Postsynaptic congenital myasthenic syndrome

Summary

Postsynaptic congenital myasthenic syndrome (MONDO:0020344) is a disease (an umbrella term covering 14 Mondo subtypes) with 13 cohort genes. The dominant Reactome pathway is Presynaptic nicotinic acetylcholine receptors (3 cohort genes).

At a glance

• Umbrella term: 14 Mondo subtypes
• Cohort genes: 13
• Phenotypes (HPO): 37

Clinical features

Signs & symptoms

Clinical features (HPO)

37 HPO clinical features (Orphanet curated; top 37 by frequency):

HPO ID	Term	Frequency
HP:0001324	Muscle weakness	Frequent (30-79%)
HP:0000218	High palate	Frequent (30-79%)
HP:0000496	Abnormality of eye movement	Frequent (30-79%)
HP:0000508	Ptosis	Frequent (30-79%)
HP:0000597	Ophthalmoparesis	Frequent (30-79%)
HP:0001315	Reduced tendon reflexes	Frequent (30-79%)
HP:0001446	Abnormality of the musculature of the upper limbs	Frequent (30-79%)
HP:0003202	Skeletal muscle atrophy	Frequent (30-79%)
HP:0003388	Easy fatigability	Frequent (30-79%)
HP:0003402	Decreased miniature endplate potentials	Frequent (30-79%)
HP:0003403	EMG: decremental response of compound muscle action potential to repetitive nerve stimulation	Frequent (30-79%)
HP:0003443	Decreased size of nerve terminals	Frequent (30-79%)
HP:0003458	EMG: myopathic abnormalities	Frequent (30-79%)
HP:0003484	Upper limb muscle weakness	Frequent (30-79%)
HP:0003547	Shoulder girdle muscle weakness	Frequent (30-79%)
HP:0003722	Neck flexor weakness	Frequent (30-79%)
HP:0003803	Type 1 muscle fiber predominance	Frequent (30-79%)
HP:0009005	Weakness of the intrinsic hand muscles	Frequent (30-79%)
HP:0010628	Facial palsy	Frequent (30-79%)
HP:0030199	Fatigable weakness of neck muscles	Frequent (30-79%)
HP:0410011	Abnormality of masticatory muscle	Frequent (30-79%)
HP:0000651	Diplopia	Occasional (5-29%)
HP:0000961	Cyanosis	Occasional (5-29%)
HP:0002091	Restrictive ventilatory defect	Occasional (5-29%)
HP:0002194	Delayed gross motor development	Occasional (5-29%)
HP:0002329	Drowsiness	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0002792	Reduced vital capacity	Occasional (5-29%)
HP:0002875	Exertional dyspnea	Occasional (5-29%)
HP:0002878	Respiratory failure	Occasional (5-29%)
HP:0005659	Thoracic kyphoscoliosis	Occasional (5-29%)
HP:0009077	Weakness of long finger extensor muscles	Occasional (5-29%)
HP:0012515	Hip flexor weakness	Occasional (5-29%)
HP:0012764	Orthopnea	Occasional (5-29%)
HP:0030196	Fatigable weakness of respiratory muscles	Occasional (5-29%)
HP:0031108	Triceps weakness	Occasional (5-29%)
HP:0031374	Ankle weakness	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	postsynaptic congenital myasthenic syndrome
Mondo ID	MONDO:0020344
Orphanet	98913
UMLS	C0751883
MedGen	199758
GARD	0015022
Is cancer (heuristic)	no

Data availability: 12 GenCC gene-disease records.

Disease family

An umbrella term covering 14 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › postsynaptic congenital myasthenic syndrome

