Congenital myasthenic syndrome 9

Summary

Congenital myasthenic syndrome 9 (MONDO:0014587) is a disease caused by MUSK (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: MUSK (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 734

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital myasthenic syndrome 9
Mondo ID	MONDO:0014587
OMIM	616325
DOID	DOID:0110670
UMLS	C4225368
MedGen	895641
GARD	0016088
Is cancer (heuristic)	no

Also known as: CMS9 · congenital myasthenic syndrome caused by mutation in MUSK · congenital myasthenic syndrome type 9 · MUSK congenital myasthenic syndrome · myasthenic syndrome, congenital, 9, associated with acetylcholine receptor deficiency

Data availability: 734 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › postsynaptic congenital myasthenic syndrome › congenital myasthenic syndrome 9

Related subtypes (13): 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 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

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

311 likely benign, 161 uncertain significance, 38 pathogenic, 30 conflicting classifications of pathogenicity, 26 likely pathogenic, 17 benign, 14 benign/likely benign, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
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
190467	NM_005592.4(MUSK):c.1724T>C (p.Ile575Thr)	MUSK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2018617	NM_005592.4(MUSK):c.31_34del (p.His11fs)	MUSK	Pathogenic	criteria provided, single submitter
2025875	NM_005592.4(MUSK):c.1466C>G (p.Ser489Ter)	MUSK	Pathogenic	criteria provided, single submitter
2080073	NM_005592.4(MUSK):c.1555C>T (p.Arg519Ter)	MUSK	Pathogenic	criteria provided, single submitter
211542	NM_005592.4(MUSK):c.79+2T>G	MUSK	Pathogenic	criteria provided, multiple submitters, no conflicts
2139033	NM_005592.4(MUSK):c.2358G>A (p.Trp786Ter)	MUSK	Pathogenic	criteria provided, single submitter
2425378	NC_000009.11:g.(?113444934)(113449568_?)del	MUSK	Pathogenic	criteria provided, single submitter
2425379	NC_000009.11:g.(?113509901)(113538955_?)del	MUSK	Pathogenic	criteria provided, single submitter
2928495	NM_005592.4(MUSK):c.1218C>A (p.Cys406Ter)	MUSK	Pathogenic	criteria provided, single submitter
2930356	NM_005592.4(MUSK):c.845_848dup (p.Ile283fs)	MUSK	Pathogenic	criteria provided, single submitter
2931558	NM_005592.4(MUSK):c.1091_1092del (p.Pro364fs)	MUSK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2931650	NM_005592.4(MUSK):c.2010del (p.Met670fs)	MUSK	Pathogenic	criteria provided, single submitter
2932520	NM_005592.4(MUSK):c.461G>A (p.Trp154Ter)	MUSK	Pathogenic	criteria provided, single submitter
2934375	NM_005592.4(MUSK):c.2034_2035del (p.His680fs)	MUSK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2936081	NM_005592.4(MUSK):c.2T>C (p.Met1Thr)	MUSK	Pathogenic	criteria provided, multiple submitters, no conflicts
2937395	NM_005592.4(MUSK):c.545dup (p.Glu183fs)	MUSK	Pathogenic	criteria provided, single submitter
2941162	NM_005592.4(MUSK):c.1840del (p.Glu614fs)	MUSK	Pathogenic	criteria provided, single submitter
2941926	NM_005592.4(MUSK):c.1826del (p.Lys609fs)	MUSK	Pathogenic	criteria provided, single submitter
2944470	NM_005592.4(MUSK):c.2021_2022dup (p.Val675fs)	MUSK	Pathogenic	criteria provided, single submitter
2945921	NM_005592.4(MUSK):c.868del (p.Glu290fs)	MUSK	Pathogenic	criteria provided, single submitter
2948129	NM_005592.4(MUSK):c.166dup (p.Gln56fs)	MUSK	Pathogenic	criteria provided, single submitter
2948197	NM_005592.4(MUSK):c.1299_1300del (p.Cys434fs)	MUSK	Pathogenic	criteria provided, single submitter
2949414	NM_005592.4(MUSK):c.1384del (p.Thr462fs)	MUSK	Pathogenic	criteria provided, single submitter
2951981	NM_005592.4(MUSK):c.790C>T (p.Arg264Ter)	MUSK	Pathogenic	criteria provided, multiple submitters, no conflicts
2953074	NM_005592.4(MUSK):c.2122C>T (p.Gln708Ter)	MUSK	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 2 · 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
MUSK	Strong	Autosomal recessive	congenital myasthenic syndrome 9	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MUSK	Orphanet:98913	Postsynaptic congenital myasthenic syndrome
MUSK	Orphanet:994	Fetal akinesia deformation sequence

