congenital myasthenic syndrome 4A

Summary

congenital myasthenic syndrome 4A (MONDO:0011600) is a disease caused by CHRNE (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: CHRNE (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 1,245

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital myasthenic syndrome 4A
Mondo ID	MONDO:0011600
OMIM	605809
DOID	DOID:0110678
UMLS	C4225413
MedGen	908188
GARD	0015387
Is cancer (heuristic)	no

Also known as: Cms Ia1 · CMS4A · congenital myasthenic syndrome type 4A · congenital myasthenic syndrome type Ia1 · myasthenic syndrome, congenital, 4A, slow-channel

Data availability: 1,245 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 4 › congenital myasthenic syndrome 4A

Related subtypes (2): congenital myasthenic syndrome 4C, congenital myasthenic syndrome 4B

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:

325 likely benign, 145 uncertain significance, 47 pathogenic, 25 conflicting classifications of pathogenicity, 25 pathogenic/likely pathogenic, 17 benign, 12 likely pathogenic, 4 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069436	NM_000080.4(CHRNE):c.590_591del (p.Glu197fs)	C17orf107	Pathogenic	criteria provided, single submitter
1072517	NM_000080.4(CHRNE):c.647_653dup (p.His218fs)	C17orf107	Pathogenic	criteria provided, single submitter
1075930	NM_000080.4(CHRNE):c.529_551del (p.Glu177fs)	C17orf107	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076387	NM_000080.4(CHRNE):c.84T>G (p.Tyr28Ter)	C17orf107	Pathogenic	criteria provided, multiple submitters, no conflicts
1076580	NM_000080.4(CHRNE):c.829dup (p.Ile277fs)	C17orf107	Pathogenic	criteria provided, single submitter
1353344	NM_000080.4(CHRNE):c.316_317del (p.Trp106fs)	C17orf107	Pathogenic	criteria provided, single submitter
1398216	NC_000017.10:g.(?4805539)(4806690_?)del	C17orf107	Pathogenic	criteria provided, single submitter
1452179	NM_000080.4(CHRNE):c.372C>G (p.Tyr124Ter)	C17orf107	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453502	NM_000080.4(CHRNE):c.114_118dup (p.Arg40fs)	C17orf107	Pathogenic	criteria provided, single submitter
1454204	NM_000080.4(CHRNE):c.802+2T>C	C17orf107	Pathogenic	criteria provided, single submitter
1459509	NM_000080.4(CHRNE):c.712C>T (p.Arg238Trp)	C17orf107	Pathogenic	criteria provided, multiple submitters, no conflicts
18343	NM_000080.4(CHRNE):c.850A>C (p.Thr284Pro)	C17orf107	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
18344	NM_000080.4(CHRNE):c.865C>T (p.Leu289Phe)	C17orf107	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
18345	NM_000080.4(CHRNE):c.500G>T (p.Arg167Leu)	C17orf107	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
18347	NM_000080.4(CHRNE):c.250C>T (p.Arg84Ter)	C17orf107	Pathogenic	criteria provided, multiple submitters, no conflicts
18352	NM_000080.4(CHRNE):c.721C>T (p.Leu241Phe)	C17orf107	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
18357	NM_000080.4(CHRNE):c.614_620del (p.Trp205fs)	C17orf107	Pathogenic	criteria provided, multiple submitters, no conflicts
1995412	NM_000080.4(CHRNE):c.327_328dup (p.Ile110fs)	C17orf107	Pathogenic	criteria provided, single submitter
2011729	NM_000080.4(CHRNE):c.453_454dup (p.Val152fs)	C17orf107	Pathogenic	criteria provided, single submitter
2022812	NM_000080.4(CHRNE):c.11_14dup (p.Leu6fs)	C17orf107	Pathogenic	criteria provided, single submitter
2032611	NM_000080.4(CHRNE):c.400_403dup (p.Ser135fs)	C17orf107	Pathogenic	criteria provided, single submitter
2035396	NM_000080.4(CHRNE):c.951_954del (p.Ile318fs)	C17orf107	Pathogenic	criteria provided, single submitter
2046867	NM_000080.4(CHRNE):c.750_751del (p.Val252fs)	C17orf107	Pathogenic	criteria provided, single submitter
2079328	NM_000080.4(CHRNE):c.866del (p.Leu289fs)	C17orf107	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2094237	NM_000080.4(CHRNE):c.264del (p.Ser88fs)	C17orf107	Pathogenic	criteria provided, single submitter
2103384	NM_000080.4(CHRNE):c.653_666dup (p.Asp223fs)	C17orf107	Pathogenic	criteria provided, single submitter
2108647	NM_000080.4(CHRNE):c.852del (p.Val285fs)	C17orf107	Pathogenic	criteria provided, single submitter
2131088	NM_000080.4(CHRNE):c.293dup (p.Arg99fs)	C17orf107	Pathogenic	criteria provided, single submitter
2137884	NM_000080.4(CHRNE):c.520G>T (p.Glu174Ter)	C17orf107	Pathogenic	criteria provided, single submitter
2137885	NM_000080.4(CHRNE):c.393C>G (p.Tyr131Ter)	C17orf107	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 1 · 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
CHRNE	Definitive	Autosomal recessive	congenital myasthenic syndrome	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CHRNE	Orphanet:98913	Postsynaptic congenital myasthenic syndrome