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

Subtypes (14): congenital myasthenic syndrome 10, congenital myasthenic syndrome 1A, congenital myasthenic syndrome 16, congenital myasthenic syndrome 8, congenital myasthenic syndrome 17, congenital myasthenic syndrome 2A, congenital myasthenic syndrome 2C, congenital myasthenic syndrome 3A, congenital myasthenic syndrome 3B, congenital myasthenic syndrome 3C, congenital myasthenic syndrome 9, congenital myasthenic syndrome 11, congenital myasthenic syndrome 19, congenital myasthenic syndrome 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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 119 · Orphanet: 29 · 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
CHRNB1	Definitive	Autosomal dominant	congenital myasthenic syndrome 2C	9
CHRNE	Definitive	Autosomal recessive	congenital myasthenic syndrome	8
DOK7	Definitive	Autosomal recessive	congenital myasthenic syndrome 10	8
AGRN	Strong	Autosomal recessive	congenital myasthenic syndrome 8	5
CHRNA1	Strong	Autosomal dominant	congenital myasthenic syndrome 1A	9
CHRND	Strong	Autosomal dominant	congenital myasthenic syndrome 3A	8
COL13A1	Strong	Autosomal recessive	congenital myasthenic syndrome 19	5
CORIN	Strong	Autosomal recessive	congenital myasthenic syndrome 17	14
LRP4	Strong	Autosomal recessive	congenital myasthenic syndrome 17	13
MUSK	Strong	Autosomal recessive	congenital myasthenic syndrome 9	6
RAPSN	Strong	Autosomal recessive	congenital myasthenic syndrome 11	9
SCN4A	Strong	Autosomal recessive	congenital myasthenic syndrome 16	24
AK9	Supportive	Autosomal recessive	postsynaptic congenital myasthenic syndrome

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
CORIN	Orphanet:275555	Preeclampsia
CHRNA1	Orphanet:33108	Lethal multiple pterygium syndrome
CHRNA1	Orphanet:98913	Postsynaptic congenital myasthenic syndrome
CHRNB1	Orphanet:98913	Postsynaptic congenital myasthenic syndrome
CHRND	Orphanet:33108	Lethal multiple pterygium syndrome
CHRND	Orphanet:98913	Postsynaptic congenital myasthenic syndrome
CHRNE	Orphanet:98913	Postsynaptic congenital myasthenic syndrome
COL13A1	Orphanet:98913	Postsynaptic congenital myasthenic syndrome
COL13A1	Orphanet:98914	Presynaptic congenital myasthenic syndromes
DOK7	Orphanet:98913	Postsynaptic congenital myasthenic syndrome
DOK7	Orphanet:994	Fetal akinesia deformation sequence
AGRN	Orphanet:98913	Postsynaptic congenital myasthenic syndrome
AGRN	Orphanet:98914	Presynaptic congenital myasthenic syndromes
AK9	Orphanet:98913	Postsynaptic congenital myasthenic syndrome
LRP4	Orphanet:3152	Sclerosteosis
LRP4	Orphanet:3258	Cenani-Lenz syndrome
LRP4	Orphanet:98913	Postsynaptic congenital myasthenic syndrome
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

Cohort genes → proteins

13 cohort genes, 13 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	13

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SCN4A	HGNC:10591	ENSG00000007314	P35499	Sodium channel protein type 4 subunit alpha	gencc
CORIN	HGNC:19012	ENSG00000145244	Q9Y5Q5	Atrial natriuretic peptide-converting enzyme	gencc
CHRNA1	HGNC:1955	ENSG00000138435	P02708	Acetylcholine receptor subunit alpha	gencc
CHRNB1	HGNC:1961	ENSG00000170175	P11230	Acetylcholine receptor subunit beta	gencc
CHRND	HGNC:1965	ENSG00000135902	Q07001	Acetylcholine receptor subunit delta	gencc
CHRNE	HGNC:1966	ENSG00000108556	Q04844	Acetylcholine receptor subunit epsilon	gencc
COL13A1	HGNC:2190	ENSG00000197467	Q5TAT6	Collagen alpha-1(XIII) chain	gencc
DOK7	HGNC:26594	ENSG00000175920	Q18PE1	Protein Dok-7	gencc
AGRN	HGNC:329	ENSG00000188157	O00468	Agrin	gencc
AK9	HGNC:33814	ENSG00000155085	Q5TCS8	Adenylate kinase 9	gencc
LRP4	HGNC:6696	ENSG00000134569	O75096	Low-density lipoprotein receptor-related protein 4	gencc
MUSK	HGNC:7525	ENSG00000030304	O15146	Muscle, skeletal receptor tyrosine-protein kinase	gencc
RAPSN	HGNC:9863	ENSG00000165917	Q13702	43 kDa receptor-associated protein of the synapse	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
CORIN	Atrial natriuretic peptide-converting enzyme	Serine-type endopeptidase involved in atrial natriuretic peptide (NPPA) and brain natriuretic peptide (NPPB) processing.
CHRNA1	Acetylcholine receptor subunit alpha	Upon acetylcholine binding, 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.
CHRNB1	Acetylcholine receptor subunit beta	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.
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.
CHRNE	Acetylcholine receptor subunit epsilon	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.
COL13A1	Collagen alpha-1(XIII) chain	Involved in cell-matrix and cell-cell adhesion interactions that are required for normal development.
DOK7	Protein Dok-7	Probable muscle-intrinsic activator of MUSK that plays an essential role in neuromuscular synaptogenesis.
AGRN	Agrin	Depending on alternative splicing and post-translational modifications, it has a role in different processes, including neuromuscular junction formation and maintenance, and regulation of neurite outgrowth.
AK9	Adenylate kinase 9	Broad-specificity nucleoside phosphate kinase involved in cellular nucleotide homeostasis by catalyzing nucleoside-phosphate interconversions.
LRP4	Low-density lipoprotein receptor-related protein 4	Mediates SOST-dependent inhibition of bone formation.
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.

