Arthrogryposis multiplex congenita 1, neurogenic, with myelin defect

Summary

Arthrogryposis multiplex congenita 1, neurogenic, with myelin defect (MONDO:0060486) is a disease caused by LGI4 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: LGI4 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 32

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	arthrogryposis multiplex congenita 1, neurogenic, with myelin defect
Mondo ID	MONDO:0060486
OMIM	617468
DOID	DOID:0080978
UMLS	C4479539
MedGen	1373185
GARD	0018566
Is cancer (heuristic)	no

Also known as: AMCNMY · arthrogryposis multiplex congenita, neurogenic, with myelin defect

Data availability: 32 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › arthrogryposis multiplex congenita › hypomyelination neuropathy-arthrogryposis syndrome › arthrogryposis multiplex congenita 1, neurogenic, with myelin defect

Related subtypes (3): lethal congenital contracture syndrome 7, lethal congenital contracture syndrome 8, neuropathy, congenital hypomyelinating, 3

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

32 retrieved; paginated sample, class counts are floors:

8 uncertain significance, 8 benign, 8 likely pathogenic, 7 pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
424865	NM_139284.3(LGI4):c.793G>A (p.Ala265Thr)	LGI4	Pathogenic	no assertion criteria provided
424866	NM_139284.3(LGI4):c.863G>A (p.Trp288Ter)	LGI4	Pathogenic	no assertion criteria provided
424867	NM_139284.3(LGI4):c.793+5G>C	LGI4	Pathogenic	no assertion criteria provided
424868	NM_139284.3(LGI4):c.1301T>A (p.Val434Asp)	LGI4	Pathogenic	no assertion criteria provided
424869	NM_139284.3(LGI4):c.1299+5G>T	LGI4	Pathogenic	no assertion criteria provided
424870	NM_139284.3(LGI4):c.773G>C (p.Arg258Pro)	LGI4	Pathogenic	no assertion criteria provided
549679	NM_139284.3(LGI4):c.1153C>T (p.Gln385Ter)	LGI4	Pathogenic	no assertion criteria provided
1252057	NM_139284.3(LGI4):c.961G>A (p.Glu321Lys)	LGI4	Likely pathogenic	no assertion criteria provided
2441163	NM_139284.3(LGI4):c.312C>A (p.Tyr104Ter)	LGI4	Likely pathogenic	criteria provided, single submitter
2444227	NM_139284.3(LGI4):c.774_778dup (p.Glu260fs)	LGI4	Likely pathogenic	criteria provided, single submitter
4845822	NM_139284.3(LGI4):c.869dup (p.Ser291fs)	LGI4	Likely pathogenic	criteria provided, single submitter
549680	NM_139284.3(LGI4):c.200T>G (p.Leu67Arg)	LGI4	Likely pathogenic	no assertion criteria provided
800799	NM_139284.3(LGI4):c.834del (p.Ser279fs)	LGI4	Likely pathogenic	criteria provided, single submitter
974840	NM_139284.3(LGI4):c.1272C>A (p.Cys424Ter)	LGI4	Likely pathogenic	criteria provided, single submitter
974841	NM_139284.3(LGI4):c.263_265del (p.Phe88del)	LGI4	Likely pathogenic	criteria provided, single submitter
1324662	NM_139284.3(LGI4):c.61A>T (p.Arg21Ter)	LGI4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1032440	NM_139284.3(LGI4):c.17T>A (p.Ile6Asn)	LGI4	Uncertain significance	criteria provided, single submitter
1032441	NM_139284.3(LGI4):c.493C>T (p.Arg165Cys)	LGI4	Uncertain significance	criteria provided, single submitter
2433426	NM_139284.3(LGI4):c.1250C>A (p.Ala417Asp)	LGI4	Uncertain significance	criteria provided, single submitter
2433427	NM_139284.3(LGI4):c.242T>A (p.Leu81His)	LGI4	Uncertain significance	criteria provided, single submitter
2433428	NM_139284.3(LGI4):c.632T>A (p.Leu211Gln)	LGI4	Uncertain significance	criteria provided, multiple submitters, no conflicts
2444314	NM_139284.3(LGI4):c.1087C>T (p.Arg363Trp)	LGI4	Uncertain significance	criteria provided, single submitter
3242075	NM_139284.3(LGI4):c.1259_1266delinsCACACCAG (p.Asp420_Phe422delinsAlaHisGln)	LGI4	Uncertain significance	criteria provided, single submitter
3362460	NM_139284.3(LGI4):c.830G>C (p.Gly277Ala)	LGI4	Uncertain significance	criteria provided, single submitter
1179838	NM_139284.3(LGI4):c.456T>C (p.His152=)	LGI4	Benign	criteria provided, multiple submitters, no conflicts
1221533	NM_139284.3(LGI4):c.*11G>A	LGI4	Benign	criteria provided, multiple submitters, no conflicts
1243198	NM_139284.3(LGI4):c.459-33G>A	LGI4	Benign	criteria provided, multiple submitters, no conflicts
1243576	NM_139284.3(LGI4):c.1396C>T (p.Leu466=)	LGI4	Benign	criteria provided, multiple submitters, no conflicts
1247001	NM_139284.3(LGI4):c.1203A>G (p.Thr401=)	LGI4	Benign	criteria provided, multiple submitters, no conflicts
1247836	NM_139284.3(LGI4):c.*10C>T	LGI4	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
LGI4	Strong	Autosomal recessive	arthrogryposis multiplex congenita 1, neurogenic, with myelin defect	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LGI4	Orphanet:2680	Hypomyelination neuropathy-arthrogryposis syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
LGI4	HGNC:18712	ENSG00000153902	Q8N135	Leucine-rich repeat LGI family member 4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LGI4	Leucine-rich repeat LGI family member 4	Component of Schwann cell signaling pathway(s) that controls axon segregation and myelin formation.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LGI4	Other/Unknown	no		Cys-rich_flank_reg_C, Leu-rich_rpt, Leu-rich_rpt_typical-subtyp

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
nerve	1
peripheral nervous system	1
tibial nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LGI4	214	broad	marker	peripheral nervous system, nerve, tibial nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LGI4	879

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LGI4	Q8N135	92.80

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 1 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
LGI-ADAM interactions	1	815.7×	0.002	LGI4
Developmental Biology	1	14.5×	0.069	LGI4

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
glial cell proliferation	1	887.0×	0.002	LGI4
myelination in peripheral nervous system	1	887.0×	0.002	LGI4
regulation of myelination	1	887.0×	0.002	LGI4
neuron maturation	1	802.5×	0.002	LGI4
adult locomotory behavior	1	300.9×	0.003	LGI4

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LGI4	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	0
E	Difficult family or no structure, no drug	1	LGI4

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)
LGI4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.