA2	Pathogenic	criteria provided, single submitter
30009	NM_003070.5(SMARCA2):c.3604G>T (p.Gly1202Cys)	SMARCA2	Pathogenic	no assertion criteria provided
30010	NM_003070.5(SMARCA2):c.3476G>A (p.Arg1159Gln)	SMARCA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30011	NM_003070.5(SMARCA2):c.3473A>T (p.Asp1158Val)	SMARCA2	Pathogenic	no assertion criteria provided
30012	NM_003070.5(SMARCA2):c.3475C>G (p.Arg1159Gly)	SMARCA2	Pathogenic	criteria provided, multiple submitters, no conflicts
30013	NM_003070.5(SMARCA2):c.2642G>T (p.Gly881Val)	SMARCA2	Pathogenic	no assertion criteria provided
30014	NM_003070.5(SMARCA2):c.3485G>A (p.Arg1162His)	SMARCA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30015	NM_003070.5(SMARCA2):c.3476G>T (p.Arg1159Leu)	SMARCA2	Pathogenic	no assertion criteria provided
30016	NM_003070.5(SMARCA2):c.2648C>T (p.Pro883Leu)	SMARCA2	Pathogenic	criteria provided, multiple submitters, no conflicts
30017	NM_003070.5(SMARCA2):c.3602C>T (p.Ala1201Val)	SMARCA2	Pathogenic	criteria provided, multiple submitters, no conflicts
30018	NM_003070.5(SMARCA2):c.2815C>T (p.His939Tyr)	SMARCA2	Pathogenic	no assertion criteria provided
30019	NM_003070.5(SMARCA2):c.2255G>C (p.Gly752Ala)	SMARCA2	Pathogenic	criteria provided, single submitter
30020	NG_032162.2:g.118997_171770del	SMARCA2	Pathogenic	no assertion criteria provided
31687	NM_003070.5(SMARCA2):c.3395G>A (p.Gly1132Asp)	SMARCA2	Pathogenic	no assertion criteria provided
373431	NM_003070.5(SMARCA2):c.3484C>T (p.Arg1162Cys)	SMARCA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3895529	NM_003070.5(SMARCA2):c.2558G>A (p.Gly853Asp)	SMARCA2	Pathogenic	criteria provided, single submitter
4072005	NM_003070.5(SMARCA2):c.2335A>C (p.Ile779Leu)	SMARCA2	Pathogenic	criteria provided, single submitter
436805	NM_003070.5(SMARCA2):c.2853G>C (p.Lys951Asn)	SMARCA2	Pathogenic	criteria provided, single submitter
561113	NM_003070.5(SMARCA2):c.2348C>T (p.Ser783Leu)	SMARCA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
68762	NM_003070.5(SMARCA2):c.2554G>A (p.Glu852Lys)	SMARCA2	Pathogenic	criteria provided, multiple submitters, no conflicts
68765	NM_003070.5(SMARCA2):c.2563C>G (p.Arg855Gly)	SMARCA2	Pathogenic	no assertion criteria provided
68769	NM_003070.5(SMARCA2):c.3313C>T (p.Arg1105Cys)	SMARCA2	Pathogenic	criteria provided, multiple submitters, no conflicts
68770	NM_003070.5(SMARCA2):c.3314G>C (p.Arg1105Pro)	SMARCA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 8 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
SMARCA2	Definitive	Autosomal dominant	intellectual disability-sparse hair-brachydactyly syndrome	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SMARCA2	Orphanet:3051	Nicolaides-Baraitser syndrome
SMARCA2	Orphanet:637013	SMARCA2-related blepharophimosis-intellectual disability syndrome
CDKL5	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
CDKL5	Orphanet:3095	Atypical Rett syndrome
CDKL5	Orphanet:505652	CDKL5-deficiency disorder
CDKL5	Orphanet:697160	Infantile epileptic spasms syndrome
ARID1B	Orphanet:1465	Coffin-Siris syndrome
ARID1B	Orphanet:251056	6q25.2q25.3 microdeletion syndrome

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SMARCA2	HGNC:11098	ENSG00000080503	P51531	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 2	gencc,clinvar
CDKL5	HGNC:11411	ENSG00000008086	O76039	Cyclin-dependent kinase-like 5	clinvar
ARID1B	HGNC:18040	ENSG00000049618	Q8NFD5	AT-rich interactive domain-containing protein 1B	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SMARCA2	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 2	ATPase involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology).
CDKL5	Cyclin-dependent kinase-like 5	Mediates phosphorylation of MECP2.
ARID1B	AT-rich interactive domain-containing protein 1B	Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology).