Protein-family classification

Druggable: 3 · Difficult: 2 · Unknown: 8 · Druggable fraction: 0.23

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	1	8.6×	0.647
Protease	1	2.8×	0.647
Kinase	1	2.1×	0.647
Scaffold/PPI	1	1.3×	0.647
Other/Unknown	8	1.1×	0.647
Transcription factor	1	0.6×	0.813

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SCN4A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_channel_a4su_mammal
CORIN	Protease	yes		SRCR, Trypsin_dom, LDrepeatLR_classA_rpt
CHRNA1	Other/Unknown	no		Nicotinic_acetylcholine_rcpt, Neurotrans-gated_channel_TM, Neur_channel
CHRNB1	Other/Unknown	no		Nicotinic_acetylcholine_rcpt, Neurotrans-gated_channel_TM, Neur_channel
CHRND	Other/Unknown	no		Nicotinic_acetylcholine_rcpt, Neurotrans-gated_channel_TM, Neur_channel
CHRNE	Other/Unknown	no		Nicotinic_acetylcholine_rcpt, Neurotrans-gated_channel_TM, Neur_channel
COL13A1	Other/Unknown	no		Collagen, Collagen_Structural_Proteins
DOK7	Scaffold/PPI	no		PH_domain, IRS_PTB, PH-like_dom_sf
AGRN	Other/Unknown	no		SEA_dom, EGF, Laminin_G
AK9	Other/Unknown	no		Adenylat/UMP-CMP_kin, AAA+_ATPase, P-loop_NTPase
LRP4	Other/Unknown	no		LDLR_classB_rpt, EGF, EGF-like_Ca-bd_dom
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

Expression context

Cohort genes with no expression data: 0.

9 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)	13
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gastrocnemius	5
hindlimb stylopod muscle	4
muscle of leg	3
male germ line stem cell (sensu Vertebrata) in testis	3
right atrium auricular region	2
right uterine tube	2
sural nerve	2
skeletal muscle tissue of rectus abdominis	1
cardiac muscle of right atrium	1
heart right ventricle	1
myocardium	1
gluteal muscle	1
adenohypophysis	1
cardiac atrium	1
cerebellar cortex	1
cerebellar hemisphere	1
cerebellum	1
apex of heart	1
tibialis anterior	1
metanephros cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SCN4A	153	tissue_specific	yes	hindlimb stylopod muscle, gastrocnemius, skeletal muscle tissue of rectus abdominis
CORIN	176	tissue_specific	marker	cardiac muscle of right atrium, heart right ventricle, myocardium
CHRNA1	149	broad	marker	gastrocnemius, gluteal muscle, muscle of leg
CHRNB1	137	ubiquitous	marker	gastrocnemius, hindlimb stylopod muscle, muscle of leg
CHRND	86	tissue_specific	yes	gastrocnemius, muscle of leg, hindlimb stylopod muscle
CHRNE	162	broad	yes	right atrium auricular region, cardiac atrium, adenohypophysis
COL13A1	209	ubiquitous	marker	cerebellar hemisphere, cerebellar cortex, cerebellum
DOK7	180	broad	yes	apex of heart, tibialis anterior, right atrium auricular region
AGRN	271	ubiquitous	marker	right uterine tube, metanephros cortex, renal medulla
AK9	221	ubiquitous	marker	sural nerve, male germ line stem cell (sensu Vertebrata) in testis, right uterine tube
LRP4	242	ubiquitous	marker	ventricular zone, dorsal motor nucleus of vagus nerve, medial globus pallidus
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

