Congenital myasthenic syndrome 8

Summary

Congenital myasthenic syndrome 8 (MONDO:0014052) is a disease caused by AGRN (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: AGRN (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 2,229

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital myasthenic syndrome 8
Mondo ID	MONDO:0014052
OMIM	615120
DOID	DOID:0110657
UMLS	C3808739
MedGen	815069
GARD	0015908
Is cancer (heuristic)	no

Also known as: AGRN congenital myasthenic syndrome · CMS8 · congenital myasthenic syndrome 8 · congenital myasthenic syndrome caused by mutation in AGRN · congenital myasthenic syndrome type 8 · myasthenic syndrome, congenital, 8 · myasthenic syndrome, congenital, 8, with pre- and postsynaptic defects · myasthenic syndrome, congenital, type 8

Data availability: 2,229 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 8

Related subtypes (13): congenital myasthenic syndrome 10, congenital myasthenic syndrome 1A, congenital myasthenic syndrome 16, 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

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

350 uncertain significance, 189 likely benign, 22 benign, 14 pathogenic, 11 conflicting classifications of pathogenicity, 11 benign/likely benign, 3 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1070058	NM_198576.4(AGRN):c.3724C>T (p.Gln1242Ter)	AGRN	Pathogenic	criteria provided, single submitter
1070394	NC_000001.10:g.(?954503)(992499_?)del	AGRN	Pathogenic	criteria provided, single submitter
1071394	NM_198576.4(AGRN):c.3973_3979dup (p.Gln1327fs)	AGRN	Pathogenic	criteria provided, single submitter
1072755	NM_198576.4(AGRN):c.543dup (p.Val182fs)	AGRN	Pathogenic	criteria provided, single submitter
1076092	NM_198576.4(AGRN):c.2002G>T (p.Glu668Ter)	AGRN	Pathogenic	criteria provided, single submitter
126556	NM_198576.4(AGRN):c.1057C>T (p.Gln353Ter)	AGRN	Pathogenic	no assertion criteria provided
1284256	NM_198576.4(AGRN):c.1385-42G>C	AGRN	Pathogenic	no assertion criteria provided
1322937	NM_198576.4(AGRN):c.4217_4218del (p.Gln1406fs)	AGRN	Pathogenic	criteria provided, multiple submitters, no conflicts
1384683	NM_198576.4(AGRN):c.1105_1106del (p.Val369fs)	AGRN	Pathogenic	criteria provided, single submitter
1397221	NM_198576.4(AGRN):c.5753_5754del (p.Tyr1918fs)	AGRN	Pathogenic	criteria provided, single submitter
1429166	NM_198576.4(AGRN):c.4744G>A (p.Gly1582Arg)	AGRN	Pathogenic	criteria provided, multiple submitters, no conflicts
1454542	NM_198576.4(AGRN):c.5703del (p.Thr1902fs)	AGRN	Pathogenic	criteria provided, single submitter
1454812	NM_198576.4(AGRN):c.1077_1083del (p.Asp359fs)	AGRN	Pathogenic	criteria provided, single submitter
1458742	NM_198576.4(AGRN):c.5554_5555dup (p.Glu1853fs)	AGRN	Pathogenic	criteria provided, single submitter
1177400	NM_198576.4(AGRN):c.4922dup (p.Asn1641fs)	AGRN	Likely pathogenic	criteria provided, single submitter
126555	NM_198576.4(AGRN):c.5179G>T (p.Val1727Phe)	AGRN	Likely pathogenic	criteria provided, single submitter
1525296	NM_198576.4(AGRN):c.3250+1G>A	AGRN	Likely pathogenic	criteria provided, single submitter
1014329	NM_198576.4(AGRN):c.1553C>T (p.Thr518Met)	AGRN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1056623	NM_198576.4(AGRN):c.1352G>A (p.Arg451His)	AGRN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1061432	NM_198576.4(AGRN):c.5096G>A (p.Arg1699His)	AGRN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1132750	NM_198576.4(AGRN):c.1929C>T (p.Cys643=)	AGRN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1156526	NM_198576.4(AGRN):c.4476C>T (p.Asp1492=)	AGRN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
128314	NM_198576.4(AGRN):c.5353G>A (p.Asp1785Asn)	AGRN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1356678	NM_198576.4(AGRN):c.5012G>A (p.Arg1671Gln)	AGRN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1383194	NM_198576.4(AGRN):c.3068G>A (p.Arg1023Gln)	AGRN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1415122	NM_198576.4(AGRN):c.4061C>A (p.Thr1354Asn)	AGRN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1417342	NM_198576.4(AGRN):c.4811G>A (p.Arg1604His)	AGRN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1499207	NM_198576.4(AGRN):c.6028G>A (p.Gly2010Ser)	AGRN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1000752	NM_198576.4(AGRN):c.4844G>A (p.Cys1615Tyr)	AGRN	Uncertain significance	criteria provided, single submitter
1000760	NM_198576.4(AGRN):c.371T>C (p.Leu124Pro)	AGRN	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 3 · 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
AGRN	Strong	Autosomal recessive	congenital myasthenic syndrome 8	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AGRN	Orphanet:98913	Postsynaptic congenital myasthenic syndrome
AGRN	Orphanet:98914	Presynaptic congenital myasthenic syndromes
TNFRSF4	Orphanet:431149	Combined immunodeficiency due to OX40 deficiency