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Kinase	1	9.2×	0.209
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SMARCA2	Other/Unknown	no		SNF2_N, Bromodomain, Helicase_C-like
CDKL5	Kinase	yes	2.7.11.22	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
ARID1B	Other/Unknown	no		ARID_dom, BAF250/Osa, BAF250_C

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
colonic epithelium	2
cortical plate	2
calcaneal tendon	1
Brodmann (1909) area 23	1
frontal pole	1
bone marrow cell	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SMARCA2	301	ubiquitous	marker	calcaneal tendon, colonic epithelium, cortical plate
CDKL5	257	ubiquitous	marker	frontal pole, Brodmann (1909) area 23, cortical plate
ARID1B	256	ubiquitous	marker	bone marrow cell, colonic epithelium, sural nerve

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SMARCA2	4,237
ARID1B	2,131
CDKL5	1,357

Intra-cohort edges

A	B	Sources
ARID1B	SMARCA2	biogrid_interaction, string_interaction

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SMARCA2	P51531	32
CDKL5	O76039	3
ARID1B	Q8NFD5	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 19. Enrichment computed across 3 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Formation of the canonical BAF (cBAF) complex	2	634.4×	4e-05	SMARCA2, ARID1B
Formation of neuronal progenitor and neuronal BAF (npBAF and nBAF)	2	456.8×	4e-05	SMARCA2, ARID1B
Regulation of endogenous retroelements	2	368.4×	5e-05	SMARCA2, ARID1B
RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known	2	300.5×	5e-05	SMARCA2, ARID1B
Regulation of MITF-M-dependent genes involved in pigmentation	2	265.6×	5e-05	SMARCA2, ARID1B
MITF-M-dependent gene expression	2	181.3×	9e-05	SMARCA2, ARID1B
RMTs methylate histone arginines	2	146.4×	1e-04	SMARCA2, ARID1B
Transcriptional regulation by RUNX1	2	146.4×	1e-04	SMARCA2, ARID1B
Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs)	2	117.7×	1e-04	SMARCA2, ARID1B
MITF-M-regulated melanocyte development	2	114.2×	1e-04	SMARCA2, ARID1B
Chromatin organization	2	81.6×	3e-04	SMARCA2, ARID1B
Chromatin modifying enzymes	2	72.3×	3e-04	SMARCA2, ARID1B
Epigenetic regulation of gene expression	2	71.4×	3e-04	SMARCA2, ARID1B
RNA Polymerase II Transcription	2	22.5×	0.003	SMARCA2, ARID1B
Formation of the non-canonical BAF (ncBAF) complex	1	335.9×	0.004	SMARCA2
Formation of the polybromo-BAF (pBAF) complex	1	317.2×	0.004	SMARCA2
Gene expression (Transcription)	2	17.8×	0.004	SMARCA2, ARID1B
Generic Transcription Pathway	2	15.1×	0.005	SMARCA2, ARID1B
Developmental Biology	2	14.5×	0.005	SMARCA2, ARID1B