Protein interactions among cohort

Intra-cohort edges: 33.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AGRN	3,117
AK9	2,977
MUSK	1,809
SCN4A	1,704
COL13A1	1,308
CORIN	1,291
LRP4	1,250
CHRNA1	1,058
CHRND	1,041
CHRNE	896

Intra-cohort edges

A	B	Sources
AGRN	CHRNB1	string_interaction
AGRN	CHRND	string_interaction
AGRN	CORIN	string_interaction
AGRN	DOK7	string_interaction
AGRN	LRP4	string_interaction
AGRN	MUSK	string_interaction
AGRN	RAPSN	string_interaction
CHRNA1	CHRNB1	intact, string_interaction
CHRNA1	CHRND	biogrid_interaction, string_interaction
CHRNA1	CHRNE	biogrid_interaction, string_interaction
CHRNA1	DOK7	string_interaction
CHRNA1	MUSK	string_interaction
CHRNA1	RAPSN	string_interaction
CHRNB1	CHRND	intact, string_interaction
CHRNB1	CHRNE	string_interaction
CHRNB1	DOK7	string_interaction
CHRNB1	MUSK	string_interaction
CHRNB1	RAPSN	string_interaction
CHRNB1	SCN4A	string_interaction
CHRND	DOK7	string_interaction
CHRND	MUSK	string_interaction
CHRND	RAPSN	string_interaction
CHRNE	DOK7	string_interaction
CHRNE	MUSK	string_interaction
CHRNE	RAPSN	string_interaction
CHRNE	SCN4A	string_interaction
DOK7	LRP4	string_interaction
DOK7	MUSK	string_interaction
DOK7	RAPSN	string_interaction
DOK7	SCN4A	string_interaction
LRP4	MUSK	string_interaction
LRP4	RAPSN	string_interaction
MUSK	RAPSN	string_interaction

Structural data

PDB: 8 · AlphaFold-only: 5 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CHRNA1	P02708	15
CHRNB1	P11230	13
CHRND	Q07001	13
CHRNE	Q04844	13
MUSK	O15146	4
SCN4A	P35499	3
AGRN	O00468	1
LRP4	O75096	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RAPSN	Q13702	93.29
AK9	Q5TCS8	73.70
CORIN	Q9Y5Q5	70.20
DOK7	Q18PE1	65.61
COL13A1	Q5TAT6	55.67

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 65. Enrichment computed across 13 evidence-associated genes (10 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 10 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Presynaptic nicotinic acetylcholine receptors	3	285.5×	4e-06	CHRNA1, CHRND, CHRNE
Acetylcholine binding and downstream events	3	244.7×	4e-06	CHRNA1, CHRND, CHRNE
Postsynaptic nicotinic acetylcholine receptors	3	244.7×	4e-06	CHRNA1, CHRND, CHRNE
Highly sodium permeable postsynaptic acetylcholine nicotinic receptors	2	326.3×	2e-04	CHRND, CHRNE
ECM proteoglycans	3	45.1×	4e-04	AGRN, LRP4, MUSK
Neurotransmitter receptors and postsynaptic signal transmission	3	30.1×	0.001	CHRNA1, CHRND, CHRNE
Transmission across Chemical Synapses	3	22.8×	0.002	CHRNA1, CHRND, CHRNE
Extracellular matrix organization	3	18.9×	0.004	AGRN, LRP4, MUSK
Neuronal System	3	13.3×	0.009	CHRNA1, CHRND, CHRNE
Integrin cell surface interactions	2	26.9×	0.015	COL13A1, AGRN
Highly calcium permeable nicotinic acetylcholine receptors	1	126.9×	0.046	CHRNA1
Highly calcium permeable postsynaptic nicotinic acetylcholine receptors	1	103.8×	0.048	CHRNA1
Early SARS-CoV-2 Infection Events	1	103.8×	0.048	AGRN
Chondroitin sulfate/dermatan sulfate metabolism	1	95.2×	0.049	AGRN
Defective EXT2 causes exostoses 2	1	81.6×	0.050	AGRN
Defective EXT1 causes exostoses 1, TRPS2 and CHDS	1	81.6×	0.050	AGRN
Diseases associated with glycosaminoglycan metabolism	1	76.1×	0.050	AGRN
Physiological factors	1	67.2×	0.050	CORIN
Attachment and Entry	1	60.1×	0.050	AGRN
Defective B4GALT7 causes EDS, progeroid type	1	57.1×	0.050	AGRN
Defective B3GAT3 causes JDSSDHD	1	57.1×	0.050	AGRN
Defective B3GALT6 causes EDSP2 and SEMDJL1	1	57.1×	0.050	AGRN
Heparan sulfate/heparin (HS-GAG) metabolism	1	54.4×	0.050	AGRN
HS-GAG degradation	1	49.6×	0.050	AGRN
Respiratory syncytial virus (RSV) attachment and entry	1	49.6×	0.050	AGRN
Initiation of coagulation cascade	1	47.6×	0.050	AGRN
Axon guidance	2	9.0×	0.050	SCN4A, AGRN
Nervous system development	2	8.6×	0.050	SCN4A, AGRN
Glycosaminoglycan-protein linkage region biosynthesis	1	39.4×	0.055	AGRN
Metabolism of fat-soluble vitamins	1	38.1×	0.055	AGRN