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
AGRN	HGNC:329	ENSG00000188157	O00468	Agrin	gencc,clinvar
TNFRSF4	HGNC:11918	ENSG00000186827	P43489	Tumor necrosis factor receptor superfamily member 4	clinvar
SLC35E2A	HGNC:20863	ENSG00000215790	P0CK97	Solute carrier family 35 member E2A	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
TNFRSF4	Tumor necrosis factor receptor superfamily member 4	Receptor for TNFSF4/OX40L/GP34.
SLC35E2A	Solute carrier family 35 member E2A	Putative transporter.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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
Transporter	1	25.9×	0.076
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AGRN	Other/Unknown	no		SEA_dom, EGF, Laminin_G
TNFRSF4	Other/Unknown	no		TNFR/NGFR_Cys_rich_reg, TNFR_4, TNFRSF4_N
SLC35E2A	Transporter	yes		Sugar_P_trans_dom, TPT_transporter

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right uterine tube	2
metanephros cortex	1
renal medulla	1
apex of heart	1
granulocyte	1
primordial germ cell in gonad	1
cortical plate	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AGRN	271	ubiquitous	marker	right uterine tube, metanephros cortex, renal medulla
TNFRSF4	160	broad	marker	apex of heart, granulocyte, primordial germ cell in gonad
SLC35E2A	205		marker	stromal cell of endometrium, cortical plate, right uterine tube

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AGRN	3,117
TNFRSF4	1,779
SLC35E2A	491

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TNFRSF4	P43489	8
AGRN	O00468	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SLC35E2A	P0CK97	54.41

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 46. Enrichment computed across 3 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Early SARS-CoV-2 Infection Events	1	519.1×	0.015	AGRN
Chondroitin sulfate/dermatan sulfate metabolism	1	475.8×	0.015	AGRN
Defective EXT2 causes exostoses 2	1	407.9×	0.015	AGRN
Defective EXT1 causes exostoses 1, TRPS2 and CHDS	1	407.9×	0.015	AGRN
Diseases associated with glycosaminoglycan metabolism	1	380.7×	0.015	AGRN
Attachment and Entry	1	300.5×	0.015	AGRN
Defective B4GALT7 causes EDS, progeroid type	1	285.5×	0.015	AGRN
Defective B3GAT3 causes JDSSDHD	1	285.5×	0.015	AGRN
Defective B3GALT6 causes EDSP2 and SEMDJL1	1	285.5×	0.015	AGRN
Heparan sulfate/heparin (HS-GAG) metabolism	1	271.9×	0.015	AGRN
HS-GAG degradation	1	248.3×	0.015	AGRN
Respiratory syncytial virus (RSV) attachment and entry	1	248.3×	0.015	AGRN
Initiation of coagulation cascade	1	237.9×	0.015	AGRN
Glycosaminoglycan-protein linkage region biosynthesis	1	196.9×	0.015	AGRN
TNFs bind their physiological receptors	1	196.9×	0.015	TNFRSF4
Metabolism of fat-soluble vitamins	1	190.3×	0.015	AGRN
HS-GAG biosynthesis	1	173.0×	0.016	AGRN
Formation of the dystrophin-glycoprotein complex (DGC)	1	154.3×	0.016	AGRN
NCAM signaling for neurite out-growth	1	135.9×	0.016	AGRN
Visual phototransduction	1	129.8×	0.016	AGRN
Dengue Virus Attachment and Entry	1	129.8×	0.016	AGRN
NCAM1 interactions	1	124.1×	0.016	AGRN
Retinoid metabolism and transport	1	124.1×	0.016	AGRN
Regulation of clotting cascade	1	116.5×	0.016	AGRN
Glycosaminoglycan metabolism	1	109.8×	0.017	AGRN
Respiratory Syncytial Virus Infection Pathway	1	98.5×	0.018	AGRN
RSV-host interactions	1	78.2×	0.021	AGRN
Non-integrin membrane-ECM interactions	1	77.2×	0.021	AGRN
ECM proteoglycans	1	75.1×	0.021	AGRN
Integrin cell surface interactions	1	67.2×	0.023	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 3 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 synaptic assembly at neuromuscular junction	1	5617.3×	0.003	AGRN
clustering of voltage-gated sodium channels	1	802.5×	0.011	AGRN
G protein-coupled acetylcholine receptor signaling pathway	1	351.1×	0.016	AGRN
filopodium assembly	1	216.1×	0.016	AGRN
receptor clustering	1	208.1×	0.016	AGRN
neuromuscular junction development	1	175.5×	0.016	AGRN
positive regulation of immunoglobulin production	1	160.5×	0.016	TNFRSF4
T cell proliferation	1	127.7×	0.017	TNFRSF4
positive regulation of B cell proliferation	1	114.6×	0.017	TNFRSF4
chondrocyte differentiation	1	100.3×	0.017	AGRN
synapse organization	1	93.6×	0.017	AGRN
transmembrane transport	1	56.2×	0.027	SLC35E2A
cell surface receptor signaling pathway	1	21.4×	0.064	AGRN
immune response	1	15.7×	0.080	TNFRSF4
inflammatory response	1	12.6×	0.093	TNFRSF4
negative regulation of transcription by RNA polymerase II	1	5.9×	0.180	TNFRSF4
signal transduction	1	5.3×	0.186	AGRN
positive regulation of transcription by RNA polymerase II	1	5.0×	0.188	AGRN

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 3

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
AGRN	0	0
TNFRSF4	0	0
SLC35E2A	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
AGRN	3	Binding:3

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

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	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	SLC35E2A
E	Difficult family or no structure, no drug	2	AGRN, TNFRSF4

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
AGRN	3	—
TNFRSF4	0	—
SLC35E2A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.