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MUSK	HGNC:7525	ENSG00000030304	O15146	Muscle, skeletal receptor tyrosine-protein kinase	gencc,clinvar
SVEP1	HGNC:15985	ENSG00000165124	Q4LDE5	Sushi, von Willebrand factor type A, EGF and pentraxin domain-containing protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
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.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Complement	1	134.0×	0.015
Kinase	1	13.9×	0.071

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MUSK	Kinase	yes		Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Ig_sub2
SVEP1	Complement	yes		EGF-type_Asp/Asn_hydroxyl_site, Sushi_SCR_CCP_dom, EGF

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	1
mucosa of stomach	1
sural nerve	1
lower lobe of lung	1
pericardium	1
placenta	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MUSK	151	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, mucosa of stomach, sural nerve
SVEP1	225	broad	marker	pericardium, lower lobe of lung, placenta

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SVEP1	2,261
MUSK	1,809

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MUSK	O15146	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SVEP1	Q4LDE5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 2 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
ECM proteoglycans	1	150.3×	0.013	MUSK
Extracellular matrix organization	1	63.1×	0.016	MUSK

GO biological processes by enrichment

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

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of protein geranylgeranylation	1	8426.0×	0.002	MUSK
lymph circulation	1	4213.0×	0.002	SVEP1
lymph vessel morphogenesis	1	2808.7×	0.002	SVEP1
Tie signaling pathway	1	1685.2×	0.002	SVEP1
tight junction organization	1	1685.2×	0.002	SVEP1
skeletal muscle acetylcholine-gated channel clustering	1	936.2×	0.003	MUSK
regulation of synaptic assembly at neuromuscular junction	1	842.6×	0.003	MUSK
negative regulation of vasoconstriction	1	842.6×	0.003	SVEP1
positive regulation of platelet activation	1	648.1×	0.003	SVEP1
neuromuscular junction development	1	263.3×	0.006	MUSK
positive regulation of protein phosphorylation	1	138.1×	0.011	MUSK
epidermis development	1	105.3×	0.013	SVEP1
memory	1	91.6×	0.014	MUSK
cell surface receptor protein tyrosine kinase signaling pathway	1	86.9×	0.014	MUSK
gene expression	1	39.9×	0.028	SVEP1
positive regulation of gene expression	1	19.4×	0.054	MUSK
cell differentiation	1	14.6×	0.068	MUSK

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MUSK	20	4
SVEP1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	MUSK
SORAFENIB	4	MUSK
NINTEDANIB	4	MUSK
SUNITINIB	4	MUSK
QUIZARTINIB	4	MUSK
CRIZOTINIB	4	MUSK
LINIFANIB	3	MUSK
DOVITINIB	3	MUSK
LESTAURTINIB	3	MUSK
DORAMAPIMOD	2	MUSK
FORETINIB	2	MUSK
SU-014813	2	MUSK
DEFOSBARASERTIB	2	MUSK
R-406	2	MUSK
MILREBRUTINIB	2	MUSK
TOZASERTIB	2	MUSK
BMS-754807	2	MUSK
KW-2449	1	MUSK
PF-06273340	1	MUSK
AST-487	1	MUSK

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

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
MUSK	247

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

20 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
SORAFENIB	4	MUSK
NINTEDANIB	4	MUSK
SUNITINIB	4	MUSK
QUIZARTINIB	4	MUSK
CRIZOTINIB	4	MUSK
LINIFANIB	3	MUSK
DOVITINIB	3	MUSK
LESTAURTINIB	3	MUSK
DORAMAPIMOD	2	MUSK
FORETINIB	2	MUSK
SU-014813	2	MUSK
DEFOSBARASERTIB	2	MUSK
R-406	2	MUSK
MILREBRUTINIB	2	MUSK
TOZASERTIB	2	MUSK
BMS-754807	2	MUSK
KW-2449	1	MUSK
PF-06273340	1	MUSK
AST-487	1	MUSK

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	MUSK
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	SVEP1
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SVEP1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.