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 13 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
synaptic transmission, cholinergic	4	246.9×	1e-07	CHRNA1, CHRNB1, CHRNE, RAPSN
acetylcholine receptor signaling pathway	4	192.1×	2e-07	CHRNA1, CHRNB1, CHRND, CHRNE
neuromuscular junction development	4	162.0×	2e-07	CHRNA1, DOK7, AGRN, MUSK
skeletal muscle contraction	4	157.1×	2e-07	CHRNA1, CHRNB1, CHRND, CHRNE
membrane depolarization	4	157.1×	2e-07	CHRNA1, CHRNB1, CHRND, CHRNE
skeletal muscle acetylcholine-gated channel clustering	3	432.1×	4e-07	LRP4, MUSK, RAPSN
muscle contraction	4	64.0×	4e-06	SCN4A, CHRNB1, CHRND, CHRNE
monoatomic ion transmembrane transport	4	64.0×	4e-06	CHRNA1, CHRNB1, CHRND, CHRNE
skeletal muscle tissue growth	2	432.1×	7e-05	CHRNA1, CHRND
musculoskeletal movement	2	432.1×	7e-05	CHRNA1, CHRND
positive regulation of skeletal muscle acetylcholine-gated channel clustering	2	288.1×	2e-04	DOK7, LRP4
enzyme-linked receptor protein signaling pathway	2	199.4×	3e-04	DOK7, LRP4
neurotransmitter receptor localization to postsynaptic specialization membrane	2	123.5×	8e-04	DOK7, RAPSN
positive regulation of Rac protein signal transduction	2	99.7×	0.001	DOK7, LRP4
receptor clustering	2	96.0×	0.001	DOK7, AGRN
neuromuscular synaptic transmission	2	92.6×	0.001	CHRNA1, CHRNB1
Rac protein signal transduction	2	86.4×	0.001	DOK7, LRP4
neuromuscular process	2	81.0×	0.001	CHRNA1, CHRND
chemical synaptic transmission	3	17.8×	0.003	CHRND, CHRNE, RAPSN
positive regulation of synaptic assembly at neuromuscular junction	1	1296.3×	0.003	AGRN
regulation of skeletal muscle contraction by action potential	1	1296.3×	0.003	SCN4A
regulation of postsynaptic membrane organization	1	1296.3×	0.003	RAPSN
positive regulation of presynaptic membrane organization	1	1296.3×	0.003	LRP4
establishment of protein localization to postsynaptic membrane	1	1296.3×	0.003	RAPSN
positive regulation of protein geranylgeranylation	1	1296.3×	0.003	MUSK
synapse organization	2	43.2×	0.003	AGRN, LRP4
regulation of membrane potential	2	35.5×	0.005	CHRNA1, CHRNB1
CDP biosynthetic process	1	648.1×	0.005	AK9
positive regulation of motor neuron apoptotic process	1	648.1×	0.005	RAPSN
regulation of systemic arterial blood pressure by atrial natriuretic peptide	1	432.1×	0.006	CORIN

Therapeutics

Drug target analysis

Approved (phase 4): 6 · Phase ≥3: 6 · Phased (≥1): 6 · Undrugged: 7

Druggability breadth: 8 of 13 evidence-associated genes (62%) 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
SCN4A	CARBAMAZEPINE
CHRNA1	VARENICLINE
CHRNB1	VARENICLINE
CHRND	VARENICLINE
CHRNE	MECAMYLAMINE
MUSK	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCN4A	24	4
MUSK	20	4
CHRNA1	12	4
CHRNB1	10	4
CHRND	10	4
CHRNE	4	4
CORIN	0	0
COL13A1	0	0
DOK7	0	0
AGRN	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CARBAMAZEPINE	4	SCN4A
PHENYTOIN	4	SCN4A
LAMOTRIGINE	4	SCN4A
RILUZOLE	4	SCN4A
LIDOCAINE	4	SCN4A
IMIPRAMINE	4	SCN4A
SERTINDOLE	4	SCN4A
PIMOZIDE	4	SCN4A
NIFEDIPINE	4	SCN4A
DILTIAZEM	4	SCN4A
MIBEFRADIL	4	SCN4A
HALOPERIDOL	4	SCN4A
MEXILETINE	4	SCN4A
AMITRIPTYLINE	4	SCN4A
AMIODARONE	4	SCN4A
CHLORPROMAZINE	4	SCN4A
VARENICLINE	4	CHRNA1, CHRNB1, CHRND
NICOTINE	4	CHRNA1, CHRNB1, CHRND, CHRNE
TROPISETRON	4	CHRNA1, CHRNB1, CHRND
BUPROPION	4	CHRNA1, CHRNB1, CHRND
MECAMYLAMINE	4	CHRNA1, CHRNB1, CHRND, CHRNE
DONEPEZIL	4	CHRNE
TACRINE	4	CHRNE
FEDRATINIB	4	MUSK
SORAFENIB	4	MUSK
NINTEDANIB	4	MUSK
SUNITINIB	4	MUSK
QUIZARTINIB	4	MUSK
CRIZOTINIB	4	MUSK
VIXOTRIGINE	3	SCN4A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
MUSK	247	Binding:247
CHRNA1	157	Binding:107, Functional:47, ADMET:2, Toxicity:1
SCN4A	95	Binding:69, Functional:18, ADMET:7, Toxicity:1
CHRNB1	87	Binding:51, Functional:36
CHRND	75	Binding:44, Functional:31
CHRNE	28	Binding:26, Functional:2
AGRN	3	Binding:3
RAPSN	1	Binding:1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
CHRNA1	157
MUSK	247

Pharmacogenomics

Cohort genes with a PharmGKB record: 13; 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)
CARBAMAZEPINE	4	SCN4A
PHENYTOIN	4	SCN4A
LAMOTRIGINE	4	SCN4A
RILUZOLE	4	SCN4A
LIDOCAINE	4	SCN4A
IMIPRAMINE	4	SCN4A
SERTINDOLE	4	SCN4A
PIMOZIDE	4	SCN4A
NIFEDIPINE	4	SCN4A
DILTIAZEM	4	SCN4A
MIBEFRADIL	4	SCN4A
HALOPERIDOL	4	SCN4A
MEXILETINE	4	SCN4A
AMITRIPTYLINE	4	SCN4A
AMIODARONE	4	SCN4A
CHLORPROMAZINE	4	SCN4A
VARENICLINE	4	CHRNA1, CHRNB1, CHRND
NICOTINE	4	CHRNA1, CHRNB1, CHRND, CHRNE
TROPISETRON	4	CHRNA1, CHRNB1, CHRND
BUPROPION	4	CHRNA1, CHRNB1, CHRND
MECAMYLAMINE	4	CHRNA1, CHRNB1, CHRND, CHRNE
DONEPEZIL	4	CHRNE
TACRINE	4	CHRNE
FEDRATINIB	4	MUSK
SORAFENIB	4	MUSK
NINTEDANIB	4	MUSK
SUNITINIB	4	MUSK
QUIZARTINIB	4	MUSK
CRIZOTINIB	4	MUSK
VIXOTRIGINE	3	SCN4A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	6	SCN4A, CHRNA1, CHRNB1, CHRND, CHRNE, MUSK
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	CORIN
E	Difficult family or no structure, no drug	6	COL13A1, DOK7, AGRN, AK9, LRP4, RAPSN

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
DOK7	0	MUSK
AGRN	3	MUSK
LRP4	0	MUSK
RAPSN	1	MUSK, CHRND, CHRNB1
CORIN	0	—
COL13A1	0	—
AK9	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.