Genetic developmental and epileptic encephalopathy

Summary

Genetic developmental and epileptic encephalopathy (MONDO:0100062) is a disease (an umbrella term covering 105 Mondo subtypes) caused by variants in DOCK7, FLNA, FRRS1L, and 9 other genes, with 65 cohort genes and 12 clinical trials. The dominant Reactome pathway is Interaction between L1 and Ankyrins (6 cohort genes). Top therapeutic interventions include glycerol phenylbutyrate and bexicaserin.

At a glance

• Causal genes: DOCK7 (GenCC Definitive), FLNA (GenCC Definitive), FRRS1L (GenCC Definitive), GABRB3 (GenCC Definitive) (+8 more)
• Umbrella term: 105 Mondo subtypes
• Cohort genes: 65
• ClinVar variants: 37
• Clinical trials: 12

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	genetic developmental and epileptic encephalopathy
Mondo ID	MONDO:0100062
OMIM	308350
DOID	DOID:0112202
NCIT	C122814
GARD	0009255
Is cancer (heuristic)	no

Also known as: developmental and epileptic encephalopathy · hereditary developmental and epileptic encephalopathy

Data availability: 37 ClinVar variants · 8 ClinGen variant curations · 51 GenCC gene-disease records · 2 cell lines.

Disease family

An umbrella term covering 105 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary neurological disease › Mendelian neurodevelopmental disorder › genetic developmental and epileptic encephalopathy

Related subtypes (275): microcephaly and chorioretinopathy, microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, autosomal dominant primary microcephaly, Prader-Willi syndrome, Smith-Magenis syndrome, microcephalic osteodysplastic primordial dwarfism type I, microcephalic osteodysplastic primordial dwarfism type II, microcephalic osteodysplastic primordial dwarfism, type 3, CK syndrome, orofaciodigital syndrome I, Rett syndrome, Wieacker-Wolff syndrome, Amish lethal microcephaly, cerebral palsy, spastic quadriplegic, 2, Pitt-Hopkins-like syndrome 2, developmental delay with autism spectrum disorder and gait instability, complex cortical dysplasia with other brain malformations 5, AHDC1-related intellectual disability - obstructive sleep apnea - mild dysmorphism syndrome, intellectual disability, autosomal dominant 29, Au-Kline syndrome, cerebellar atrophy, visual impairment, and psychomotor retardation;, neurodevelopmental disorder with or without anomalies of the brain, eye, or heart, cerebral palsy, spastic quadriplegic, 3, Okur-Chung neurodevelopmental syndrome, Harel-Yoon syndrome, neurodevelopmental disorder with hypotonia, seizures, and absent language, alternating hemiplegia of childhood, autosomal recessive primary microcephaly, Rubinstein-Taybi syndrome, neurodevelopmental disorder with cerebellar atrophy and with or without seizures, neurodevelopmental disorder with or without autistic features and/or structural brain abnormalities, neurodevelopmental disorder with hypotonia, microcephaly, and seizures, neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures, neurodevelopmental disorder and structural brain anomalies with or without seizures and spasticity, neurodevelopmental disorder with language impairment and behavioral abnormalities, neurodevelopmental disorder with seizures, hypotonia, and brain imaging abnormalities, neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, neurodevelopmental disorder with dysmorphic facies, sleep disturbance, and brain abnormalities, neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities, neurodevelopmental disorder with or without early-onset generalized epilepsy, neurodevelopmental disorder with or without autism or seizures, neurodevelopmental disorder with cerebral atrophy and variable facial dysmorphism, neurodevelopmental disorder with dysmorphic facies and variable seizures, squalene synthase deficiency, intellectual developmental disorder and retinitis pigmentosa; IDDRP, neurodevelopmental disorder with impaired intellectual development, hypotonia, and ataxia, Houge-Janssens syndrome 3, neurodevelopmental disorder with central and peripheral motor dysfunction, neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination, neurodevelopmental disorder with impaired speech and hyperkinetic movements, developmental delay with variable intellectual impairment and behavioral abnormalities, neurodevelopmental disorder with or without variable brain abnormalities; NEDBA, neurodevelopmental disorder with seizures and speech and walking impairment, neurodevelopmental disorder with microcephaly and structural brain anomalies, neurodevelopmental disorder with seizures and nonepileptic hyperkinetic movements, neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities, neurodevelopmental disorder with visual defects and brain anomalies, neurodevelopmental disorder with ataxia, hypotonia, and microcephaly, neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies, neurodevelopmental disorder with cerebellar hypoplasia and spasticity, neurodevelopmental disorder with structural brain anomalies and dysmorphic facies, neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalities, neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies, neurodevelopmental disorder with spastic quadriplegia, optic atrophy, seizures, and structural brain anomalies, neurodevelopmental disorder with dysmorphic facies and distal skeletal anomalies, neurodevelopmental disorder with absent language and variable seizures, neurodevelopmental disorder with nonspecific brain abnormalities and with or without seizures, neurodevelopmental disorder with behavioral abnormalities, absent speech, and hypotonia, neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity, neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies, Poirier-Bienvenu neurodevelopmental syndrome, neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy, neurodevelopmental disorder with hypotonia and autistic features with or without hyperkinetic movements, neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulation, neurodevelopmental disorder with microcephaly and dysmorphic facies, neurodevelopmental disorder with relative macrocephaly and with or without cardiac or endocrine anomalies, neurodevelopmental disorder with dysmorphic facies, impaired speech, and hypotonia, neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities, neurodevelopmental disorder with speech impairment and dysmorphic facies, neurodevelopmental disorder with alopecia and brain abnormalities, neurodevelopmental disorder with seizures and brain atrophy, neurodevelopmental disorder with microcephaly, seizures, and brain atrophy, Delpire-McNeill syndrome, neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination, developmental delay and seizures with or without movement abnormalities, Stankiewicz-Isidor syndrome, neurodevelopmental disorder with midbrain and hindbrain malformations, neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies, neurodevelopmental disorder with involuntary movements, neurodevelopmental disorder with hypotonia, neuropathy, and deafness, neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies, encephalopathy, neonatal severe, with lactic acidosis and brain abnormalities, neurodevelopmental disorder with microcephaly, ataxia, and seizures, neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures, neurodevelopmental disorder with dysmorphic facies and distal limb anomalies, neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy, neurodevelopmental disorder with severe motor impairment and absent language, neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter, neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy, neurodevelopmental disorder with or without seizures and gait abnormalities, neurodevelopmental disorder with movement abnormalities, abnormal gait, and autistic features, neurodevelopmental disorder with poor language and loss of hand skills, neurodevelopmental disorder with microcephaly, cataracts, and renal abnormalities, neurodevelopmental disorder with spastic quadriplegia and brain abnormalities with or without seizures, neurodevelopmental disorder with spasticity and poor growth, neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures, neurodevelopmental disorder with epilepsy and hypoplasia of the corpus callosum, FOXG1 disorder, X-linked complex neurodevelopmental disorder, PPP2R1A-related intellectual disability, intellectual disability, autosomal dominant, CACNA1A-related complex neurodevelopmental disorder, X-linked intellectual disability, PAX5-related B lymphopenia and autism spectrum disorder, neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, KCNH1 associated disorder, AFG2B-related complex neurodevelopmental disorder with motor features and hearing loss, intellectual disability, autosomal recessive, FAT4-related neurodevelopmental disorder, SOX11-related complex neurodevelopmental disorder with or without congenital anomalies, microcephaly with lissencephaly and/or hydranencephaly, MYH10-related neurodevelopmental disorder with congenital anomalies, CNOT9-related developmental disorder with seizures, HMGB1-related brachyphalangy, polydactyly and tibial aplasia syndrome, ATXN7L3-related developmental delay, hypotonia and facial dysmorphism, DIP2C-related developmental disorder with speech delay, EPB41L3-related developmental disorder with delayed myelination and seizures, GABRA4-related neurodevelopmental disorder with seizures, GABRD-related neurodevelopmental disorder with epilepsy, KCNK3-related developmental delay with sleep apnea, RFX3-related neurodevelopmental disorder with autism and other behavioural abnormalities, RFX4-related neurodevelopmental disorder with autism and other behavioural abnormalities, KDM2B-related neurodevelopmental disorder, TRA2B-related neurodevelopmental disorder, WDR5-related neurodevelopmental disorder, ARF3-related neurodevelopmental disorder, CBX1-related neurodevelopmental disorder, DDX17-related neurodevelopmental disorder, FEZF2-related neurodevelopmental disorder, HDAC3-related neurodevelopmental disorder, DEAF1-associated neurodevelopmental disorder, SYNCRIP-related neurodevelopmental disorder, HNRNPC-related neurodevelopmental disorder, NACC1-related neurodevelopmental disorder with epilepsy, cataracts and episodic irritability, SETD2-related neurodevelopmental disorder without or with macrocephaly/overgrowth, neurodevelopmental disorder with gait disturbance, dysmorphic facies, and behavioral abnormalities, X-linked, Alzahrani-Kuwahara syndrome, neurodevelopmental disorder with spasticity, cataracts, and cerebellar hypoplasia, neurodevelopmental disorder with dysmorphic facies and cerebellar hypoplasia, Hiatt-Neu-Cooper neurodevelopmental syndrome, neurodevelopmental disorder with seizures and gingival overgrowth, neurodevelopmental disorder with cerebellar atrophy and motor dysfunction, neurodevelopmental disorder with infantile epileptic spasms, neurodevelopmental disorder with hypotonia, facial dysmorphism, and brain abnormalities, neurodevelopmental disorder with motor and speech delay and behavioral abnormalities, neurodevelopmental disorder with dysmorphic facies and thin corpus callosum, neurodevelopmental disorder with hypotonia and dysmorphic facies, neurodevelopmental disorder with hypotonia and brain abnormalities, neurodevelopmental disorder with impaired language and ataxia and with or without seizures, neurodevelopmental disorder with hearing loss and spasticity, neurodevelopmental disorder with hypotonia and gross motor and speech delay, neurodevelopmental disorder with hyperkinetic movements and dyskinesia, neurodevelopmental disorder, nonprogressive, with spasticity and transient opisthotonus, Marbach-Schaaf neurodevelopmental syndrome, neurodevelopmental disorder with microcephaly, seizures, and neonatal cholestasis, Brunet-Wagner neurodevelopmental syndrome, Ferguson-Bonni neurodevelopmental syndrome, neurodevelopmental disorder with or without variable movement or behavioral abnormalities, neurodevelopmental disorder with central hypotonia and dysmorphic facies, neurodevelopmental disorder with neuromuscular and skeletal abnormalities, Chilton-Okur-Chung neurodevelopmental syndrome, neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalities, parenti-mignot neurodevelopmental syndrome, neurodevelopmental disorder with microcephaly, hypotonia, nystagmus, and seizures, Dentici-Novelli neurodevelopmental syndrome, neurodevelopmental disorder with poor growth and skeletal anomalies, neurodevelopmental disorder with language delay and seizures, neurodevelopmental disorder with dystonia and seizures, Dworschak-Punetha neurodevelopmental syndrome, neurodevelopmental disorder with epilepsy and brain atrophy, neurodevelopmental disorder with severe motor impairment, absent language, cerebral hypomyelination, and brain atrophy, neurodevelopmental disorder with speech delay and variable ocular anomalies, neurodevelopmental disorder with intention tremor, pyramidal signs, dyspraxia, and ocular anomalies, neurodevelopmental disorder with spasticity, seizures, and brain abnormalities, neurodevelopmental disorder with microcephaly, movement abnormalities, and seizures, neurodevelopmental disorder with seizures, microcephaly, and brain abnormalities, neurodevelopmental disorder with microcephaly, short stature, and speech delay, neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures, neurodevelopmental disorder with microcephaly, cerebral atrophy, and visual impairment, neurodevelopmental disorder with short stature, prominent forehead, and feeding difficulties, neurodevelopmental disorder with dysmorphic facies and skeletal and brain abnormalities, neurodevelopmental disorder with facial dysmorphism, absent language, and pseudo-pelger-huet anomaly, neurodevelopmental disorder with craniofacial dysmorphism and skeletal defects, neurodevelopmental disorder with eye movement abnormalities and ataxia, neurodevelopmental disorder with growth retardation, dysmorphic facies, and corpus callosum abnormalities, neurodevelopmental disorder with speech impairment and with or without seizures, neurodevelopmental disorder with hypotonia, dysmorphic facies, and skin abnormalities, neurodevelopmental disorder with poor growth, large ears, and dysmorphic facies, neurodevelopmental disorder with dysmorphic facies and ischiopubic hypoplasia, neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures, neurodevelopmental disorder with poor growth and behavioral abnormalities, neurodevelopmental disorder with seizures, spasticity, and complete or partial agenesis of the corpus callosum, neurodevelopmental disorder with absent speech and movement and behavioral abnormalities, neurodevelopmental disorder with language delay and behavioral abnormalities, with or without seizures, neurodevelopmental disorder with microcephaly and speech delay, with or without brain abnormalities, neurodevelopmental disorder with intracranial hemorrhage, seizures, and spasticity, neurodevelopmental disorder with motor and language delay, ocular defects, and brain abnormalities, neurodevelopmental disorder with microcephaly and movement abnormalities, neurodevelopmental disorder with hypotonia and speech delay, with or without seizures, neurodevelopmental disorder with dysmorphic facies and behavioral abnormalities, neurodevelopmental disorder with impaired language, behavioral abnormalities, and dysmorphic facies, neurodevelopmental disorder with language delay and variable cognitive abnormalities, neurodevelopmental disorder with motor regression, progressive spastic paraplegia, and oromotor dysfunction, Hao-Fountain syndrome due to USP7 mutation, neurodevelopmental disorder with motor abnormalities, seizures, and facial dysmorphism, neurodevelopmental disorder with hyperkinetic movements, seizures, and structural brain abnormalities, neurodevelopmental disorder with hypotonia and characteristic brain abnormalities, neurodevelopmental disorder with early-onset parkinsonism and behavioral abnormalities, Jeffries-Lakhani neurodevelopmental syndrome, neurodevelopmental disorder with language impairment, autism, and attention deficit-hyperactivity disorder, neurodevelopmental disorder plus optic atrophy, neurodevelopmental disorder with progressive movement abnormalities, aplasia cutis-enamel dysplasia syndrome, neurodevelopmental disorder with hypotonia and seizures, El Hayek-Chahrour neurodevelopmental disorder, neurodevelopmental disorder with hypotonia, feeding difficulties, facial dysmorphism, and brain abnormalities, neurodevelopmental disorder with hypotonia, brain anomalies, distinctive facies, and absent language, otofacial neurodevelopmental syndrome, neurodevelopmental disorder with characteristic facial and ectodermal features and tetraparesis 1, Kariminejad neurodevelopmental syndrome, Karayol-Borroto-Haghshenas neurodevelopmental syndrome, neurodevelopmental disorder with dysmorphic facies, absent speech and ambulation, and brain abnormalities, neurodevelopmental disorder with variable familial hypercholanemia, intellectual developmental disorder with polymicrogyria and seizures, neurodevelopmental disorder with speech or visual impairment and brain hypomyelination, neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, neurodevelopmental disorder with hypotonia, poor growth, dysmorphic facies, and agammaglobulinemia, neurodevelopmental disorder with progressive spasticity and brain abnormalities, neurodevelopmental disorder with thin corpus callosum, hypotonia, and absent language, neurodevelopmental disorder with white matter abnormalities and gait disturbance, neurodevelopmental disorder with poor growth, seizures, and brain abnormalities, neurodevelopmental disorder with poor or absent speech, dysmorphic facies, and behavioral abnormalities, neurodevelopmental disorder with ataxia and brain abnormalities, neurodevelopmental disorder with dysmorphic facies, brain anomalies, and seizures, Li-Takada-Miyake syndrome, neurodevelopmental disorder with behavioral, ear, and skeletal abnormalities, Nil-Deshwar neurodevelopmental syndrome, Popov-Chang syndrome, neurodevelopmental disorder with achalasia, polyneuropathy, and alacrima, Dursun-Ozgul neurodevelopmental syndrome, neurodevelopmental disorder with growth impairment, quadriparesis, and poor or absent speech, neurodevelopmental disorder with speech delay and behavioral abnormalities, Harel-Tora neurodevelopmental syndrome, neurocardiorenal malformation syndrome, neurodevelopmental disorder with behavioral abnormalities and childhood-onset spastic paraplegia, neurodevelopmental disorder with early-onset seizures, facial dysmorphism, and behavioral abnormalities, neurodevelopmental disorder with structural brain abnormalities and craniofacial abnormalities, Ramond-Elliott neurodevelopmental syndrome, microcephaly, progressive, with simplified gyral pattern and cerebellar hypoplasia, neurodevelopmental disorder with hypotonia, epilepsy, and absent speech, neurodevelopmental disorder with speech delay, movement abnormalities, and seizures, neurodevelopmental disorder with spasticity, thin corpus callosum, and decreased brain white matter, neurodevelopmental disorder with congenital cardiac defects and variable renal and ocular abnormalities, neurodevelopmental disorder with seizures, hypotonia, and variable spasticity, PIP5K1C-related neurodevelopmental disorder, KCND2-related neurodevelopmental disorder with or without seizures, PRPF19-related neurodevelopmental disorder, CTR9-related neurodevelopmental disorder, CAMK2D-related neurodevelopmental disorder and dilated cardiomyopathy, PPFIA3-related neurodevelopmental disorder, dyneinopathy, MYCBP2-related developmental delay with corpus callosum defects, GRIN-related complex neurodevelopmental disorder, RNU5B-1 related neurodevelopmental disorder with seizures and joint laxity, TSEN2-related neurodevelopmental disorder with or without thrombotic microangiopathy

Subtypes (105): developmental and epileptic encephalopathy, 9, developmental and epileptic encephalopathy, 8, developmental and epileptic encephalopathy, 2, multiple congenital anomalies-hypotonia-seizures syndrome 2, developmental and epileptic encephalopathy, 36, developmental and epileptic encephalopathy, 1, developmental and epileptic encephalopathy, 3, developmental and epileptic encephalopathy, 4, microcephaly, seizures, and developmental delay, developmental and epileptic encephalopathy, 5, developmental and epileptic encephalopathy, 7, developmental and epileptic encephalopathy, 11, neonatal-onset encephalopathy with rigidity and seizures, developmental and epileptic encephalopathy, 14, developmental and epileptic encephalopathy, 15, developmental and epileptic encephalopathy, 17, developmental and epileptic encephalopathy, 18, developmental and epileptic encephalopathy, 19, developmental and epileptic encephalopathy, 23, developmental and epileptic encephalopathy, 27, developmental and epileptic encephalopathy, 30, developmental and epileptic encephalopathy, 50, developmental and epileptic encephalopathy, 35, developmental and epileptic encephalopathy, 37, developmental and epileptic encephalopathy, 38, developmental and epileptic encephalopathy, 40, developmental and epileptic encephalopathy, 48, developmental and epileptic encephalopathy, 49, developmental and epileptic encephalopathy, 51, Lennox-Gastaut syndrome, developmental and epileptic encephalopathy 91, developmental and epileptic encephalopathy 92, developmental and epileptic encephalopathy 93, developmental and epileptic encephalopathy 96, developmental and epileptic encephalopathy, 90, developmental and epileptic encephalopathy, 85, with or without midline brain defects, developmental and epileptic encephalopathy, 67, developmental and epileptic encephalopathy, 86, developmental and epileptic encephalopathy, 87, developmental and epileptic encephalopathy, 88, developmental and epileptic encephalopathy 6B, developmental and epileptic encephalopathy 97, developmental and epileptic encephalopathy 98, developmental and epileptic encephalopathy 99, developmental and epileptic encephalopathy 100, developmental and epileptic encephalopathy 101, developmental and epileptic encephalopathy 89, developmental and epileptic encephalopathy 102, developmental and epileptic encephalopathy 103, developmental and epileptic encephalopathy 104, developmental and epileptic encephalopathy 105 with hypopituitarism, developmental and epileptic encephalopathy 106, developmental and epileptic encephalopathy 107, developmental and epileptic encephalopathy, 68, developmental and epileptic encephalopathy, 69, developmental and epileptic encephalopathy, 70, developmental and epileptic encephalopathy, 71, developmental and epileptic encephalopathy, 72, developmental and epileptic encephalopathy, 74, developmental and epileptic encephalopathy, 75, developmental and epileptic encephalopathy, 76, developmental and epileptic encephalopathy, 77, developmental and epileptic encephalopathy, 78, developmental and epileptic encephalopathy, 79, developmental and epileptic encephalopathy, 80, developmental and epileptic encephalopathy, 81, developmental and epileptic encephalopathy, 82, developmental and epileptic encephalopathy, 83, developmental and epileptic encephalopathy, 84, developmental and epileptic encephalopathy, 52, developmental and epileptic encephalopathy, 53, developmental and epileptic encephalopathy, 54, developmental and epileptic encephalopathy, 55, developmental and epileptic encephalopathy, 56, developmental and epileptic encephalopathy, 57, developmental and epileptic encephalopathy, 58, developmental and epileptic encephalopathy, 59, developmental and epileptic encephalopathy, 60, developmental and epileptic encephalopathy, 61, developmental and epileptic encephalopathy, 62, developmental and epileptic encephalopathy, 63, developmental and epileptic encephalopathy, 64, developmental and epileptic encephalopathy, 65, developmental and epileptic encephalopathy, 73, developmental and epileptic encephalopathy, 66, developmental and epileptic encephalopathy, 6A, non-neonatal early infantile epileptic encephalopathy, Dravet syndrome, neonatal-onset developmental and epileptic encephalopathy, hemiplegic migraine-developmental and epileptic encephalopathy spectrum, DNM1-encephalopathy and neurodevelopmental disorder, TMEM63B-related developmental and epileptic encephalopathy with anemia, developmental and epileptic encephalopathy 108, developmental and epileptic encephalopathy 109, developmental and epileptic encephalopathy 110, developmental and epileptic encephalopathy 111, developmental and epileptic encephalopathy 112, developmental and epileptic encephalopathy 113, developmental and epileptic encephalopathy 114, developmental and epileptic encephalopathy 115, developmental and epileptic encephalopathy 116, developmental and epileptic encephalopathy 118, developmental and epileptic encephalopathy 120, developmental and epileptic encephalopathy 121, developmental and epileptic encephalopathy 119

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

37 retrieved; paginated sample, class counts are floors:

11 uncertain significance, 9 benign/likely benign, 6 conflicting classifications of pathogenicity, 3 pathogenic/likely pathogenic, 3 likely benign, 3 pathogenic, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
4846761	GRCh38/hg38 Xp22.31-22.13(chrX:9415628-17605610)x3	ACE2	Pathogenic	criteria provided, single submitter
4074761	NM_001242896.3(DEPDC5):c.643G>T (p.Glu215Ter)	DEPDC5	Pathogenic	criteria provided, single submitter
211088	NM_020988.3(GNAO1):c.680C>T (p.Ala227Val)	GNAO1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
280435	NM_006245.4(PPP2R5D):c.619T>C (p.Trp207Arg)	PPP2R5D	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
694617	NM_001037.5(SCN1B):c.449-2A>G	SCN1B	Pathogenic	reviewed by expert panel
207019	NM_001040142.2(SCN2A):c.4886G>A (p.Arg1629His)	SCN2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4072125	NM_001367721.1(CASK):c.184G>A (p.Glu62Lys)	CASK	Likely pathogenic	criteria provided, single submitter
4074794	NM_014489.4(PGAP2):c.509A>G (p.Tyr170Cys)	PGAP2	Likely pathogenic	criteria provided, single submitter
700166	NM_025114.4(CEP290):c.2873C>T (p.Ser958Phe)	CEP290	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
92725	NM_000276.4(OCRL):c.439+3A>G	OCRL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
982374	NM_006245.4(PPP2R5D):c.632A>C (p.Gln211Pro)	PPP2R5D	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
464907	NM_001040142.2(SCN2A):c.3529C>T (p.Arg1177Trp)	SCN2A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
95601	NM_014467.3(SRPX2):c.605G>A (p.Arg202Gln)	SRPX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3771215	NM_006885.4(ZFHX3):c.694C>T (p.Arg232Cys)	ZFHX3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
4074984	NM_000489.6(ATRX):c.5543A>G (p.Gln1848Arg)	ATRX	Uncertain significance	criteria provided, single submitter
2073331	NM_001205293.3(CACNA1E):c.6382C>A (p.Gln2128Lys)	CACNA1E	Uncertain significance	criteria provided, multiple submitters, no conflicts
2073334	NM_001205293.3(CACNA1E):c.6431C>T (p.Pro2144Leu)	CACNA1E	Uncertain significance	criteria provided, multiple submitters, no conflicts
1696401	NM_025114.4(CEP290):c.4865G>A (p.Arg1622His)	CEP290	Uncertain significance	criteria provided, multiple submitters, no conflicts
4072102	NM_001170629.2(CHD8):c.1424G>A (p.Arg475His)	CHD8	Uncertain significance	criteria provided, single submitter
4074914	NM_001195553.2(DCX):c.925G>A (p.Asp309Asn)	DCX	Uncertain significance	criteria provided, single submitter
1393902	NM_198904.4(GABRG2):c.836C>T (p.Thr279Ile)	GABRG2	Uncertain significance	criteria provided, multiple submitters, no conflicts
4074868	NM_000217.3(KCNA1):c.1142T>G (p.Val381Gly)	KCNA1	Uncertain significance	criteria provided, single submitter
4846751	GRCh38/hg38 11q13.1-13.2(chr11:66060294-66209223)x1	LOC121832794	Uncertain significance	criteria provided, single submitter
944261	NM_001040142.2(SCN2A):c.5704C>T (p.Arg1902Cys)	SCN2A	Uncertain significance	criteria provided, multiple submitters, no conflicts
1049951	NM_006922.4(SCN3A):c.2626G>A (p.Gly876Ser)	SCN3A	Uncertain significance	reviewed by expert panel
128447	NM_004840.3(ARHGEF6):c.362G>A (p.Arg121His)	ARHGEF6	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
377731	NM_000393.5(COL5A2):c.799-6A>G	COL5A2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
376776	NM_005334.3(HCFC1):c.3794C>T (p.Ser1265Leu)	HCFC1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
4072146	NM_031407.7(HUWE1):c.1490-565_1490-560del	HUWE1	Likely benign	criteria provided, single submitter
1923935	NM_019066.5(MAGEL2):c.3046C>T (p.Pro1016Ser)	MAGEL2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 311 · Orphanet: 141 · 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
CDKL5	Definitive	X-linked	developmental and epileptic encephalopathy, 2	9
DOCK7	Definitive	Autosomal recessive	genetic developmental and epileptic encephalopathy	6
FLNA	Definitive	X-linked	genetic developmental and epileptic encephalopathy	30
FRRS1L	Definitive	Autosomal recessive	genetic developmental and epileptic encephalopathy	6
GABRB3	Definitive	Autosomal dominant	developmental and epileptic encephalopathy, 43	8
GNAO1	Definitive	Autosomal dominant	genetic developmental and epileptic encephalopathy	10
SCN1A	Definitive	Autosomal dominant	developmental and epileptic encephalopathy, 6A	20
SCN1B	Definitive	Autosomal recessive	genetic developmental and epileptic encephalopathy	15
SCN2A	Definitive	Autosomal dominant	developmental and epileptic encephalopathy, 11	16
SCN3A	Definitive	Autosomal dominant	genetic developmental and epileptic encephalopathy	7
SIK1	Definitive	Autosomal dominant	developmental and epileptic encephalopathy, 30	7
SPTAN1	Definitive	Autosomal dominant	genetic developmental and epileptic encephalopathy	10
STXBP1	Definitive	Autosomal recessive	developmental and epileptic encephalopathy, 4	12
ARX	Strong	X-linked	developmental and epileptic encephalopathy, 1	16
ATP6V0C	Strong	Autosomal dominant	epilepsy, early-onset, 3, with or without developmental delay	3
CAMK2G	Strong	Autosomal dominant	intellectual developmental disorder 59	6
DMXL2	Strong	Autosomal recessive	developmental and epileptic encephalopathy, 81	13
NECAP1	Strong	Autosomal recessive	developmental and epileptic encephalopathy, 21	5
NEUROD2	Strong	Autosomal dominant	developmental and epileptic encephalopathy, 72	4
PIGP	Strong	Autosomal recessive	developmental and epileptic encephalopathy, 55	5
PIGQ	Strong	Autosomal recessive	developmental and epileptic encephalopathy, 77	5
PNKP	Strong	Autosomal recessive	microcephaly, seizures, and developmental delay	11
SLC25A22	Strong	Autosomal recessive	developmental and epileptic encephalopathy, 3	6
TMEM63B	Strong	Autosomal dominant	genetic developmental and epileptic encephalopathy	3
ZFHX3	Strong	Autosomal recessive	genetic developmental and epileptic encephalopathy	7
SNAP25	Moderate	Autosomal dominant	genetic developmental and epileptic encephalopathy	5
CASK	Supportive	Autosomal dominant	genetic developmental and epileptic encephalopathy	8
KCNA1	Supportive	Autosomal dominant	genetic developmental and epileptic encephalopathy	10
TRIM8	Supportive	Autosomal dominant	genetic developmental and epileptic encephalopathy	4
ARHGEF15	Limited	Autosomal dominant	genetic developmental and epileptic encephalopathy	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SCN1B	Orphanet:130	Brugada syndrome
SCN1B	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
SCN1B	Orphanet:33069	Dravet syndrome
SCN1B	Orphanet:334	Hereditary atrial fibrillation
SCN1B	Orphanet:36387	Genetic epilepsy with febrile seizure plus
SCN1B	Orphanet:871	Hereditary progressive cardiac conduction defect
SCN2A	Orphanet:140927	Self-limited neonatal-infantile epilepsy
SCN2A	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
SCN2A	Orphanet:2131	Alternating hemiplegia of childhood
SCN2A	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
SCN2A	Orphanet:306	Self-limited infantile epilepsy
SCN2A	Orphanet:33069	Dravet syndrome
SCN2A	Orphanet:36387	Genetic epilepsy with febrile seizure plus
SCN2A	Orphanet:697160	Infantile epileptic spasms syndrome
SCN3A	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
SCN3A	Orphanet:98820	Familial focal epilepsy with variable foci
CASK	Orphanet:163937	X-linked intellectual disability, Najm type
CASK	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
CASK	Orphanet:777	X-linked non-syndromic intellectual disability
GNAO1	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
GNAO1	Orphanet:592564	GNAO1-related developmental delay-seizures-movement disorder spectrum
KCNA1	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
KCNA1	Orphanet:199326	Isolated autosomal dominant hypomagnesemia, Glaudemans type
KCNA1	Orphanet:37612	Episodic ataxia type 1
KCNA1	Orphanet:972	Hereditary continuous muscle fiber activity
KCNA1	Orphanet:98809	Paroxysmal kinesigenic dyskinesia
SCN1A	Orphanet:1942	Epilepsy with myoclonic-atonic seizures
SCN1A	Orphanet:2382	Lennox-Gastaut syndrome
SCN1A	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
SCN1A	Orphanet:33069	Dravet syndrome
SCN1A	Orphanet:36387	Genetic epilepsy with febrile seizure plus
SCN1A	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
SCN1A	Orphanet:569	Familial or sporadic hemiplegic migraine
SNAP25	Orphanet:98914	Presynaptic congenital myasthenic syndromes
SIK1	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
SIK1	Orphanet:697160	Infantile epileptic spasms syndrome
SPTAN1	Orphanet:697160	Infantile epileptic spasms 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
STXBP1	Orphanet:495818	9q33.3q34.11 microdeletion syndrome
STXBP1	Orphanet:599373	STXBP1-related encephalopathy
USP8	Orphanet:401795	Autosomal recessive spastic paraplegia type 59
USP8	Orphanet:96253	Cushing disease
FRRS1L	Orphanet:725	Developmental and epileptic encephalopathy with spike-wave activation in sleep
FRRS1L	Orphanet:88616	Autosomal recessive non-syndromic intellectual disability
CACNA2D1	Orphanet:130	Brugada syndrome
CACNA2D1	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
CACNA2D1	Orphanet:51083	Congenital short QT syndrome

Cohort genes → proteins

65 cohort genes, 65 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	65

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SCN1B	HGNC:10586	ENSG00000105711	Q07699	Sodium channel regulatory subunit beta-1	gencc,clinvar
SCN2A	HGNC:10588	ENSG00000136531	Q99250	Sodium channel protein type 2 subunit alpha	gencc,clinvar
SCN3A	HGNC:10590	ENSG00000153253	Q9NY46	Sodium channel protein type 3 subunit alpha	gencc,clinvar
CASK	HGNC:1497	ENSG00000147044	O14936	Peripheral plasma membrane protein CASK	gencc,clinvar
GNAO1	HGNC:4389	ENSG00000087258	P09471	Guanine nucleotide-binding protein G(o) subunit alpha	gencc,clinvar
KCNA1	HGNC:6218	ENSG00000111262	Q09470	Potassium voltage-gated channel subfamily A member 1	gencc,clinvar
ZFHX3	HGNC:777	ENSG00000140836	Q15911	Zinc finger homeobox protein 3	gencc,clinvar
RYR3	HGNC:10485	ENSG00000198838	Q15413	Ryanodine receptor 3	gencc
SCN1A	HGNC:10585	ENSG00000144285	P35498	Sodium channel protein type 1 subunit alpha	gencc
SNAP25	HGNC:11132	ENSG00000132639	P60880	Synaptosomal-associated protein 25	gencc
SIK1	HGNC:11142	ENSG00000142178	P57059	Serine/threonine-protein kinase SIK1	gencc
SPTAN1	HGNC:11273	ENSG00000197694	Q13813	Spectrin alpha chain, non-erythrocytic 1	gencc
ST7	HGNC:11351	ENSG00000004866	Q9NRC1	Suppressor of tumorigenicity 7 protein	gencc
CDKL5	HGNC:11411	ENSG00000008086	O76039	Cyclin-dependent kinase-like 5	gencc
STXBP1	HGNC:11444	ENSG00000136854	P61764	Syntaxin-binding protein 1	gencc
USP8	HGNC:12631	ENSG00000138592	P40818	Ubiquitin carboxyl-terminal hydrolase 8	gencc
FRRS1L	HGNC:1362	ENSG00000260230	Q9P0K9	DOMON domain-containing protein FRRS1L	gencc
CACNA2D1	HGNC:1399	ENSG00000153956	P54289	Voltage-dependent calcium channel subunit alpha-2/delta-1	gencc
PIGQ	HGNC:14135	ENSG00000007541	Q9BRB3	Phosphatidylinositol N-acetylglucosaminyltransferase subunit Q	gencc
CAMK2G	HGNC:1463	ENSG00000148660	Q13555	Calcium/calmodulin-dependent protein kinase type II subunit gamma	gencc
TRIM8	HGNC:15579	ENSG00000171206	Q9BZR9	E3 ubiquitin-protein ligase TRIM8	gencc
ARHGEF15	HGNC:15590	ENSG00000198844	O94989	Rho guanine nucleotide exchange factor 15	gencc
TMEM63B	HGNC:17735	ENSG00000137216	Q5T3F8	Mechanosensitive cation channel TMEM63B	gencc
ARX	HGNC:18060	ENSG00000004848	Q96QS3	Homeobox protein ARX	gencc
CELSR1	HGNC:1850	ENSG00000075275	Q9NYQ6	Cadherin EGF LAG seven-pass G-type receptor 1	gencc
MAGI2	HGNC:18957	ENSG00000187391	Q86UL8	Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 2	gencc
DOCK7	HGNC:19190	ENSG00000116641	Q96N67	Dedicator of cytokinesis protein 7	gencc
SLC25A22	HGNC:19954	ENSG00000177542	Q9H936	Mitochondrial glutamate carrier 1	gencc
CSNK1E	HGNC:2453	ENSG00000213923	P49674	Casein kinase I isoform epsilon	gencc
NECAP1	HGNC:24539	ENSG00000089818	Q8NC96	Adaptin ear-binding coat-associated protein 1	gencc
DMXL2	HGNC:2938	ENSG00000104093	Q8TDJ6	DmX-like protein 2	gencc
PIGP	HGNC:3046	ENSG00000185808	P57054	Phosphatidylinositol N-acetylglucosaminyltransferase subunit P	gencc
FLNA	HGNC:3754	ENSG00000196924	P21333	Filamin-A	gencc
GABRA4	HGNC:4078	ENSG00000109158	P48169	Gamma-aminobutyric acid receptor subunit alpha-4	gencc
GABRB3	HGNC:4083	ENSG00000166206	P28472	Gamma-aminobutyric acid receptor subunit beta-3	gencc
GABRG1	HGNC:4086	ENSG00000163285	Q8N1C3	Gamma-aminobutyric acid receptor subunit gamma-1	gencc
GTF3C3	HGNC:4666	ENSG00000119041	Q9Y5Q9	General transcription factor 3C polypeptide 3	gencc
KCNQ3	HGNC:6297	ENSG00000184156	O43525	Potassium voltage-gated channel subfamily KQT member 3	gencc
NEUROD2	HGNC:7763	ENSG00000171532	Q15784	Neurogenic differentiation factor 2	gencc
ATP6V0C	HGNC:855	ENSG00000185883	P27449	V-type proton ATPase 16 kDa proteolipid subunit c	gencc
PNKP	HGNC:9154	ENSG00000039650	Q96T60	Bifunctional polynucleotide phosphatase/kinase	gencc
TAF1	HGNC:11535	ENSG00000147133	P21675	Transcription initiation factor TFIID subunit 1	clinvar
ACE2	HGNC:13557	ENSG00000130234	Q9BYF1	Angiotensin-converting enzyme 2	clinvar
CACNA1E	HGNC:1392	ENSG00000198216	Q15878	Voltage-dependent R-type calcium channel subunit alpha-1E	clinvar
PORCN	HGNC:17652	ENSG00000102312	Q9H237	Protein-serine O-palmitoleoyltransferase porcupine	clinvar
PGAP2	HGNC:17893	ENSG00000148985	Q9UHJ9	Acyltransferase PGAP2	clinvar
SETD2	HGNC:18420	ENSG00000181555	Q9BYW2	Histone-lysine N-methyltransferase SETD2	clinvar
DEPDC5	HGNC:18423	ENSG00000100150	O75140	GATOR1 complex protein DEPDC5	clinvar
CHD8	HGNC:20153	ENSG00000100888	Q9HCK8	ATP-dependent chromatin remodeler CHD8	clinvar
COL5A2	HGNC:2210	ENSG00000204262	P05997	Collagen alpha-2(V) chain	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SCN1B	Sodium channel regulatory subunit beta-1	Regulatory subunit of multiple voltage-gated sodium (Nav) channels directly mediating the depolarization of excitable membranes.
SCN2A	Sodium channel protein type 2 subunit alpha	Mediates the voltage-dependent sodium ion permeability of excitable membranes.
SCN3A	Sodium channel protein type 3 subunit alpha	Pore-forming subunit of Nav1.3, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes.
CASK	Peripheral plasma membrane protein CASK	Multidomain scaffolding Mg(2+)-independent protein kinase that catalyzes the phosphotransfer from ATP to proteins such as NRXN1, and plays a role in synaptic transmembrane protein anchoring and ion channel trafficking.
GNAO1	Guanine nucleotide-binding protein G(o) subunit alpha	Guanine nucleotide-binding proteins (G proteins) function as transducers downstream of G protein-coupled receptors (GPCRs) in numerous signaling cascades.
KCNA1	Potassium voltage-gated channel subfamily A member 1	Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes, primarily in the brain and the central nervous system, but also in the kidney.
ZFHX3	Zinc finger homeobox protein 3	Transcriptional regulator which can act as an activator or a repressor.
RYR3	Ryanodine receptor 3	Cytosolic calcium-activated calcium channel that mediates the release of Ca(2+) from the sarcoplasmic reticulum into the cytoplasm in muscle and thereby plays a role in triggering muscle contraction.
SCN1A	Sodium channel protein type 1 subunit alpha	Pore-forming subunit of Nav1.1, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes.
SNAP25	Synaptosomal-associated protein 25	t-SNARE involved in the molecular regulation of neurotransmitter release.
SIK1	Serine/threonine-protein kinase SIK1	Serine/threonine-protein kinase involved in various processes such as cell cycle regulation, gluconeogenesis and lipogenesis regulation, muscle growth and differentiation and tumor suppression.
SPTAN1	Spectrin alpha chain, non-erythrocytic 1	Fodrin, which seems to be involved in secretion, interacts with calmodulin in a calcium-dependent manner and is thus candidate for the calcium-dependent movement of the cytoskeleton at the membrane.
ST7	Suppressor of tumorigenicity 7 protein	May act as a tumor suppressor.
CDKL5	Cyclin-dependent kinase-like 5	Mediates phosphorylation of MECP2.
STXBP1	Syntaxin-binding protein 1	Participates in the regulation of synaptic vesicle docking and fusion through interaction with GTP-binding proteins.
USP8	Ubiquitin carboxyl-terminal hydrolase 8	Hydrolase that can remove conjugated ubiquitin from proteins and therefore plays an important regulatory role at the level of protein turnover by preventing degradation.
FRRS1L	DOMON domain-containing protein FRRS1L	Important modulator of glutamate signaling pathway.
CACNA2D1	Voltage-dependent calcium channel subunit alpha-2/delta-1	The alpha-2/delta subunit of voltage-dependent calcium channels regulates calcium current density and activation/inactivation kinetics of the calcium channel.
PIGQ	Phosphatidylinositol N-acetylglucosaminyltransferase subunit Q	Part of the glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT) complex that catalyzes the transfer of N-acetylglucosamine from UDP-N-acetylglucosamine to phosphatidylinositol and participates in the first step of GPI bi…
CAMK2G	Calcium/calmodulin-dependent protein kinase type II subunit gamma	Calcium/calmodulin-dependent protein kinase that functions autonomously after Ca(2+)/calmodulin-binding and autophosphorylation, and is involved in sarcoplasmic reticulum Ca(2+) transport in skeletal muscle and may function in dendritic sp…
TRIM8	E3 ubiquitin-protein ligase TRIM8	E3 ubiquitin-protein ligase that participates in multiple biological processes including cell survival, differentiation, apoptosis, and in particular, the innate immune response.
ARHGEF15	Rho guanine nucleotide exchange factor 15	Guanine nucleotide exchange factor (GEF) that activates RhoA, playing a role in the regulation of actin cytoskeleton organization.
TMEM63B	Mechanosensitive cation channel TMEM63B	Mechanosensitive cation channel with low conductance and high activation threshold.
ARX	Homeobox protein ARX	Transcription factor.
CELSR1	Cadherin EGF LAG seven-pass G-type receptor 1	Receptor that may have an important role in cell/cell signaling during nervous system formation.
MAGI2	Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 2	Seems to act as a scaffold molecule at synaptic junctions by assembling neurotransmitter receptors and cell adhesion proteins.
DOCK7	Dedicator of cytokinesis protein 7	Functions as a guanine nucleotide exchange factor (GEF), which activates Rac1 and Rac3 Rho small GTPases by exchanging bound GDP for free GTP.
SLC25A22	Mitochondrial glutamate carrier 1	Mitochondrial glutamate/H(+) symporter.
CSNK1E	Casein kinase I isoform epsilon	Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates.
NECAP1	Adaptin ear-binding coat-associated protein 1	Involved in endocytosis.
DMXL2	DmX-like protein 2	May serve as a scaffold protein for MADD and RAB3GA on synaptic vesicles.
PIGP	Phosphatidylinositol N-acetylglucosaminyltransferase subunit P	Part of the glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT) complex that catalyzes the transfer of N-acetylglucosamine from UDP-N-acetylglucosamine to phosphatidylinositol and participates in the first step of GPI bi…
FLNA	Filamin-A	Promotes orthogonal branching of actin filaments and links actin filaments to membrane glycoproteins.
GABRA4	Gamma-aminobutyric acid receptor subunit alpha-4	Alpha subunit of the heteropentameric ligand-gated chloride channel gated by gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain.
GABRB3	Gamma-aminobutyric acid receptor subunit beta-3	Beta subunit of the heteropentameric ligand-gated chloride channel gated by gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain.
GABRG1	Gamma-aminobutyric acid receptor subunit gamma-1	Gamma subunit of the heteropentameric ligand-gated chloride channel gated by gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain.
GTF3C3	General transcription factor 3C polypeptide 3	Involved in RNA polymerase III-mediated transcription.
KCNQ3	Potassium voltage-gated channel subfamily KQT member 3	Pore-forming subunit of the voltage-gated potassium (Kv) M-channel which is responsible for the M-current, a key controller of neuronal excitability.
NEUROD2	Neurogenic differentiation factor 2	Transcriptional regulator implicated in neuronal determination.
ATP6V0C	V-type proton ATPase 16 kDa proteolipid subunit c	Proton-conducting pore forming subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons.
PNKP	Bifunctional polynucleotide phosphatase/kinase	Plays a key role in the repair of DNA damage, functioning as part of both the non-homologous end-joining (NHEJ) and base excision repair (BER) pathways.
TAF1	Transcription initiation factor TFIID subunit 1	The TFIID basal transcription factor complex plays a major role in the initiation of RNA polymerase II (Pol II)-dependent transcription.
ACE2	Angiotensin-converting enzyme 2	Essential counter-regulatory carboxypeptidase of the renin-angiotensin hormone system that is a critical regulator of blood volume, systemic vascular resistance, and thus cardiovascular homeostasis.
CACNA1E	Voltage-dependent R-type calcium channel subunit alpha-1E	Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells.
PORCN	Protein-serine O-palmitoleoyltransferase porcupine	Protein-serine O-palmitoleoyltransferase that acts as a key regulator of the Wnt signaling pathway by mediating the attachment of palmitoleate, a 16-carbon monounsaturated fatty acid (C16:1(9Z)), to Wnt proteins.
PGAP2	Acyltransferase PGAP2	Involved in the fatty acid remodeling steps of GPI-anchor maturation where the unsaturated acyl chain at sn-2 of inositol phosphate is replaced by a saturated stearoyl chain.
SETD2	Histone-lysine N-methyltransferase SETD2	Histone methyltransferase that specifically trimethylates ‘Lys-36’ of histone H3 (H3K36me3) using dimethylated ‘Lys-36’ (H3K36me2) as substrate.
DEPDC5	GATOR1 complex protein DEPDC5	As a component of the GATOR1 complex functions as an inhibitor of the amino acid-sensing branch of the mTORC1 pathway.
CHD8	ATP-dependent chromatin remodeler CHD8	ATP-dependent chromatin-remodeling factor, it slides nucleosomes along DNA; nucleosome sliding requires ATP.
COL5A2	Collagen alpha-2(V) chain	Type V collagen is a member of group I collagen (fibrillar forming collagen).

Protein-family classification

Druggable: 29 · Difficult: 12 · Unknown: 24 · Druggable fraction: 0.45

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
Ion channel	7	12.0×	2e-05
Kinase	6	2.6×	0.177
Complement	1	4.1×	0.648
Antibody/Immunoglobulin	4	1.8×	0.648
Scaffold/PPI	5	1.3×	0.775
Phosphatase	1	1.3×	0.824
Transporter	1	1.2×	0.824
Protease	2	1.1×	0.824
Enzyme (other)	5	0.9×	0.824
Transcription factor	7	0.9×	0.824
GPCR	2	0.7×	0.830
Other/Unknown	24	0.7×	0.999

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SCN1B	Antibody/Immunoglobulin	yes		Ig_V-set, Ig-like_fold, Na_channel_b1/b3
SCN2A	Ion channel	yes		IQ_motif_EF-hand-BS, Na_channel_asu, Ion_trans_dom
SCN3A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_trans_assoc_dom
CASK	Kinase	yes	2.7.11.1	Prot_kinase_dom, SH3_domain, PDZ
GNAO1	Other/Unknown	no		Gprotein_alpha_su, Gprotein_alpha_I, GproteinA_insert
KCNA1	Ion channel	yes		BTB/POZ_dom, T1-type_BTB, K_chnl_volt-dep_Kv
ZFHX3	Transcription factor	no		HD, Matrin/U1-like-C_Znf_C2H2, Homeodomain-like_sf
RYR3	Ion channel	yes		RIH_dom, B30.2/SPRY, EF_hand_dom
SCN1A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_channel_a1su
SNAP25	Other/Unknown	no		T_SNARE_dom, SNAP-25_dom, SNAP-25_N_SNARE_chord
SIK1	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
SPTAN1	Scaffold/PPI	no		SH3_domain, Spectrin_repeat, EF_hand_dom
ST7	Other/Unknown	no		ST7
CDKL5	Kinase	yes	2.7.11.22	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
STXBP1	Other/Unknown	no		Sec1-like, Sec1-like_dom2, Sec1-like_sf
USP8	Protease	yes	3.4.19.12	Peptidase_C19_UCH, Rhodanese-like_dom, USP8_dimer
FRRS1L	Other/Unknown	no		DOMON_domain, FRRS1L
CACNA2D1	Other/Unknown	no		VWF_A, VWA_N, VDCC_a2/dsu
PIGQ	Enzyme (other)	yes	2.4.1.198	PigQ/GPI1
CAMK2G	Kinase	yes	2.7.11.17	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
TRIM8	Transcription factor	no		Znf_RING, Znf_RING/FYVE/PHD, Znf_RING_CS
ARHGEF15	Other/Unknown	no		DH_dom, PH-like_dom_sf, DBL_dom_sf
TMEM63B	GPCR	yes		CSC1/OSCA1-like_7TM, CSC1/OSCA1-like_cyt, CSC1/OSCA1-like_N
ARX	Transcription factor	no		HD, OAR_dom, Homeodomain-like_sf
CELSR1	GPCR	yes		EGF-type_Asp/Asn_hydroxyl_site, GPS, EGF
MAGI2	Kinase	yes		WW_dom, PDZ, Guanylate_kin-like_dom
DOCK7	Other/Unknown	no		DOCK_C/D_N, DOCK, C2_DOCK-type_domain
SLC25A22	Transporter	yes		MCP, MCP_transmembrane, MCP_dom_sf
CSNK1E	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
NECAP1	Other/Unknown	no		PH-like_dom_sf, NECAP_PHear
DMXL2	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, Rav1p_C
PIGP	Enzyme (other)	yes	2.4.1.198	PIG-P, PIG-P_GPI19, GPI_Anchor_Biosynth
FLNA	Antibody/Immunoglobulin	yes		Filamin/ABP280_rpt, Actinin_actin-bd_CS, CH_dom
GABRA4	Other/Unknown	no		GABAAa_rcpt, GABBAa4_rcpt, GABAA/Glycine_rcpt
GABRB3	Other/Unknown	no		GABAAb_rcpt, GABAA/Glycine_rcpt, Neurotrans-gated_channel_TM
GABRG1	Other/Unknown	no		GABRG-1/4, GABBAg1_rcpt, GABAA/Glycine_rcpt
GTF3C3	Other/Unknown	no		TPR-like_helical_dom_sf, TPR_rpt, Tfc4/TFIIIC-102/Sfc4
KCNQ3	Ion channel	yes		K_chnl_volt-dep_KCNQ, K_chnl_volt-dep_KCNQ3, Ion_trans_dom
NEUROD2	Transcription factor	no		bHLH_dom, TF_bHLH_NeuroD, NeuroD_DUF
ATP6V0C	Other/Unknown	no		ATPase_proteolipid_csu, ATPase_proteolipid_c-like_dom, ATPase_proteolipid_su_C_euk
PNKP	Phosphatase	yes	2.7.1.78	HAD-SF_hydro_IIIA, PNKP, Polynucleotide_phosphatase
TAF1	Transcription factor	no	2.3.1.48	Bromodomain, TAF_II_230-bd, TAF1_animal
ACE2	Protease	yes	3.4.15.1	Peptidase_M2, Collectrin_dom
CACNA1E	Ion channel	yes		EF_hand_dom, VDCCAlpha1, VDCC_R_a1su
PORCN	Enzyme (other)	yes	2.3.1.250	MBOAT_fam, LPLAT_7/PORCN-like
PGAP2	Other/Unknown	no		CWH43_N, PGAP2
SETD2	Scaffold/PPI	no	2.1.1.359	WW_dom, SET_dom, Post-SET_dom
DEPDC5	Other/Unknown	no		DEP_dom, IML1, WH-like_DNA-bd_sf
CHD8	Other/Unknown	no		SNF2_N, Chromo/chromo_shadow_dom, Helicase_C-like
COL5A2	Other/Unknown	no		Fib_collagen_C, VWF_dom, Collagen

Expression context

Cohort genes with no expression data: 0.

64 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)	65
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cortical plate	14
Brodmann (1909) area 23	11
calcaneal tendon	9
middle temporal gyrus	8
ganglionic eminence	7
right hemisphere of cerebellum	6
endothelial cell	6
sural nerve	6
ventricular zone	6
colonic epithelium	5
cerebellar cortex	4
right uterine tube	4
buccal mucosa cell	3
lateral nuclear group of thalamus	3
skin of abdomen	3
frontal pole	3
skeletal muscle tissue of biceps brachii	3
medial globus pallidus	3
lower esophagus mucosa	3
adrenal tissue	3

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SCN1B	133	ubiquitous	marker	primary visual cortex, right hemisphere of cerebellum, cerebellum
SCN2A	187	broad	marker	middle temporal gyrus, Brodmann (1909) area 23, cerebellar vermis
SCN3A	221	broad	marker	endothelial cell, cortical plate, middle temporal gyrus
CASK	284	ubiquitous	marker	buccal mucosa cell, hair follicle, cortical plate
GNAO1	261	broad	marker	cortical plate, superficial temporal artery, entorhinal cortex
KCNA1	151	broad	marker	endothelial cell, Brodmann (1909) area 23, middle temporal gyrus
ZFHX3	274	ubiquitous	marker	saphenous vein, buccal mucosa cell, synovial joint
RYR3	233	broad	marker	diaphragm, sural nerve, right hemisphere of cerebellum
SCN1A	154	tissue_specific	marker	Brodmann (1909) area 23, lateral nuclear group of thalamus, primary visual cortex
SNAP25	220	broad	marker	pons, cerebellar cortex, cerebellum
SIK1	138	not_expressed	marker	mucosa of stomach, skin of abdomen, zone of skin
SPTAN1	293	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
ST7	281	broad	marker	cortical plate, ventricular zone, ganglionic eminence
CDKL5	257	ubiquitous	marker	frontal pole, Brodmann (1909) area 23, cortical plate
STXBP1	287	ubiquitous	marker	middle temporal gyrus, lateral nuclear group of thalamus, Brodmann (1909) area 23
USP8	284	ubiquitous	marker	calcaneal tendon, sural nerve, colonic epithelium
FRRS1L	189	broad	marker	middle temporal gyrus, Brodmann (1909) area 23, orbitofrontal cortex
CACNA2D1	261	ubiquitous	marker	biceps brachii, skeletal muscle tissue of biceps brachii, skeletal muscle tissue of rectus abdominis
PIGQ	186	broad	marker	right lobe of thyroid gland, right uterine tube, left lobe of thyroid gland
CAMK2G	287	ubiquitous	marker	frontal pole, postcentral gyrus, right frontal lobe
TRIM8	292	ubiquitous	marker	endothelial cell, nasal cavity epithelium, medial globus pallidus
ARHGEF15	198	broad	marker	apex of heart, omental fat pad, peritoneum
TMEM63B	254	ubiquitous	marker	cardiac muscle of right atrium, cortical plate, left ventricle myocardium
ARX	162	broad	marker	left ovary, ovary, right ovary
CELSR1	224	ubiquitous	marker	ventricular zone, lower esophagus mucosa, bronchial epithelial cell
MAGI2	267	ubiquitous	marker	calcaneal tendon, corpus callosum, Brodmann (1909) area 23
DOCK7	260	ubiquitous	marker	ventricular zone, calcaneal tendon, sural nerve
SLC25A22	228	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
CSNK1E	275	ubiquitous	marker	cortical plate, ganglionic eminence, left ovary
NECAP1	279	ubiquitous	marker	cortical plate, prefrontal cortex, cerebellar cortex

Protein interactions among cohort

Intra-cohort edges: 47.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ACE2	5,940
ATRX	5,796
HUWE1	5,793
FLNA	5,321
CHD8	4,791
SETD2	4,668
CASK	4,223
TAF1	3,445
GNAO1	3,437
ATP6V0C	3,353

Intra-cohort edges

A	B	Sources
ARHGEF6	OPHN1	string_interaction
ARX	CDKL5	string_interaction
ARX	PNKP	string_interaction
ARX	SCN1A	string_interaction
ARX	SETD2	biogrid_interaction, intact
ARX	SLC25A22	string_interaction
ARX	SPTAN1	string_interaction
ARX	STXBP1	string_interaction
CACNA1E	CACNA2D1	string_interaction
CAMK2G	FLNA	biogrid_interaction
CDKL5	GABRB3	string_interaction
CDKL5	SCN1A	string_interaction
CDKL5	SCN2A	string_interaction
CDKL5	SLC25A22	string_interaction
CDKL5	STXBP1	string_interaction
CEP290	CSNK1E	biogrid_interaction
CHD8	SCN2A	string_interaction
COL5A2	GTF3C3	string_interaction
CSNK1E	PPP2R5D	biogrid_interaction
GABRA4	GABRB3	intact
GABRA4	GABRG1	string_interaction
GABRA4	GABRG2	intact
GABRB3	GABRG2	intact
GABRB3	SCN1A	string_interaction
GABRG1	GABRG2	biogrid_interaction, intact
GABRG2	SCN1A	string_interaction
GABRG2	SCN1B	string_interaction
GABRG2	SCN2A	string_interaction
KCNA1	SCN2A	string_interaction
KCNQ3	SCN1A	string_interaction
KCNQ3	SCN2A	string_interaction
OPHN1	ZC4H2	string_interaction
PIGP	PIGQ	biogrid_interaction, intact, string_interaction
PNKP	SLC25A22	string_interaction
SCN1A	SCN1B	biogrid_interaction, string_interaction
SCN1A	SCN2A	biogrid_interaction, string_interaction
SCN1A	SLC25A22	string_interaction
SCN1A	STXBP1	string_interaction
SCN1B	SCN2A	string_interaction
SCN1B	SCN3A	string_interaction
SCN2A	SCN3A	intact
SCN2A	SLC25A22	string_interaction
SCN2A	STXBP1	string_interaction
SLC25A22	SPTAN1	string_interaction
SLC25A22	STXBP1	string_interaction
SNAP25	STXBP1	biogrid_interaction, intact
SPTAN1	STXBP1	string_interaction