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of G0 to G1 transition	2	449.4×	1e-04	SMARCA2, ARID1B
regulation of nucleotide-excision repair	2	401.2×	1e-04	SMARCA2, ARID1B
regulation of mitotic metaphase/anaphase transition	2	330.4×	1e-04	SMARCA2, ARID1B
positive regulation of T cell differentiation	2	303.6×	1e-04	SMARCA2, ARID1B
positive regulation of myoblast differentiation	2	244.2×	1e-04	SMARCA2, ARID1B
positive regulation of double-strand break repair	2	229.3×	1e-04	SMARCA2, ARID1B
regulation of G1/S transition of mitotic cell cycle	2	204.3×	1e-04	SMARCA2, ARID1B
positive regulation of cell differentiation	2	178.3×	2e-04	SMARCA2, ARID1B
chromatin remodeling	2	48.6×	0.002	SMARCA2, ARID1B
nervous system development	2	30.6×	0.004	SMARCA2, ARID1B
regulation of dendrite development	1	330.4×	0.009	CDKL5
positive regulation of dendrite morphogenesis	1	295.6×	0.009	CDKL5
positive regulation of DNA-templated transcription	2	18.6×	0.009	SMARCA2, ARID1B
positive regulation of Rac protein signal transduction	1	216.1×	0.011	CDKL5
regulation of cilium assembly	1	200.6×	0.011	CDKL5
regulation of postsynapse organization	1	175.5×	0.011	CDKL5
positive regulation of axon extension	1	170.2×	0.011	CDKL5
transcription initiation-coupled chromatin remodeling	1	127.7×	0.014	ARID1B
positive regulation of stem cell population maintenance	1	114.6×	0.015	SMARCA2
negative regulation of cell differentiation	1	95.2×	0.017	SMARCA2
heterochromatin formation	1	85.1×	0.018	SMARCA2
modulation of chemical synaptic transmission	1	61.1×	0.024	CDKL5
spermatid development	1	48.4×	0.027	SMARCA2
negative regulation of cell growth	1	48.0×	0.027	SMARCA2
regulation of transcription by RNA polymerase II	2	7.8×	0.027	SMARCA2, ARID1B
neuron migration	1	44.6×	0.027	CDKL5
negative regulation of cell population proliferation	1	14.0×	0.082	SMARCA2
positive regulation of cell population proliferation	1	11.2×	0.098	SMARCA2
regulation of DNA-templated transcription	1	10.5×	0.098	SMARCA2
negative regulation of DNA-templated transcription	1	10.5×	0.098	SMARCA2

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 2 · Undrugged: 1

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
CDKL5	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CDKL5	14	4
SMARCA2	2	2
ARID1B	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	CDKL5
CAPMATINIB	4	CDKL5
DEFACTINIB	3	CDKL5
ALVOCIDIB	3	CDKL5
LESTAURTINIB	3	CDKL5
RUBOXISTAURIN	3	CDKL5
MOLIBRESIB	2	SMARCA2
CAMIBIRSTAT	2	SMARCA2
FORETINIB	2	CDKL5
RG-547	2	CDKL5
AT-7519	2	CDKL5
TOZASERTIB	2	CDKL5
BMS-387032	1	CDKL5
PF-03758309	1	CDKL5
5-(6-BENZOTHIAZOLYLMETHYLENE)-3,5-DIHYDRO-2-(((1S)-1-(METHOXYMETHYL)-3-METHYLBUTYL)AMINO)-4H-IMIDAZOL-4-ONE, (5Z)-	1	CDKL5
AST-487	1	CDKL5

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
SMARCA2	311	Binding:274, Functional:25, ADMET:12
CDKL5	74	Binding:74

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CDKL5	2.7.11.22	cyclin-dependent kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
SMARCA2	311

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

16 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
FEDRATINIB	4	CDKL5
CAPMATINIB	4	CDKL5
DEFACTINIB	3	CDKL5
ALVOCIDIB	3	CDKL5
LESTAURTINIB	3	CDKL5
RUBOXISTAURIN	3	CDKL5
MOLIBRESIB	2	SMARCA2
CAMIBIRSTAT	2	SMARCA2
FORETINIB	2	CDKL5
RG-547	2	CDKL5
AT-7519	2	CDKL5
TOZASERTIB	2	CDKL5
BMS-387032	1	CDKL5
PF-03758309	1	CDKL5
5-(6-BENZOTHIAZOLYLMETHYLENE)-3,5-DIHYDRO-2-(((1S)-1-(METHOXYMETHYL)-3-METHYLBUTYL)AMINO)-4H-IMIDAZOL-4-ONE, (5Z)-	1	CDKL5
AST-487	1	CDKL5

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CDKL5
B	Phased (≥1) drug, not yet approved	1	SMARCA2
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ARID1B

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
ARID1B	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford