Fetal akinesia deformation sequence 1

Summary

Fetal akinesia deformation sequence 1 (MONDO:0100101) is a disease caused by MUSK (GenCC Strong), with 52 cohort genes. The dominant Reactome pathway is Muscle contraction (6 cohort genes).

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Causal gene: MUSK (GenCC Strong)
• Cohort genes: 52
• ClinVar variants: 2,459
• Phenotypes (HPO): 24

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 1 000 000	0.6	Europe	Validated
Point prevalence	<1 / 1 000 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

24 HPO clinical features (Orphanet curated; top 24 by frequency):

HPO ID	Term	Frequency
HP:0000347	Micrognathia	Very frequent (80-99%)
HP:0001262	Excessive daytime somnolence	Very frequent (80-99%)
HP:0001511	Intrauterine growth retardation	Very frequent (80-99%)
HP:0001989	Fetal akinesia sequence	Very frequent (80-99%)
HP:0002089	Pulmonary hypoplasia	Very frequent (80-99%)
HP:0002093	Respiratory insufficiency	Very frequent (80-99%)
HP:0002304	Akinesia	Very frequent (80-99%)
HP:0002375	Hypokinesia	Very frequent (80-99%)
HP:0002804	Arthrogryposis multiplex congenita	Very frequent (80-99%)
HP:0002828	Multiple joint contractures	Very frequent (80-99%)
HP:0010489	Absent palmar crease	Very frequent (80-99%)
HP:0100490	Camptodactyly of finger	Very frequent (80-99%)
HP:0000028	Cryptorchidism	Frequent (30-79%)
HP:0000175	Cleft palate	Frequent (30-79%)
HP:0000316	Hypertelorism	Frequent (30-79%)
HP:0000358	Posteriorly rotated ears	Frequent (30-79%)
HP:0000476	Cystic hygroma	Frequent (30-79%)
HP:0001561	Polyhydramnios	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0003700	Generalized amyotrophy	Frequent (30-79%)
HP:0005280	Depressed nasal bridge	Frequent (30-79%)
HP:0001059	Pterygium	Occasional (5-29%)
HP:0001305	Dandy-Walker malformation	Occasional (5-29%)
HP:0005245	Intestinal hypoplasia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	fetal akinesia deformation sequence 1
Mondo ID	MONDO:0100101
OMIM	208150
Orphanet	994
DOID	DOID:0111377
UMLS	C1276035
MedGen	220903
GARD	0026048
Is cancer (heuristic)	no

Also known as: FADS1 · Pena-Shokeir syndrome type 1 · Pena-Shokeir syndrome, type 1

Data availability: 2,459 ClinVar variants · 7 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › fetal akinesia deformation sequence › fetal akinesia deformation sequence 1

Related subtypes (4): fetal akinesia syndrome, X-linked, fetal akinesia deformation sequence 2, fetal akinesia deformation sequence 3, fetal akinesia deformation sequence 4

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

600 retrieved; paginated sample, class counts are floors:

257 uncertain significance, 235 likely benign, 25 pathogenic, 25 benign, 16 conflicting classifications of pathogenicity, 16 pathogenic/likely pathogenic, 15 likely pathogenic, 11 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069243	NM_173660.5(DOK7):c.1387G>T (p.Glu463Ter)	DOK7	Pathogenic	criteria provided, single submitter
1074328	NM_173660.5(DOK7):c.1267C>T (p.Gln423Ter)	DOK7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075034	NM_173660.5(DOK7):c.978_1018del (p.Gln326fs)	DOK7	Pathogenic	criteria provided, single submitter
1197436	NM_173660.5(DOK7):c.1441dup (p.His481fs)	DOK7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1273	NM_173660.5(DOK7):c.1124_1127dup (p.Ala378fs)	DOK7	Pathogenic	criteria provided, multiple submitters, no conflicts
1274	NM_173660.5(DOK7):c.1263dup (p.Ser422fs)	DOK7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1276	NM_173660.5(DOK7):c.1339_1342dup (p.Gly448fs)	DOK7	Pathogenic	criteria provided, multiple submitters, no conflicts
1277	NM_173660.5(DOK7):c.1143dup (p.Glu382fs)	DOK7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1279	NM_173660.5(DOK7):c.601C>T (p.Arg201Ter)	DOK7	Pathogenic	criteria provided, multiple submitters, no conflicts
1282	NM_173660.5(DOK7):c.1378dup (p.Gln460fs)	DOK7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453023	NM_173660.5(DOK7):c.299G>A (p.Trp100Ter)	DOK7	Pathogenic	criteria provided, single submitter
1454703	NM_173660.5(DOK7):c.1323del (p.Cys442fs)	DOK7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1459045	NC_000004.11:g.(?3465103)(3465298_?)del	DOK7	Pathogenic	criteria provided, single submitter
1275	NM_173660.5(DOK7):c.548_551del (p.Phe183fs)	LOC126806951	Pathogenic	criteria provided, single submitter
1068787	NM_005592.4(MUSK):c.581dup (p.Asn194fs)	MUSK	Pathogenic	criteria provided, single submitter
1452397	NM_005592.4(MUSK):c.2170C>T (p.Arg724Ter)	MUSK	Pathogenic	criteria provided, single submitter
1458702	NM_005592.4(MUSK):c.582del (p.Asn194fs)	MUSK	Pathogenic	criteria provided, single submitter
1460076	NC_000009.11:g.(?113449377)(113457830_?)del	MUSK	Pathogenic	criteria provided, single submitter
1460264	NC_000009.11:g.(?113431185)(113550138_?)del	MUSK	Pathogenic	criteria provided, single submitter
137629	NM_001378183.1(PIEZO2):c.8396G>A (p.Arg2799His)	PIEZO2	Pathogenic	criteria provided, multiple submitters, no conflicts
1067929	NM_005055.5(RAPSN):c.531+1G>T	RAPSN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070359	NM_005055.5(RAPSN):c.418C>T (p.Gln140Ter)	RAPSN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072315	NM_005055.5(RAPSN):c.599G>A (p.Trp200Ter)	RAPSN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073877	NM_005055.5(RAPSN):c.291C>A (p.Cys97Ter)	RAPSN	Pathogenic	criteria provided, multiple submitters, no conflicts
1073878	NM_005055.5(RAPSN):c.46dup (p.Leu16fs)	RAPSN	Pathogenic	criteria provided, multiple submitters, no conflicts
1076821	NM_005055.5(RAPSN):c.838G>T (p.Gly280Ter)	RAPSN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323519	NM_005055.5(RAPSN):c.300_319del (p.His100fs)	RAPSN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1324987	NM_005055.5(RAPSN):c.679G>T (p.Glu227Ter)	RAPSN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1405025	NM_005055.5(RAPSN):c.537C>A (p.Tyr179Ter)	RAPSN	Pathogenic	criteria provided, single submitter
1407552	NM_005055.5(RAPSN):c.7C>T (p.Gln3Ter)	RAPSN	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 36 · Orphanet: 106 · 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
RAPSN	Definitive	Autosomal recessive	fetal akinesia deformation sequence 2	9
DOK7	Strong	Autosomal recessive	fetal akinesia deformation sequence 3	8
MUSK	Strong	Autosomal recessive	fetal akinesia deformation sequence 1	6
NUP88	Strong	Autosomal recessive	fetal akinesia deformation sequence 4	3
MYOD1	Supportive	Autosomal recessive	fetal akinesia deformation sequence 1	4
SLC18A3	Supportive	Autosomal recessive	fetal akinesia deformation sequence 1	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DOK7	Orphanet:98913	Postsynaptic congenital myasthenic syndrome
DOK7	Orphanet:994	Fetal akinesia deformation sequence
MUSK	Orphanet:98913	Postsynaptic congenital myasthenic syndrome
MUSK	Orphanet:994	Fetal akinesia deformation sequence
RAPSN	Orphanet:33108	Lethal multiple pterygium syndrome
RAPSN	Orphanet:98913	Postsynaptic congenital myasthenic syndrome
RAPSN	Orphanet:994	Fetal akinesia deformation sequence
SLC18A3	Orphanet:98914	Presynaptic congenital myasthenic syndromes
SLC18A3	Orphanet:994	Fetal akinesia deformation sequence
MYOD1	Orphanet:994	Fetal akinesia deformation sequence
NUP88	Orphanet:994	Fetal akinesia deformation sequence
ROR2	Orphanet:1507	Autosomal recessive Robinow syndrome
ROR2	Orphanet:572385	Brachydactyly type B1
RYR1	Orphanet:169186	Autosomal recessive centronuclear myopathy
RYR1	Orphanet:169189	Autosomal dominant centronuclear myopathy
RYR1	Orphanet:178145	Moderate multiminicore disease with hand involvement
RYR1	Orphanet:324581	Benign Samaritan congenital myopathy
RYR1	Orphanet:33108	Lethal multiple pterygium syndrome
RYR1	Orphanet:423	Malignant hyperthermia of anesthesia
RYR1	Orphanet:424107	Congenital myopathy with myasthenic-like onset
RYR1	Orphanet:466650	Exercise-induced malignant hyperthermia
RYR1	Orphanet:597	Central core disease
RYR1	Orphanet:700188	Calf-predominant weakness-gastrocnemius medialis atrophy-distal myopathy
RYR1	Orphanet:98905	Congenital multicore myopathy with external ophthalmoplegia
RYR1	Orphanet:99741	King-Denborough syndrome
SCN4A	Orphanet:681	Hypokalemic periodic paralysis
SCN4A	Orphanet:682	Hyperkalemic periodic paralysis
SCN4A	Orphanet:684	Paramyotonia congenita of Von Eulenburg
SCN4A	Orphanet:98913	Postsynaptic congenital myasthenic syndrome
SCN4A	Orphanet:99734	Myotonia fluctuans
SCN4A	Orphanet:99735	Myotonia permanens
SCN4A	Orphanet:99736	Acetazolamide-responsive myotonia
SCN5A	Orphanet:101016	Romano-Ward syndrome
SCN5A	Orphanet:130	Brugada syndrome
SCN5A	Orphanet:1344	Isolated atrial standstill
SCN5A	Orphanet:154	Familial isolated dilated cardiomyopathy
SCN5A	Orphanet:166282	Hereditary sick sinus syndrome
SCN5A	Orphanet:228140	Idiopathic ventricular fibrillation
SCN5A	Orphanet:334	Hereditary atrial fibrillation
SCN5A	Orphanet:871	Hereditary progressive cardiac conduction defect
SCN8A	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
SCN8A	Orphanet:306	Self-limited infantile epilepsy
SCN8A	Orphanet:352582	Familial infantile myoclonic epilepsy
SCN8A	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
SPI1	Orphanet:33110	Autosomal non-syndromic agammaglobulinemia
TMPO	Orphanet:154	Familial isolated dilated cardiomyopathy
ACTA1	Orphanet:171430	Severe congenital nemaline myopathy
ACTA1	Orphanet:171433	Intermediate nemaline myopathy
ACTA1	Orphanet:171436	Typical nemaline myopathy
ACTA1	Orphanet:171439	Childhood-onset nemaline myopathy

Cohort genes → proteins

52 cohort genes, 52 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	52

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DOK7	HGNC:26594	ENSG00000175920	Q18PE1	Protein Dok-7	gencc,clinvar
MUSK	HGNC:7525	ENSG00000030304	O15146	Muscle, skeletal receptor tyrosine-protein kinase	gencc,clinvar
RAPSN	HGNC:9863	ENSG00000165917	Q13702	43 kDa receptor-associated protein of the synapse	gencc,clinvar
SLC18A3	HGNC:10936	ENSG00000187714	Q16572	Vesicular acetylcholine transporter	gencc
MYOD1	HGNC:7611	ENSG00000129152	P15172	Myoblast determination protein 1	gencc
NUP88	HGNC:8067	ENSG00000108559	Q99567	Nuclear pore complex protein Nup88	gencc
ROR2	HGNC:10257	ENSG00000169071	Q01974	Tyrosine-protein kinase transmembrane receptor ROR2	clinvar
RYR1	HGNC:10483	ENSG00000196218	P21817	Ryanodine receptor 1	clinvar
SCN4A	HGNC:10591	ENSG00000007314	P35499	Sodium channel protein type 4 subunit alpha	clinvar
SCN5A	HGNC:10593	ENSG00000183873	Q14524	Sodium channel protein type 5 subunit alpha	clinvar
SCN8A	HGNC:10596	ENSG00000196876	Q9UQD0	Sodium channel protein type 8 subunit alpha	clinvar
SPI1	HGNC:11241	ENSG00000066336	P17947	Transcription factor PU.1	clinvar
TMPO	HGNC:11875	ENSG00000120802	P42166	Lamina-associated polypeptide 2, isoform alpha	clinvar
ACTA1	HGNC:129	ENSG00000143632	P68133	Actin, alpha skeletal muscle	clinvar
AVEN	HGNC:13509	ENSG00000169857	Q9NQS1	Cell death regulator Aven	clinvar
GFRA4	HGNC:13821	ENSG00000125861	Q9GZZ7	GDNF family receptor alpha-4	clinvar
ZEB2	HGNC:14881	ENSG00000169554	O60315	Zinc finger E-box-binding homeobox 2	clinvar
SETBP1	HGNC:15573	ENSG00000152217	Q9Y6X0	SET-binding protein	clinvar
SVEP1	HGNC:15985	ENSG00000165124	Q4LDE5	Sushi, von Willebrand factor type A, EGF and pentraxin domain-containing protein 1	clinvar
UNC50	HGNC:16046	ENSG00000115446	Q53HI1	Protein unc-50 homolog	clinvar
PRICKLE1	HGNC:17019	ENSG00000139174	Q96MT3	Prickle-like protein 1	clinvar
EXOSC3	HGNC:17944	ENSG00000107371	Q9NQT5	Exosome complex component RRP40	clinvar
LGI4	HGNC:18712	ENSG00000153902	Q8N135	Leucine-rich repeat LGI family member 4	clinvar
ASPM	HGNC:19048	ENSG00000066279	Q8IZT6	Abnormal spindle-like microcephaly-associated protein	clinvar
NALCN	HGNC:19082	ENSG00000102452	Q8IZF0	Sodium leak channel NALCN	clinvar
CHRND	HGNC:1965	ENSG00000135902	Q07001	Acetylcholine receptor subunit delta	clinvar
CHRNG	HGNC:1967	ENSG00000196811	P07510	Acetylcholine receptor subunit gamma	clinvar
ADSS1	HGNC:20093	ENSG00000185100	Q8N142	Adenylosuccinate synthetase isozyme 1	clinvar
DQX1	HGNC:20410	ENSG00000144045	Q8TE96	ATP-dependent RNA helicase homolog DQX1	clinvar
SPAG16	HGNC:23225	ENSG00000144451	Q8N0X2	Sperm-associated antigen 16 protein	clinvar
VPS13D	HGNC:23595	ENSG00000048707	Q5THJ4	Intermembrane lipid transfer protein VPS13D	clinvar
ASCC1	HGNC:24268	ENSG00000138303	Q8N9N2	Activating signal cointegrator 1 complex subunit 1	clinvar
PIEZO2	HGNC:26270	ENSG00000154864	Q9H5I5	Piezo-type mechanosensitive ion channel component 2	clinvar
BLTP1	HGNC:26953	ENSG00000138688	Q2LD37	Bridge-like lipid transfer protein family member 1	clinvar
IQSEC3	HGNC:29193	ENSG00000120645	Q9UPP2	IQ motif and SEC7 domain-containing protein 3	clinvar
EARS2	HGNC:29419	ENSG00000103356	Q5JPH6	Nondiscriminating glutamyl-tRNA synthetase EARS2, mitochondrial	clinvar
GLDN	HGNC:29514	ENSG00000186417	Q6ZMI3	Gliomedin	clinvar
DYNC1H1	HGNC:2961	ENSG00000197102	Q14204	Cytoplasmic dynein 1 heavy chain 1	clinvar
MAGI3	HGNC:29647	ENSG00000081026	Q5TCQ9	Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 3	clinvar
FBLN1	HGNC:3600	ENSG00000077942	P23142	Fibulin-1	clinvar
FBN2	HGNC:3604	ENSG00000138829	P35556	Fibrillin-2	clinvar
ALDH5A1	HGNC:408	ENSG00000112294	P51649	Succinate-semialdehyde dehydrogenase, mitochondrial	clinvar
GBE1	HGNC:4180	ENSG00000114480	Q04446	1,4-alpha-glucan-branching enzyme	clinvar
GCN1	HGNC:4199	ENSG00000089154	Q92616	Stalled ribosome sensor GCN1	clinvar
HGFAC	HGNC:4894	ENSG00000109758	Q04756	Hepatocyte growth factor activator serine protease	clinvar
ZNF875	HGNC:4928	ENSG00000181666	P10072	Zinc finger protein 875	clinvar
ASAH1	HGNC:735	ENSG00000104763	Q13510	Acid ceramidase	clinvar
NAGA	HGNC:7631	ENSG00000198951	P17050	Alpha-N-acetylgalactosaminidase	clinvar
CNTNAP1	HGNC:8011	ENSG00000108797	P78357	Contactin-associated protein 1	clinvar
ATP2B3	HGNC:816	ENSG00000067842	Q16720	Plasma membrane calcium-transporting ATPase 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DOK7	Protein Dok-7	Probable muscle-intrinsic activator of MUSK that plays an essential role in neuromuscular synaptogenesis.
MUSK	Muscle, skeletal receptor tyrosine-protein kinase	Receptor tyrosine kinase which plays a central role in the formation and the maintenance of the neuromuscular junction (NMJ), the synapse between the motor neuron and the skeletal muscle.
RAPSN	43 kDa receptor-associated protein of the synapse	Postsynaptic protein required for clustering of nicotinic acetylcholine receptors (nAChRs) at the neuromuscular junction.
SLC18A3	Vesicular acetylcholine transporter	Electrogenic antiporter that exchanges one cholinergic neurotransmitter, acetylcholine or choline, with two intravesicular protons across the membrane of synaptic vesicles.
MYOD1	Myoblast determination protein 1	Acts as a transcriptional activator that promotes transcription of muscle-specific target genes and plays a role in muscle differentiation.
NUP88	Nuclear pore complex protein Nup88	Component of nuclear pore complex.
ROR2	Tyrosine-protein kinase transmembrane receptor ROR2	Tyrosine-protein kinase receptor which may be involved in the early formation of the chondrocytes.
RYR1	Ryanodine receptor 1	Cytosolic calcium-activated calcium channel that mediates the release of Ca(2+) from the sarcoplasmic reticulum into the cytosol and thereby plays a key role in triggering muscle contraction following depolarization of T-tubules.
SCN4A	Sodium channel protein type 4 subunit alpha	Pore-forming subunit of Nav1.4, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes.
SCN5A	Sodium channel protein type 5 subunit alpha	Pore-forming subunit of Nav1.5, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes.
SCN8A	Sodium channel protein type 8 subunit alpha	Pore-forming subunit of a voltage-gated sodium channel complex assuming opened or closed conformations in response to the voltage difference across membranes and through which sodium ions selectively pass along their electrochemical gradie…
SPI1	Transcription factor PU.1	Pioneer transcription factor, which controls hematopoietic cell fate by decompacting stem cell heterochromatin and allowing other transcription factors to enter otherwise inaccessible genomic sites.
TMPO	Lamina-associated polypeptide 2, isoform alpha	May be involved in the structural organization of the nucleus and in the post-mitotic nuclear assembly.
ACTA1	Actin, alpha skeletal muscle	Actins are highly conserved proteins that are involved in various types of cell motility and are ubiquitously expressed in all eukaryotic cells.
AVEN	Cell death regulator Aven	Protects against apoptosis mediated by Apaf-1.
GFRA4	GDNF family receptor alpha-4	Receptor for persephin (PSPN), a growth factor that exhibits neurotrophic activity on mesencephalic dopaminergic and motor neurons.
ZEB2	Zinc finger E-box-binding homeobox 2	Transcriptional inhibitor that binds to DNA sequence 5’-CACCT-3’ in different promoters.
SVEP1	Sushi, von Willebrand factor type A, EGF and pentraxin domain-containing protein 1	Required for morphological development, cell alignment and migration of lymphatic endothelial cells during embryonic development, potentially via modulation of ANGPT2-TIE1 signaling and subsequent activation of FOXC2 transcription.
UNC50	Protein unc-50 homolog	Involved in the cell surface expression of neuronal nicotinic receptors.
PRICKLE1	Prickle-like protein 1	Involved in the planar cell polarity pathway that controls convergent extension during gastrulation and neural tube closure.
EXOSC3	Exosome complex component RRP40	Non-catalytic component of the RNA exosome complex which has 3’->5’ exoribonuclease activity and participates in a multitude of cellular RNA processing and degradation events.
LGI4	Leucine-rich repeat LGI family member 4	Component of Schwann cell signaling pathway(s) that controls axon segregation and myelin formation.
ASPM	Abnormal spindle-like microcephaly-associated protein	Involved in mitotic spindle regulation and coordination of mitotic processes.
NALCN	Sodium leak channel NALCN	Voltage-gated ion channel responsible for the resting Na(+) permeability that controls neuronal excitability.
CHRND	Acetylcholine receptor subunit delta	After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane.
CHRNG	Acetylcholine receptor subunit gamma	After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane.
ADSS1	Adenylosuccinate synthetase isozyme 1	Component of the purine nucleotide cycle (PNC), which interconverts IMP and AMP to regulate the nucleotide levels in various tissues, and which contributes to glycolysis and ammoniagenesis.
DQX1	ATP-dependent RNA helicase homolog DQX1	Might be involved in RNA metabolism; it is missing helicase motif III and may not have helicase activity.
SPAG16	Sperm-associated antigen 16 protein	Necessary for sperm flagellar function.
VPS13D	Intermembrane lipid transfer protein VPS13D	Mediates the transfer of lipids between membranes at organelle contact sites.
ASCC1	Activating signal cointegrator 1 complex subunit 1	Plays a role in DNA damage repair as component of the ASCC complex.
PIEZO2	Piezo-type mechanosensitive ion channel component 2	Pore-forming subunit of the mechanosensitive non-specific cation Piezo channel required for rapidly adapting mechanically activated (MA) currents and has a key role in sensing touch and tactile pain.
BLTP1	Bridge-like lipid transfer protein family member 1	Bridge-like lipid transfer protein that functions as molecular bridges between endoplasmic reticulum and the membranes targeted for lipid delivery.
IQSEC3	IQ motif and SEC7 domain-containing protein 3	Acts as a guanine nucleotide exchange factor (GEF) for ARF1.
EARS2	Nondiscriminating glutamyl-tRNA synthetase EARS2, mitochondrial	Non-discriminating glutamyl-tRNA synthetase that catalyzes aminoacylation of both mitochondrial tRNA(Glu) and tRNA(Gln) and participates in RNA aminoacylation for mitochondrial protein translation.
GLDN	Gliomedin	Ligand for NRCAM and NFASC/neurofascin that plays a role in the formation and maintenance of the nodes of Ranvier on myelinated axons.
DYNC1H1	Cytoplasmic dynein 1 heavy chain 1	Cytoplasmic dynein 1 acts as a motor for the intracellular retrograde motility of vesicles and organelles along microtubules.
MAGI3	Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 3	Acts as a scaffolding protein at cell-cell junctions, thereby regulating various cellular and signaling processes.
FBLN1	Fibulin-1	Incorporated into fibronectin-containing matrix fibers.
FBN2	Fibrillin-2	Fibrillins are structural components of 10-12 nm extracellular calcium-binding microfibrils, which occur either in association with elastin or in elastin-free bundles.
ALDH5A1	Succinate-semialdehyde dehydrogenase, mitochondrial	Catalyzes one step in the degradation of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA).
GBE1	1,4-alpha-glucan-branching enzyme	Glycogen-branching enzyme participates in the glycogen biosynthetic process along with glycogenin and glycogen synthase.
GCN1	Stalled ribosome sensor GCN1	Ribosome collision sensor that plays a key role in the RNF14-RNF25 translation quality control pathway, a pathway that takes place when a ribosome has stalled during translation, and which promotes ubiquitination and degradation of transla…
HGFAC	Hepatocyte growth factor activator serine protease	Serine protease that hydrolyzes the inactive zymogen hepatocyte growth factor (HGFsc) to an activated disulfide-linked heterodimer, then initiating hepatocyte growth factor receptor signaling pathway.
ZNF875	Zinc finger protein 875	May be involved in transcriptional regulation.
ASAH1	Acid ceramidase	Lysosomal ceramidase that hydrolyzes sphingolipid ceramides into sphingosine and free fatty acids at acidic pH.
NAGA	Alpha-N-acetylgalactosaminidase	Removes terminal alpha-N-acetylgalactosamine residues from glycolipids and glycopeptides.
CNTNAP1	Contactin-associated protein 1	Required, with CNTNAP2, for radial and longitudinal organization of myelinated axons.
ATP2B3	Plasma membrane calcium-transporting ATPase 3	ATP-driven Ca(2+) ion pump involved in the maintenance of basal intracellular Ca(2+) levels at the presynaptic terminals.
PRG4	Proteoglycan 4	Plays a role in boundary lubrication within articulating joints.

Protein-family classification

Druggable: 18 · Difficult: 8 · Unknown: 26 · Druggable fraction: 0.35

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	5	10.7×	0.001
Complement	2	10.3×	0.081
Kinase	3	1.6×	0.838
Transporter	1	1.5×	0.838
Antibody/Immunoglobulin	2	1.1×	0.838
Transcription factor	6	0.9×	0.838
Enzyme (other)	4	0.9×	0.838
Other/Unknown	26	0.9×	0.838
Protease	1	0.7×	0.838
Scaffold/PPI	2	0.7×	0.838

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DOK7	Scaffold/PPI	no		PH_domain, IRS_PTB, PH-like_dom_sf
MUSK	Kinase	yes		Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Ig_sub2
RAPSN	Transcription factor	no		Postsynaptic, Znf_RING, TPR-like_helical_dom_sf
SLC18A3	Transporter	yes		MFS, MFS_dom, MFS_trans_sf
MYOD1	Transcription factor	no		MyoD_N, bHLH_dom, Myf5
NUP88	Other/Unknown	no		Nucleoporin_Nup88, NUP88/NUP82
ROR2	Kinase	yes	2.7.10.1	Kringle, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
RYR1	Ion channel	yes		RIH_dom, B30.2/SPRY, Ryanodine_rcpt
SCN4A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_channel_a4su_mammal
SCN5A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_channel_a5su
SCN8A	Ion channel	yes		IQ_motif_EF-hand-BS, Na_channel_asu, Ion_trans_dom
SPI1	Other/Unknown	no		Ets_dom, WH-like_DNA-bd_sf, WH_DNA-bd_sf
TMPO	Other/Unknown	no		LEM_dom, LEM/LEM-like_dom_sf, LEM-like_dom
ACTA1	Other/Unknown	no		Actin, Actin_CS, Actin/actin-like_CS
AVEN	Other/Unknown	no		Aven
GFRA4	Other/Unknown	no		GDNF_rcpt, GDNF/GAS1, GDNF_alpha
ZEB2	Transcription factor	no		HD, Di19_Zn-bd, Homeodomain-like_sf
SETBP1	Other/Unknown	no		AT_hook_DNA-bd_motif
SVEP1	Complement	yes		EGF-type_Asp/Asn_hydroxyl_site, Sushi_SCR_CCP_dom, EGF
UNC50	Other/Unknown	no		UNC-50
PRICKLE1	Transcription factor	no		Znf_LIM, PET_domain, PET_prickle
EXOSC3	Other/Unknown	no		KH_dom_type_1, NA-bd_OB-fold, Exosome_RNA_bind1/RRP40/RRP4
LGI4	Other/Unknown	no		Cys-rich_flank_reg_C, Leu-rich_rpt, Leu-rich_rpt_typical-subtyp
ASPM	Antibody/Immunoglobulin	yes		IQ_motif_EF-hand-BS, CH_dom, ARM-like
NALCN	Ion channel	yes		Ion_trans_dom, Volt_channel_dom_sf, NALCN
CHRND	Other/Unknown	no		Nicotinic_acetylcholine_rcpt, Neurotrans-gated_channel_TM, Neur_channel
CHRNG	Other/Unknown	no		Nicotinic_acetylcholine_rcpt, Neurotrans-gated_channel_TM, Neur_channel
ADSS1	Enzyme (other)	yes	6.3.4.4	Adenylosuccinate_synthetase, Adenylosuccin_syn_GTP-bd, P-loop_NTPase
DQX1	Other/Unknown	no		Helicase-assoc_dom, DEAD-box_helicase_OB_fold, Helicase_ATP-bd
SPAG16	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WD40_repeat_CS
VPS13D	Other/Unknown	no		UBA-like_sf, VPS13_VAB, UBA
ASCC1	Other/Unknown	no		KH_dom_type_1, Cyclic_Pdiesterase, ASCC1
PIEZO2	Other/Unknown	no		Piezo, Piezo_cap_dom, Piezo_TM25-28
BLTP1	Other/Unknown	no		BLTP1, BLTP1_N, BLTP1_M
IQSEC3	Other/Unknown	no		Sec7_dom, PH-like_dom_sf, Sec7_C_sf
EARS2	Other/Unknown	no		Glu/Gln-tRNA-synth, aa-tRNA-synth_I_CS, Glu-tRNA-ligase_bac/mito
GLDN	Other/Unknown	no		Olfac-like_dom, Collagen, Olfactomedin-like_domain
DYNC1H1	Other/Unknown	no		AAA+_ATPase, Dhc_D6_P-loop, Dynein_heavy_tail
MAGI3	Kinase	yes		WW_dom, PDZ, Guanylate_kin-like_dom
FBLN1	Complement	yes		Anaphylatoxin/fibulin, EGF-type_Asp/Asn_hydroxyl_site, EGF
FBN2	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom
ALDH5A1	Enzyme (other)	yes	1.2.1.24	Succ_semiAld_DH, Aldehyde_DH_dom, Ald_DH_CS_CYS
GBE1	Antibody/Immunoglobulin	yes		Glyco_hydro_13_N, GH13_cat_dom, A-amylase/branching_C
GCN1	Other/Unknown	no		ARM-like, ARM-type_fold, HEAT_type_2
HGFAC	Protease	yes		Kringle, Fibronectin_type1, FN_type2_dom
ZNF875	Transcription factor	no		KRAB, Znf_C2H2_type, KRAB_dom_sf
ASAH1	Enzyme (other)	yes	3.5.1.23	Acid_ceramidase-like, Acid_ceramidase_N, CBAH/NAAA_C
NAGA	Enzyme (other)	yes	3.2.1.49	Glyco_hydro_27/36_CS, Glyco_hydro_27, Glyco_hydro_b
CNTNAP1	Other/Unknown	no		FA58C, EGF, Laminin_G
ATP2B3	Transcription factor	no	7.2.2.10	P_typ_ATPase, ATPase_P-typ_cation-transptr_N, ATPase_P-typ_cation-transptr_C

Expression context

Cohort genes with no expression data: 0.

42 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)	52
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gastrocnemius	6
ventricular zone	6
sural nerve	5
hindlimb stylopod muscle	4
gluteal muscle	4
Brodmann (1909) area 23	4
apex of heart	3
male germ line stem cell (sensu Vertebrata) in testis	3
skeletal muscle tissue of biceps brachii	3
middle temporal gyrus	3
monocyte	3
pericardium	3
tendon of biceps brachii	3
corpus callosum	3
muscle of leg	3
pancreatic ductal cell	3
tibialis anterior	2
mucosa of stomach	2
primordial germ cell in gonad	2
right testis	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DOK7	180	broad	yes	apex of heart, tibialis anterior, right atrium auricular region
MUSK	151	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, mucosa of stomach, sural nerve
RAPSN	159	tissue_specific	marker	hindlimb stylopod muscle, male germ line stem cell (sensu Vertebrata) in testis, gastrocnemius
SLC18A3	60	tissue_specific	yes	primordial germ cell in gonad, endometrium epithelium, putamen
MYOD1	51	tissue_specific	yes	triceps brachii, skeletal muscle tissue of biceps brachii, gluteal muscle
NUP88	290	ubiquitous	marker	right testis, left testis, testis
ROR2	188	ubiquitous	marker	muscle layer of sigmoid colon, mucosa of stomach, body of uterus
RYR1	214	broad	marker	gluteal muscle, gastrocnemius, hindlimb stylopod muscle
SCN4A	153	tissue_specific	yes	hindlimb stylopod muscle, gastrocnemius, skeletal muscle tissue of rectus abdominis
SCN5A	161	broad	yes	apex of heart, heart left ventricle, cardiac ventricle
SCN8A	194	ubiquitous	marker	Brodmann (1909) area 23, middle temporal gyrus, postcentral gyrus
SPI1	170	broad	marker	granulocyte, monocyte, leukocyte
TMPO	287	ubiquitous	marker	ventricular zone, ganglionic eminence, embryo
ACTA1	203	broad	marker	gluteal muscle, skeletal muscle tissue of biceps brachii, diaphragm
AVEN	252	ubiquitous	marker	heart right ventricle, cervix squamous epithelium, ascending aorta
GFRA4	36		yes	male germ line stem cell (sensu Vertebrata) in testis, diaphragm, olfactory bulb
ZEB2	290	ubiquitous	marker	cortical plate, sural nerve, monocyte
SETBP1	280	ubiquitous	marker	ventricular zone, buccal mucosa cell, caput epididymis
SVEP1	225	broad	marker	pericardium, lower lobe of lung, placenta
UNC50	294	ubiquitous	marker	palpebral conjunctiva, adenohypophysis, left lobe of thyroid gland
PRICKLE1	243	ubiquitous	marker	buccal mucosa cell, tendon of biceps brachii, lateral nuclear group of thalamus
EXOSC3	246	ubiquitous	marker	oocyte, secondary oocyte, tendon of biceps brachii
LGI4	214	broad	marker	peripheral nervous system, nerve, tibial nerve
ASPM	176	ubiquitous	marker	oocyte, ventricular zone, secondary oocyte
NALCN	201	ubiquitous	marker	middle temporal gyrus, Brodmann (1909) area 23, corpus callosum
CHRND	86	tissue_specific	yes	gastrocnemius, muscle of leg, hindlimb stylopod muscle
CHRNG	54	tissue_specific	marker	pancreatic ductal cell, gastrocnemius, muscle of leg
ADSS1	242	ubiquitous	marker	quadriceps femoris, vastus lateralis, skeletal muscle tissue of rectus abdominis
DQX1	154	tissue_specific	marker	mucosa of transverse colon, rectum, jejunal mucosa
SPAG16	289	ubiquitous	marker	bronchial epithelial cell, epithelium of bronchus, bronchus

Protein interactions among cohort

Intra-cohort edges: 16.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PSMC3	4,843
ALDH5A1	4,219
DYNC1H1	4,215
HGFAC	4,212
GCN1	3,919
SPI1	3,823
MAGI3	3,725
EARS2	3,667
MYOD1	3,624
GBE1	3,402

Intra-cohort edges

A	B	Sources
ASAH1	NAGA	string_interaction
ASPM	SVEP1	string_interaction
CHRND	DOK7	string_interaction
CHRND	MUSK	string_interaction
CHRND	RAPSN	string_interaction
CHRNG	DOK7	string_interaction
CHRNG	MUSK	string_interaction
CHRNG	RAPSN	string_interaction
CNTNAP1	GLDN	string_interaction
CNTNAP1	LGI4	string_interaction
DOK7	MUSK	string_interaction
DOK7	RAPSN	string_interaction
DOK7	SCN4A	string_interaction
MAGI3	SCN4A	intact
MAGI3	SCN8A	intact
MUSK	RAPSN	string_interaction

Structural data

PDB: 26 · AlphaFold-only: 26 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PSMC3	P17980	130
DYNC1H1	Q14204	97
SPI1	P17947	35
SCN5A	Q14524	16
TMPO	P42166	14
CHRND	Q07001	13
SLC18A3	Q16572	11
EXOSC3	Q9NQT5	8
SCN8A	Q9UQD0	7
HGFAC	Q04756	7
NAGA	P17050	7
ROR2	Q01974	6
ACTA1	P68133	5
NALCN	Q8IZF0	5
ALDH5A1	P51649	5
MUSK	O15146	4
NUP88	Q99567	3
SCN4A	P35499	3
GBE1	Q04446	3
RYR1	P21817	2
PIEZO2	Q9H5I5	2
ASAH1	Q13510	2
ZEB2	O60315	1
ASCC1	Q8N9N2	1
GLDN	Q6ZMI3	1
MAGI3	Q5TCQ9	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RAPSN	Q13702	93.29
ADSS1	Q8N142	93.10
LGI4	Q8N135	92.80
EARS2	Q5JPH6	89.84
UNC50	Q53HI1	88.86
DQX1	Q8TE96	87.42
GCN1	Q92616	82.45
CHRNG	P07510	81.91
CNTNAP1	P78357	81.51
FBLN1	P23142	79.49
SPAG16	Q8N0X2	77.12
ATP2B3	Q16720	74.57
GFRA4	Q9GZZ7	69.21
ZNF875	P10072	66.73
DOK7	Q18PE1	65.61
MYOD1	P15172	62.04
AVEN	Q9NQS1	58.86
IQSEC3	Q9UPP2	58.76
PRICKLE1	Q96MT3	55.55
PRG4	Q92954	48.76
SETBP1	Q9Y6X0	43.30
SVEP1	Q4LDE5
ASPM	Q8IZT6
VPS13D	Q5THJ4
BLTP1	Q2LD37
FBN2	P35556

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 234. Enrichment computed across 52 evidence-associated genes (37 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 37 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Muscle contraction	6	12.5×	0.002	RYR1, SCN4A, SCN5A, SCN8A, ACTA1, ATP2B3
Cardiac conduction	5	14.7×	0.002	RYR1, SCN4A, SCN5A, SCN8A, ATP2B3
Interaction between L1 and Ankyrins	3	29.9×	0.009	SCN4A, SCN5A, SCN8A
Phase 0 - rapid depolarisation	3	28.1×	0.009	SCN4A, SCN5A, SCN8A
Highly sodium permeable postsynaptic acetylcholine nicotinic receptors	2	88.2×	0.010	CHRND, CHRNG
Presynaptic nicotinic acetylcholine receptors	2	51.4×	0.026	CHRND, CHRNG
Acetylcholine binding and downstream events	2	44.1×	0.027	CHRND, CHRNG
Postsynaptic nicotinic acetylcholine receptors	2	44.1×	0.027	CHRND, CHRNG
L1CAM interactions	3	9.8×	0.092	SCN4A, SCN5A, SCN8A
Degradation of GABA	1	154.3×	0.129	ALDH5A1
Molecules associated with elastic fibres	2	16.7×	0.129	FBLN1, FBN2
Ion channel transport	3	7.8×	0.129	RYR1, NALCN, ATP2B3
Glycogen storage disease type IV (GBE1)	1	102.9×	0.174	GBE1
ALKBH3 mediated reversal of alkylation damage	1	77.2×	0.183	ASCC1
Asymmetric localization of PCP proteins	2	11.0×	0.183	PRICKLE1, PSMC3
Ion homeostasis	2	11.0×	0.183	RYR1, ATP2B3
Transmission across Chemical Synapses	3	6.2×	0.183	CHRND, CHRNG, ALDH5A1
Developmental Biology	7	2.7×	0.183	SCN4A, SCN5A, SCN8A, SPI1, LGI4, ASAH1, MYOD1
MET Receptor Activation	1	51.4×	0.238	HGFAC
DNA Damage Reversal	1	44.1×	0.239	ASCC1
Reversal of alkylation damage by DNA dioxygenases	1	44.1×	0.239	ASCC1
Activation of STAT3 by cadherin engagement	2	8.8×	0.239	ACTA1, PSMC3
Formation of apoptosome	1	38.6×	0.250	AVEN
Neurofascin interactions	1	38.6×	0.250	CNTNAP1
Cytochrome c-mediated apoptotic response	1	34.3×	0.259	AVEN
Formation of the posterior neural plate	1	30.9×	0.259	ZEB2
Purine ribonucleoside monophosphate biosynthesis	1	28.1×	0.259	ADSS1
Regulation of the apoptosome activity	1	28.1×	0.259	AVEN
Regulation of CDH11 gene transcription	1	28.1×	0.259	ZEB2
Formation of the anterior neural plate	1	28.1×	0.259	ZEB2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 50 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
muscle contraction	5	20.8×	0.002	RYR1, SCN4A, ACTA1, CHRND, CHRNG
cardiac muscle cell action potential involved in contraction	3	42.1×	0.009	SCN4A, SCN5A, SCN8A
skeletal muscle fiber development	3	32.6×	0.009	RYR1, ACTA1, MYOD1
membrane depolarization	3	30.6×	0.009	SCN5A, CHRND, CHRNG
monoatomic ion transmembrane transport	4	16.6×	0.009	NALCN, CHRND, CHRNG, ATP2B3
sodium ion transmembrane transport	4	16.2×	0.009	SCN4A, SCN5A, SCN8A, NALCN
skeletal muscle acetylcholine-gated channel clustering	2	74.9×	0.018	MUSK, RAPSN
sodium ion transport	3	16.3×	0.043	SCN4A, SCN5A, SCN8A
host-mediated perturbation of viral transcription	1	337.0×	0.048	PSMC3
negative regulation of asymmetric cell division	1	337.0×	0.048	ASPM
mammillary axonal complex development	1	337.0×	0.048	ZEB2
regulation of programmed necrotic cell death	1	337.0×	0.048	ASAH1
tRNA aminoacylation for mitochondrial protein translation	1	337.0×	0.048	EARS2
neuromuscular junction development, skeletal muscle fiber	1	337.0×	0.048	CNTNAP1
regulation of skeletal muscle contraction by action potential	1	337.0×	0.048	SCN4A
regulation of postsynaptic membrane organization	1	337.0×	0.048	RAPSN
establishment of protein localization to postsynaptic membrane	1	337.0×	0.048	RAPSN
negative regulation of transformation of host cell by virus	1	337.0×	0.048	FBLN1
positive regulation of myofibroblast contraction	1	337.0×	0.048	ZEB2
regulation of blood-brain barrier permeability	1	337.0×	0.048	ZEB2
positive regulation of protein geranylgeranylation	1	337.0×	0.048	MUSK
pro-T cell differentiation	1	168.5×	0.048	SPI1
lymph circulation	1	168.5×	0.048	SVEP1
glutamyl-tRNA aminoacylation	1	168.5×	0.048	EARS2
myoblast fate determination	1	168.5×	0.048	MYOD1
GABA catabolic process	1	168.5×	0.048	ALDH5A1
glycolipid catabolic process	1	168.5×	0.048	NAGA
forebrain neuroblast division	1	168.5×	0.048	ASPM
microvillus organization	1	168.5×	0.048	GLDN
negative regulation of neutrophil degranulation	1	168.5×	0.048	SPI1

Therapeutics

Drug target analysis

Approved (phase 4): 7 · Phase ≥3: 8 · Phased (≥1): 10 · Undrugged: 42

Druggability breadth: 19 of 52 evidence-associated genes (37%) 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
MUSK	FEDRATINIB
SCN4A	CARBAMAZEPINE
SCN5A	BEPRIDIL
SCN8A	IMIPRAMINE
CHRND	VARENICLINE
CHRNG	VARENICLINE
PSMC3	BORTEZOMIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCN5A	108	4
SCN8A	25	4
SCN4A	24	4
MUSK	20	4
CHRND	10	4
CHRNG	10	4
HGFAC	2	3
PSMC3	2	4
DYNC1H1	1	2
ASAH1	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	MUSK, SCN5A
SORAFENIB	4	MUSK
NINTEDANIB	4	MUSK, SCN5A
SUNITINIB	4	MUSK, SCN5A
QUIZARTINIB	4	MUSK
CRIZOTINIB	4	MUSK
CARBAMAZEPINE	4	SCN4A, SCN5A
PHENYTOIN	4	SCN4A, SCN5A
LAMOTRIGINE	4	SCN4A, SCN5A
RILUZOLE	4	SCN4A, SCN5A
LIDOCAINE	4	SCN4A, SCN5A
IMIPRAMINE	4	SCN4A, SCN5A, SCN8A
SERTINDOLE	4	SCN4A, SCN5A, SCN8A
PIMOZIDE	4	SCN4A, SCN5A, SCN8A
NIFEDIPINE	4	SCN4A, SCN5A, SCN8A
DILTIAZEM	4	SCN4A, SCN5A, SCN8A
MIBEFRADIL	4	SCN4A, SCN5A, SCN8A
HALOPERIDOL	4	SCN4A, SCN5A, SCN8A
MEXILETINE	4	SCN4A, SCN5A, SCN8A
AMITRIPTYLINE	4	SCN4A, SCN5A, SCN8A
AMIODARONE	4	SCN4A, SCN5A, SCN8A
CHLORPROMAZINE	4	SCN4A, SCN5A, SCN8A
BEPRIDIL	4	SCN5A
CANDESARTAN CILEXETIL	4	SCN5A
TELMISARTAN	4	SCN5A
DIBUCAINE	4	SCN5A
DROPERIDOL	4	SCN5A
PONATINIB	4	SCN5A
DULOXETINE	4	SCN5A
PALONOSETRON	4	SCN5A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 6.

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

Symbol	Assays	Type breakdown
SCN5A	594	Binding:380, Functional:98, ADMET:72, Toxicity:43, Unclassified:1
MUSK	247	Binding:247
SCN8A	173	Binding:148, Functional:16, ADMET:7, Toxicity:2
ASAH1	111	Binding:108, Functional:3
SCN4A	95	Binding:69, Functional:18, ADMET:7, Toxicity:1
CHRND	75	Binding:44, Functional:31
CHRNG	67	Binding:36, Functional:31
PSMC3	27	Binding:27
HGFAC	18	Binding:18
SLC18A3	17	Binding:17
RYR1	16	Binding:13, Functional:3
GCN1	12	Binding:8, Functional:4
TMPO	7	Binding:7
DYNC1H1	7	Binding:7
ALDH5A1	5	Binding:5
ROR2	4	Binding:4
MAGI3	4	Binding:4
NAGA	4	Binding:4
RAPSN	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ROR2	2.7.10.1	receptor protein-tyrosine kinase
ADSS1	6.3.4.4	adenylosuccinate synthase
ALDH5A1	1.2.1.24	succinate-semialdehyde dehydrogenase (NAD+)
ASAH1	3.5.1.23	ceramidase
NAGA	3.2.1.49	alpha-N-acetylgalactosaminidase
ATP2B3	7.2.2.10	P-type Ca2+ transporter

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
MUSK	247
SCN5A	594
SCN8A	173
ASAH1	111

Pharmacogenomics

Cohort genes with a PharmGKB record: 52; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
RYR1	1

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)
FEDRATINIB	4	MUSK, SCN5A
SORAFENIB	4	MUSK
NINTEDANIB	4	MUSK, SCN5A
SUNITINIB	4	MUSK, SCN5A
QUIZARTINIB	4	MUSK
CRIZOTINIB	4	MUSK
CARBAMAZEPINE	4	SCN4A, SCN5A
PHENYTOIN	4	SCN4A, SCN5A
LAMOTRIGINE	4	SCN4A, SCN5A
RILUZOLE	4	SCN4A, SCN5A
LIDOCAINE	4	SCN4A, SCN5A
IMIPRAMINE	4	SCN4A, SCN5A, SCN8A
SERTINDOLE	4	SCN4A, SCN5A, SCN8A
PIMOZIDE	4	SCN4A, SCN5A, SCN8A
NIFEDIPINE	4	SCN4A, SCN5A, SCN8A
DILTIAZEM	4	SCN4A, SCN5A, SCN8A
MIBEFRADIL	4	SCN4A, SCN5A, SCN8A
HALOPERIDOL	4	SCN4A, SCN5A, SCN8A
MEXILETINE	4	SCN4A, SCN5A, SCN8A
AMITRIPTYLINE	4	SCN4A, SCN5A, SCN8A
AMIODARONE	4	SCN4A, SCN5A, SCN8A
CHLORPROMAZINE	4	SCN4A, SCN5A, SCN8A
BEPRIDIL	4	SCN5A
CANDESARTAN CILEXETIL	4	SCN5A
TELMISARTAN	4	SCN5A
DIBUCAINE	4	SCN5A
DROPERIDOL	4	SCN5A
PONATINIB	4	SCN5A
DULOXETINE	4	SCN5A
PALONOSETRON	4	SCN5A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	7	MUSK, SCN4A, SCN5A, SCN8A, CHRND, CHRNG, PSMC3
B	Phased (≥1) drug, not yet approved	3	DYNC1H1, HGFAC, ASAH1
C	Druggable family + PDB, no drug	8	SLC18A3, ROR2, RYR1, NALCN, MAGI3, ALDH5A1, GBE1, NAGA
D	Druggable family + AlphaFold only, no drug	4	SVEP1, ASPM, ADSS1, FBLN1
E	Difficult family or no structure, no drug	30	DOK7, RAPSN, MYOD1, NUP88, SPI1, TMPO, ACTA1, AVEN, GFRA4, ZEB2 (+20 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
DOK7	0	MUSK
RAPSN	1	MUSK, CHRND
SLC18A3	17	—
MYOD1	0	—
NUP88	0	—
ROR2	4	—
RYR1	16	—
SPI1	0	—
TMPO	7	—
ACTA1	0	—
AVEN	0	—
GFRA4	0	—
ZEB2	0	—
SETBP1	0	—
SVEP1	0	—
UNC50	0	—
PRICKLE1	0	—
EXOSC3	0	—
LGI4	0	—
ASPM	0	—
NALCN	0	—
ADSS1	0	—
DQX1	0	—
SPAG16	0	—
VPS13D	0	—
ASCC1	0	—
PIEZO2	0	—
BLTP1	0	—
IQSEC3	0	—
EARS2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.