Structural data

PDB: 44 · AlphaFold-only: 21 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ACE2	Q9BYF1	345
GABRB3	P28472	95
GNAO1	P09471	86
GABRG2	P18507	75
TAF1	P21675	64
SETD2	Q9BYW2	43
SCN1B	Q07699	39
CACNA2D1	P54289	30
FLNA	P21333	26
CASK	O14936	22
HUWE1	Q7Z6Z7	19
KCNQ3	O43525	16
SNAP25	P60880	14
DCX	O43602	14
ATRX	P46100	12
DEPDC5	O75140	11
HCFC1	P51610	11
RYR3	Q15413	10
USP8	P40818	9
ATP6V0C	P27449	9
SPTAN1	Q13813	7
PORCN	Q9H237	7
SCN2A	Q99250	5
MAGI2	Q86UL8	5
GABRA4	P48169	5
CACNA1E	Q15878	5
OCRL	Q01968	5
ZFHX3	Q15911	3
CDKL5	O76039	3
SCN3A	Q9NY46	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PGAP2	Q9UHJ9	90.00
SRPX2	O60687	86.75
PIGP	P57054	82.42
PHKA2	P46019	81.36
ST7	Q9NRC1	80.60
FRRS1L	Q9P0K9	80.60
GABRG1	Q8N1C3	79.06
KCNA1	Q09470	78.74
SLC25A22	Q9H936	78.48
OPHN1	O60890	74.86
TRIM8	Q9BZR9	72.26
PIGQ	Q9BRB3	64.70
ARHGEF15	O94989	62.96
SIK1	P57059	61.31
NEUROD2	Q15784	60.91
CEP290	O15078	60.90
MED13L	Q71F56	56.79
ARX	Q96QS3	56.51
COL5A2	P05997	53.15
MAGEL2	Q9UJ55	44.28
DMXL2	Q8TDJ6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 346. Enrichment computed across 65 evidence-associated genes (52 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 52 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Interaction between L1 and Ankyrins	6	42.5×	2e-06	SCN1B, SCN2A, SCN3A, SCN1A, SPTAN1, KCNQ3
Phase 0 - rapid depolarisation	5	33.3×	6e-05	SCN1B, SCN2A, SCN3A, SCN1A, CAMK2G
L1CAM interactions	6	13.9×	5e-04	SCN1B, SCN2A, SCN3A, SCN1A, SPTAN1, KCNQ3
Cardiac conduction	6	12.6×	7e-04	SCN1B, SCN2A, SCN3A, RYR3, SCN1A, CAMK2G
Muscle contraction	6	8.9×	0.004	SCN1B, SCN2A, SCN3A, RYR3, SCN1A, CAMK2G
Dopamine Neurotransmitter Release Cycle	3	28.6×	0.008	CASK, SNAP25, STXBP1
Nephrin family interactions	3	27.4×	0.008	CASK, SPTAN1, MAGI2
Integration of energy metabolism	4	13.5×	0.008	SNAP25, STXBP1, CACNA1E, PPP2R5D
Sensory Perception	5	9.2×	0.008	SCN1B, SCN2A, SCN3A, SNAP25, SPTAN1
Sensory perception of taste	3	19.4×	0.017	SCN1B, SCN2A, SCN3A
GABA receptor activation	3	18.3×	0.018	GABRA4, GABRB3, GABRG2
Sensory perception of sweet, bitter, and umami (glutamate) taste	3	16.1×	0.024	SCN1B, SCN2A, SCN3A
Axon guidance	6	5.2×	0.026	SCN1B, SCN2A, SCN3A, SCN1A, SPTAN1, KCNQ3
Neuronal System	6	5.1×	0.026	KCNA1, SNAP25, STXBP1, CACNA1E, CAMK2G, KCNQ3
Nervous system development	6	5.0×	0.029	SCN1B, SCN2A, SCN3A, SCN1A, SPTAN1, KCNQ3
Regulation of insulin secretion	3	12.7×	0.036	SNAP25, STXBP1, CACNA1E
Acetylcholine Neurotransmitter Release Cycle	2	25.8×	0.047	SNAP25, STXBP1
Cell-extracellular matrix interactions	2	25.8×	0.047	FLNA, ARHGEF6
Synthesis of glycosylphosphatidylinositol (GPI)	2	24.4×	0.047	PIGQ, PIGP
Serotonin Neurotransmitter Release Cycle	2	24.4×	0.047	SNAP25, STXBP1
Norepinephrine Neurotransmitter Release Cycle	2	24.4×	0.047	SNAP25, STXBP1
GABA synthesis, release, reuptake and degradation	2	24.4×	0.047	SNAP25, STXBP1
Sensory processing of sound by inner hair cells of the cochlea	3	9.4×	0.059	CASK, SNAP25, SPTAN1
Alternative Lengthening of Telomeres (ALT)	1	219.6×	0.061	ATRX
Defective Inhibition of DNA Recombination at Telomere	1	219.6×	0.061	ATRX
Diseases of Telomere Maintenance	1	219.6×	0.061	ATRX
Glutamate Neurotransmitter Release Cycle	2	17.6×	0.071	SNAP25, STXBP1
CDC42 GTPase cycle	4	5.6×	0.071	ARHGEF15, DOCK7, ARHGEF6, OPHN1
Cell-Cell communication	3	7.9×	0.076	SPTAN1, MAGI2, ARHGEF6
Syndecan interactions	2	16.3×	0.077	CASK, COL5A2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 65 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cardiac muscle cell action potential involved in contraction	5	54.0×	2e-05	SCN1B, SCN2A, SCN3A, SCN1A, CACNA2D1
membrane depolarization during action potential	3	77.8×	9e-04	SCN1B, SCN3A, SCN1A
inhibitory synapse assembly	4	38.4×	9e-04	GABRA4, GABRB3, GABRG1, GABRG2
gamma-aminobutyric acid signaling pathway	4	33.5×	9e-04	GABRA4, GABRB3, GABRG1, GABRG2
synaptic transmission, GABAergic	4	30.5×	9e-04	GABRA4, GABRB3, GABRG1, GABRG2
neuronal action potential	4	29.6×	9e-04	SCN2A, KCNA1, SCN1A, KCNQ3
negative regulation of synapse maturation	2	172.8×	0.003	ARHGEF15, NEUROD2
presynaptic dense core vesicle exocytosis	2	129.6×	0.005	SNAP25, STXBP1
nervous system development	8	5.7×	0.005	SCN2A, CAMK2G, MAGI2, ZC4H2, DCX, NEUROD2, OPHN1, PPP2R5D
chloride transmembrane transport	4	14.6×	0.009	GABRA4, GABRB3, GABRG1, GABRG2
cellular response to histamine	2	86.4×	0.011	GABRB3, GABRG2
cellular response to magnesium ion	2	74.1×	0.012	KCNA1, RYR3
GPI anchor biosynthetic process	3	22.9×	0.012	PIGQ, PGAP2, PIGP
sodium ion transmembrane transport	4	12.5×	0.012	SCN1B, SCN2A, SCN3A, SCN1A
cellular response to nerve growth factor stimulus	3	21.6×	0.013	USP8, MAGI2, CSNK1E
neuronal action potential propagation	2	43.2×	0.032	SCN1B, SCN1A
detection of mechanical stimulus involved in sensory perception of pain	2	34.6×	0.047	KCNA1, SCN1A
sodium ion transport	3	12.5×	0.053	SCN2A, SCN3A, SCN1A
reproductive behavior	1	259.3×	0.058	GABRB3
corticospinal neuron axon guidance	1	259.3×	0.058	SCN1B
circadian sleep/wake cycle, REM sleep	1	259.3×	0.058	GABRB3
apoptosome assembly	1	259.3×	0.058	KCNQ3
regulation of action potential firing threshold	1	259.3×	0.058	KCNQ3
obsolete positive regulation of vesicle docking	1	259.3×	0.058	STXBP1
positive regulation of androgen receptor signaling pathway	1	259.3×	0.058	TAF1
regulation of membrane repolarization during atrial cardiac muscle cell action potential	1	259.3×	0.058	FLNA
regulation of membrane repolarization during cardiac muscle cell action potential	1	259.3×	0.058	FLNA
regulation of acrosomal vesicle exocytosis	1	259.3×	0.058	STXBP1
nerve development	2	28.8×	0.058	SCN1A, KCNQ3
cellular response to ATP	2	27.3×	0.058	RYR3, TAF1

Therapeutics

Drug target analysis

Approved (phase 4): 17 · Phase ≥3: 18 · Phased (≥1): 25 · Undrugged: 40

Druggability breadth: 39 of 65 evidence-associated genes (60%) 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
SCN2A	BEPRIDIL
SCN3A	BEPRIDIL
CASK	FEDRATINIB
KCNA1	NIFEDIPINE
SCN1A	MEXILETINE HYDROCHLORIDE
SIK1	FEDRATINIB
CDKL5	FEDRATINIB
CACNA2D1	PREGABALIN
CAMK2G	MOMELOTINIB
CSNK1E	AFATINIB
GABRA4	ENZALUTAMIDE
GABRB3	LINDANE
GABRG1	ENZALUTAMIDE
KCNQ3	FLUPIRTINE
ACE2	CAPTOPRIL
CACNA1E	NIMODIPINE
GABRG2	ENZALUTAMIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCN2A	99	4
SCN1A	94	4
SCN3A	93	4
GABRG2	55	4
CAMK2G	39	4
CSNK1E	37	4
GABRB3	32	4
SIK1	19	4
GABRA4	18	4
GABRG1	15	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEPRIDIL	4	SCN1A, SCN2A, SCN3A
DIBUCAINE	4	SCN1A, SCN2A, SCN3A
ARTICAINE	4	SCN1A, SCN2A, SCN3A
BUPIVACAINE	4	SCN1A, SCN2A, SCN3A
IMIPRAMINE	4	SCN1A, SCN2A, SCN3A
DROPERIDOL	4	SCN1A, SCN2A, SCN3A
DICYCLOMINE	4	SCN1A, SCN2A, SCN3A
TETRABENAZINE	4	SCN1A, SCN2A, SCN3A
PHENIRAMINE	4	SCN1A, SCN2A, SCN3A
PRILOCAINE	4	SCN1A, SCN2A, SCN3A
PROPOXYCAINE	4	SCN1A, SCN2A, SCN3A
PROPARACAINE	4	SCN1A, SCN2A, SCN3A
HEXYLCAINE	4	SCN1A, SCN2A, SCN3A
PRAMOXINE	4	SCN1A, SCN2A, SCN3A
BENOXINATE	4	SCN1A, SCN2A, SCN3A
QUINIDINE	4	SCN1A, SCN2A, SCN3A
FELODIPINE	4	SCN1A, SCN2A, SCN3A
PHENYTOIN	4	SCN1A, SCN2A, SCN3A
QUININE	4	SCN1A, SCN2A, SCN3A
NISOLDIPINE	4	SCN1A, SCN2A, SCN3A
NIFEDIPINE	4	KCNA1, SCN1A, SCN2A, SCN3A
PRAZOSIN	4	SCN1A, SCN2A, SCN3A
DILTIAZEM	4	SCN1A, SCN2A, SCN3A
PRENYLAMINE	4	SCN1A, SCN2A, SCN3A
COCAINE	4	SCN1A, SCN2A, SCN3A
TRIFLUOPERAZINE	4	SCN1A, SCN2A, SCN3A
CINNARIZINE	4	SCN1A, SCN2A, SCN3A
THIORIDAZINE	4	SCN1A, SCN2A, SCN3A
ETIDOCAINE	4	SCN1A, SCN2A, SCN3A
CHLORPHENIRAMINE	4	SCN1A, SCN2A, SCN3A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 15.