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
CHRNE	HGNC:1966	ENSG00000108556	Q04844	Acetylcholine receptor subunit epsilon	gencc,clinvar
C17orf107	HGNC:37238	ENSG00000205710	Q6ZR85	Uncharacterized protein C17orf107	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CHRNE	Other/Unknown	no		Nicotinic_acetylcholine_rcpt, Neurotrans-gated_channel_TM, Neur_channel
C17orf107	Other/Unknown	no		C17orf107

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
adenohypophysis	2
right atrium auricular region	2
cardiac atrium	1
pituitary gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CHRNE	162	broad	yes	right atrium auricular region, cardiac atrium, adenohypophysis
C17orf107	131	broad	yes	adenohypophysis, pituitary gland, right atrium auricular region

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CHRNE	896
C17orf107	110

Intra-cohort edges

A	B	Sources
C17orf107	CHRNE	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CHRNE	Q04844	13

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
C17orf107	Q6ZR85	58.75

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. 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
Highly sodium permeable postsynaptic acetylcholine nicotinic receptors	1	1631.4×	0.002	CHRNE
Presynaptic nicotinic acetylcholine receptors	1	951.7×	0.002	CHRNE
Acetylcholine binding and downstream events	1	815.7×	0.002	CHRNE
Postsynaptic nicotinic acetylcholine receptors	1	815.7×	0.002	CHRNE
Neurotransmitter receptors and postsynaptic signal transmission	1	100.2×	0.014	CHRNE
Transmission across Chemical Synapses	1	76.1×	0.015	CHRNE
Neuronal System	1	44.3×	0.023	CHRNE

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
synaptic transmission, cholinergic	1	802.5×	0.004	CHRNE
acetylcholine receptor signaling pathway	1	624.1×	0.004	CHRNE
skeletal muscle contraction	1	510.7×	0.004	CHRNE
membrane depolarization	1	510.7×	0.004	CHRNE
muscle contraction	1	208.1×	0.006	CHRNE
monoatomic ion transmembrane transport	1	208.1×	0.006	CHRNE
chemical synaptic transmission	1	77.3×	0.015	CHRNE
signal transduction	1	16.1×	0.062	CHRNE

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
CHRNE	MECAMYLAMINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CHRNE	4	4
C17orf107	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MECAMYLAMINE	4	CHRNE
NICOTINE	4	CHRNE
DONEPEZIL	4	CHRNE
TACRINE	4	CHRNE

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
CHRNE	28	Binding:26, Functional:2

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

4 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)
MECAMYLAMINE	4	CHRNE
NICOTINE	4	CHRNE
DONEPEZIL	4	CHRNE
TACRINE	4	CHRNE

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CHRNE
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	C17orf107

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)
C17orf107	0	CHRNE

Clinical trials & evidence

Clinical trials

Clinical trials: 0.