Congenital myasthenic syndrome 10

Summary

Congenital myasthenic syndrome 10 (MONDO:0009690) is a disease caused by DOK7 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: DOK7 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 1,071

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital myasthenic syndrome 10
Mondo ID	MONDO:0009690
MeSH	C563716
OMIM	254300, 609456
DOID	DOID:0110638, DOID:0110668
SNOMED CT	230687001
UMLS	C1850792
MedGen	376880
GARD	0015206
Is cancer (heuristic)	no

Also known as: CMS Ib · Cms Ib · CMS10 · CMS1B · congenital muscular dystrophy merosin-positive · congenital myasthenic syndrome 10 · congenital myasthenic syndrome caused by mutation in DOK7 · congenital myasthenic syndrome type 10 · congenital myasthenic syndrome type IB · DOK7 congenital myasthenic syndrome · myasthenia, limb-girdle, familial · myasthenic myopathy · myasthenic syndrome, congenital, 10 · myasthenic syndrome, congenital, type 10

Data availability: 1,071 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › congenital muscular dystrophy › congenital myasthenic syndrome 10

Related subtypes (22): Ullrich congenital muscular dystrophy, Bethlem myopathy, arthrogryposis due to muscular dystrophy, congenital muscular dystrophy-infantile cataract-hypogonadism syndrome, muscular dystrophy, congenital, with rapid progression, megaconial type congenital muscular dystrophy, congenital muscular dystrophy 1B, congenital merosin-deficient muscular dystrophy 1A, congenital muscular dystrophy due to integrin alpha-7 deficiency, congenital muscular dystrophy due to LMNA mutation, congenital muscular dystrophy-respiratory failure-skin abnormalities-joint hyperlaxity syndrome, congenital myopathy, Paradas type, autosomal recessive myogenic arthrogryposis multiplex congenita, muscular dystrophy-dystroglycanopathy, congenital muscular dystrophy with hyperlaxity, muscle-eye-brain disease, rigid spine syndrome, congenital muscular dystrophy with cataracts and intellectual disability, SNUPN-related muscular dystrophy with or without multi-system involvement, congenital muscular dystrophy caused by variation in POMGNT2, collagen 6-related congenital muscular dystrophy, congenital muscular dystrophy without intellectual disability

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:

293 likely benign, 187 uncertain significance, 29 pathogenic, 26 conflicting classifications of pathogenicity, 22 benign, 15 benign/likely benign, 14 likely pathogenic, 14 pathogenic/likely pathogenic

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
1280	NM_173660.5(DOK7):c.55-1G>T	DOK7	Pathogenic	no assertion criteria provided
1282	NM_173660.5(DOK7):c.1378dup (p.Gln460fs)	DOK7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1332706	NM_173660.5(DOK7):c.930_933del (p.Met311fs)	DOK7	Pathogenic	criteria provided, single submitter
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
1804863	NM_173660.5(DOK7):c.451C>T (p.Gln151Ter)	DOK7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1952562	NM_173660.5(DOK7):c.473G>A (p.Arg158Gln)	DOK7	Pathogenic	criteria provided, multiple submitters, no conflicts
198626	NM_173660.5(DOK7):c.957del (p.Lys320fs)	DOK7	Pathogenic	criteria provided, multiple submitters, no conflicts
1994082	NM_173660.5(DOK7):c.429del (p.Asp143fs)	DOK7	Pathogenic	criteria provided, single submitter
2059967	NM_173660.5(DOK7):c.1324_1357del (p.Cys442fs)	DOK7	Pathogenic	criteria provided, multiple submitters, no conflicts
209148	NM_173660.5(DOK7):c.1476_1485dup (p.Gly496fs)	DOK7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
209149	NM_173660.5(DOK7):c.1138dup (p.Ala380fs)	DOK7	Pathogenic	criteria provided, multiple submitters, no conflicts
2102209	NM_173660.5(DOK7):c.1257_1269del (p.Ser419fs)	DOK7	Pathogenic	criteria provided, single submitter
210856	NM_173660.5(DOK7):c.596del (p.Ile199fs)	DOK7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2203504	NM_173660.5(DOK7):c.1001_1011dup (p.Ser338fs)	DOK7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2203505	NM_173660.5(DOK7):c.1361_1374del (p.Leu454fs)	DOK7	Pathogenic	criteria provided, single submitter
2413517	NM_173660.5(DOK7):c.1367dup (p.Met456fs)	DOK7	Pathogenic	criteria provided, single submitter
242521	NM_173660.5(DOK7):c.1263del (p.Ser422fs)	DOK7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2427510	NC_000004.11:g.(?3494466)(3495228_?)del	DOK7	Pathogenic	criteria provided, single submitter
2674876	NM_173660.5(DOK7):c.1247_1250dup (p.Asp417fs)	DOK7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · 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
DOK7	Definitive	Autosomal recessive	congenital myasthenic syndrome 10	8

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

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
DOK7	HGNC:26594	ENSG00000175920	Q18PE1	Protein Dok-7	gencc,clinvar
HGFAC	HGNC:4894	ENSG00000109758	Q04756	Hepatocyte growth factor activator serine protease	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.
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.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.5

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
Protease	1	18.3×	0.108
Scaffold/PPI	1	8.6×	0.112

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DOK7	Scaffold/PPI	no		PH_domain, IRS_PTB, PH-like_dom_sf
HGFAC	Protease	yes		Kringle, Fibronectin_type1, FN_type2_dom

Expression context

Cohort genes with no expression data: 0.

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
apex of heart	1
right atrium auricular region	1
tibialis anterior	1
liver	1
right lobe of liver	1
right testis	1

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
HGFAC	151	tissue_specific	yes	right lobe of liver, liver, right testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HGFAC	4,212
DOK7	704

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HGFAC	Q04756	7

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DOK7	Q18PE1	65.61

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
MET Receptor Activation	1	1903.3×	5e-04	HGFAC

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 tyrosine kinase activity	1	1053.2×	0.005	DOK7
positive regulation of skeletal muscle acetylcholine-gated channel clustering	1	936.2×	0.005	DOK7
enzyme-linked receptor protein signaling pathway	1	648.1×	0.005	DOK7
neurotransmitter receptor localization to postsynaptic specialization membrane	1	401.2×	0.005	DOK7
zymogen activation	1	337.0×	0.005	HGFAC
positive regulation of Rac protein signal transduction	1	324.1×	0.005	DOK7
receptor clustering	1	312.1×	0.005	DOK7
Rac protein signal transduction	1	280.9×	0.005	DOK7
neuromuscular junction development	1	263.3×	0.005	DOK7
blood coagulation	1	86.9×	0.013	HGFAC
proteolysis	1	17.1×	0.058	HGFAC

Therapeutics

Drug target analysis

Approved (phase 4): 0 · 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).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HGFAC	2	3
DOK7	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NAFAMOSTAT	3	HGFAC
CAMOSTAT	3	HGFAC

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
HGFAC	18	Binding:18

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

2 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)
NAFAMOSTAT	3	HGFAC
CAMOSTAT	3	HGFAC

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	HGFAC
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	DOK7

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)
DOK7	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.