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

Symbol	Assays	Type breakdown
GABRG2	1,155	Binding:940, Functional:201, ADMET:10, Toxicity:4
GABRB3	887	Binding:722, Functional:156, ADMET:6, Toxicity:3
CSNK1E	420	Binding:416, ADMET:2, Functional:2
CAMK2G	291	Binding:290, Functional:1
GABRA4	273	Binding:233, Functional:36, Toxicity:3, ADMET:1
SIK1	210	Binding:205, Toxicity:4, ADMET:1
SCN2A	203	Binding:172, Functional:20, ADMET:10, Toxicity:1
GABRG1	188	Binding:169, Functional:15, Toxicity:3, ADMET:1
SCN1A	149	Binding:115, Functional:18, ADMET:14, Toxicity:2
TAF1	140	Binding:139, Functional:1
ACE2	107	Binding:98, Functional:6, ADMET:3
SCN3A	102	Binding:79, Functional:18, ADMET:4, Toxicity:1
KCNQ3	97	Binding:91, Functional:4, ADMET:1, Toxicity:1
CASK	92	Binding:92
CDKL5	74	Binding:74
SETD2	64	Binding:64
KCNA1	59	Binding:52, Functional:6, Toxicity:1
USP8	54	Binding:51, Functional:3
PHKA2	48	Binding:48
CACNA2D1	47	Binding:45, ADMET:1, Toxicity:1
PORCN	31	Binding:31
SCN1B	15	Binding:7, ADMET:6, Toxicity:2
CACNA1E	14	Binding:14
GNAO1	12	Functional:10, Binding:2
PNKP	8	Binding:8
HCFC1	8	Binding:8
SPTAN1	7	Binding:7
FLNA	7	Binding:7
CHD8	7	Binding:7
ARHGEF6	6	Binding:6
HUWE1	4	Binding:3, Functional:1
RYR3	2	Binding:2
STXBP1	1	Binding:1
GTF3C3	1	Binding:1
ATP6V0C	1	Binding:1
DCX	1	Binding:1
PPP2R5D	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CASK	2.7.11.1, 2.7.4.8	non-specific serine/threonine protein kinase, guanylate kinase
CDKL5	2.7.11.22	cyclin-dependent kinase
USP8	3.4.19.12	ubiquitinyl hydrolase 1
PIGQ	2.4.1.198	phosphatidylinositol N-acetylglucosaminyltransferase
CAMK2G	2.7.11.17	Ca2+/calmodulin-dependent protein kinase
CSNK1E	2.7.11.1	non-specific serine/threonine protein kinase
PIGP	2.4.1.198	phosphatidylinositol N-acetylglucosaminyltransferase
PNKP	2.7.1.78, 3.1.3.32	polynucleotide 5’-hydroxyl-kinase, polynucleotide 3’-phosphatase
TAF1	2.3.1.48	histone acetyltransferase
ACE2	3.4.15.1, 3.4.17.23	peptidyl-dipeptidase A, angiotensin-converting enzyme 2
PORCN	2.3.1.250	[Wnt protein] O-palmitoleoyl transferase
SETD2	2.1.1.359	[histone H3]-lysine36 N-trimethyltransferase
HUWE1	2.3.2.26	HECT-type E3 ubiquitin transferase
OCRL	3.1.3.36	phosphoinositide 5-phosphatase
PHKA2	2.7.11.19	phosphorylase kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SCN2A	203
SCN3A	102
SCN1A	149
SIK1	210
CAMK2G	291
CSNK1E	420
GABRA4	273
GABRB3	887
GABRG1	188
TAF1	140
ACE2	107
GABRG2	1,155

Pharmacogenomics

Cohort genes with a PharmGKB record: 65; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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)
BEPRIDIL	4	SCN1A, SCN2A, SCN3A
DIBUCAINE	4	SCN1A, SCN2A, SCN3A
ARTICAINE	4	SCN1A, SCN2A, SCN3A
BUPIVACAINE	4	SCN1A, SCN2A, SCN3A
IMIPRAMINE	4	SCN1A, SCN2A, SCN3A
DROPERIDOL	4	SCN1A, SCN2A, SCN3A
DICYCLOMINE	4	SCN1A, SCN2A, SCN3A
TETRABENAZINE	4	SCN1A, SCN2A, SCN3A
PHENIRAMINE	4	SCN1A, SCN2A, SCN3A
PRILOCAINE	4	SCN1A, SCN2A, SCN3A
PROPOXYCAINE	4	SCN1A, SCN2A, SCN3A
PROPARACAINE	4	SCN1A, SCN2A, SCN3A
HEXYLCAINE	4	SCN1A, SCN2A, SCN3A
PRAMOXINE	4	SCN1A, SCN2A, SCN3A
BENOXINATE	4	SCN1A, SCN2A, SCN3A
QUINIDINE	4	SCN1A, SCN2A, SCN3A
FELODIPINE	4	SCN1A, SCN2A, SCN3A
PHENYTOIN	4	SCN1A, SCN2A, SCN3A
QUININE	4	SCN1A, SCN2A, SCN3A
NISOLDIPINE	4	SCN1A, SCN2A, SCN3A
NIFEDIPINE	4	KCNA1, SCN1A, SCN2A, SCN3A
PRAZOSIN	4	SCN1A, SCN2A, SCN3A
DILTIAZEM	4	SCN1A, SCN2A, SCN3A
PRENYLAMINE	4	SCN1A, SCN2A, SCN3A
COCAINE	4	SCN1A, SCN2A, SCN3A
TRIFLUOPERAZINE	4	SCN1A, SCN2A, SCN3A
CINNARIZINE	4	SCN1A, SCN2A, SCN3A
THIORIDAZINE	4	SCN1A, SCN2A, SCN3A
ETIDOCAINE	4	SCN1A, SCN2A, SCN3A
CHLORPHENIRAMINE	4	SCN1A, SCN2A, SCN3A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	17	SCN2A, SCN3A, CASK, KCNA1, SCN1A, SIK1, CDKL5, CACNA2D1, CAMK2G, CSNK1E (+7 more)
B	Phased (≥1) drug, not yet approved	8	SCN1B, SPTAN1, FLNA, TAF1, PORCN, SETD2, CHD8, HCFC1
C	Druggable family + PDB, no drug	8	RYR3, USP8, TMEM63B, CELSR1, MAGI2, PNKP, HUWE1, OCRL
D	Druggable family + AlphaFold only, no drug	5	PIGQ, SLC25A22, PIGP, SRPX2, PHKA2
E	Difficult family or no structure, no drug	27	GNAO1, ZFHX3, SNAP25, ST7, STXBP1, FRRS1L, TRIM8, ARHGEF15, ARX, DOCK7 (+17 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ARX	0	CDKL5
SLC25A22	0	CDKL5
GNAO1	12	—
ZFHX3	0	—
RYR3	2	—
SNAP25	0	—
ST7	0	—
STXBP1	1	—
USP8	54	—
FRRS1L	0	—
PIGQ	0	—
TRIM8	0	—
ARHGEF15	0	—
TMEM63B	0	—
CELSR1	0	—
MAGI2	0	—
DOCK7	0	—
NECAP1	0	—
DMXL2	0	—
PIGP	0	—
GTF3C3	1	—
NEUROD2	0	—
ATP6V0C	1	—
PNKP	8	—
PGAP2	0	—
DEPDC5	0	—
COL5A2	0	—
MED13L	0	—
ZC4H2	0	—
DCX	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 12.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	5
PHASE3	2
PHASE1/PHASE2	2
PHASE2	1
EARLY_PHASE1	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06719141	PHASE3	RECRUITING	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathies (DEE)
NCT06908226	PHASE3	ENROLLING_BY_INVITATION	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathy (DEE)
NCT05364021	PHASE1/PHASE2	COMPLETED	Study to Investigate LP352 in Subjects With Developmental and Epileptic Encephalopathies
NCT05626634	PHASE2	COMPLETED	Open-label, Long-term Safety Study of LP352 in Subjects With Developmental and Epileptic Encephalopathy
NCT06983158	PHASE1/PHASE2	SUSPENDED	A Clinical Trial of CAP-002 Gene Therapy in Pediatric Patients With Syntaxin-Binding Protein 1 (STXBP1) Encephalopathy
NCT06700811	PHASE1	RECRUITING	Ketogenic Diet for Prevention of Epileptic Spasms in Infantile Onset Genetic Epilepsies
NCT04937062	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	Phenylbutyrate for Monogenetic Developmental and Epileptic Encephalopathy
NCT06149663	Not specified	AVAILABLE	Intermediate-Size Expanded Access Protocol (EAP) for LP352
NCT06380192	Not specified	RECRUITING	Developmental and Epileptic Encephalopathy of Genetic Etiology: Natural History Through Reuse of Clinical Data
NCT07396883	Not specified	NOT_YET_RECRUITING	Developmental and Epileptic Encephalopathies Diagnosed Via Long-read Genome Sequencing
NCT07531511	Not specified	NOT_YET_RECRUITING	SLC6A1-NDD Prospective Longitudinal Natural History Study
NCT07585643	Not specified	NOT_YET_RECRUITING	IBIS - Investigating Reliability of BIS and SEDLINE Monitoring in Children With Developmental and Epileptic Encephalopathies (DEE).

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
GLYCEROL PHENYLBUTYRATE	4	1
BEXICASERIN	2	1