Arthrogryposis multiplex congenita 2, neurogenic type

Summary

Arthrogryposis multiplex congenita 2, neurogenic type (MONDO:0008823) is a disease caused by ERGIC1 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: Unknown (Europe)
• Causal gene: ERGIC1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 3
• Phenotypes (HPO): 33

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 100 000	4.3	Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

33 HPO clinical features (Orphanet curated; top 33 by frequency):

HPO ID	Term	Frequency
HP:0001371	Flexion contracture	Obligate (100%)
HP:0003444	EMG: chronic denervation signs	Very frequent (80-99%)
HP:0001239	Wrist flexion contracture	Frequent (30-79%)
HP:0001284	Areflexia	Frequent (30-79%)
HP:0002987	Elbow flexion contracture	Frequent (30-79%)
HP:0003202	Skeletal muscle atrophy	Frequent (30-79%)
HP:0003484	Upper limb muscle weakness	Frequent (30-79%)
HP:0006380	Knee flexion contracture	Frequent (30-79%)
HP:0006466	Ankle flexion contracture	Frequent (30-79%)
HP:0007340	Lower limb muscle weakness	Frequent (30-79%)
HP:0008180	Mildly elevated creatine kinase	Frequent (30-79%)
HP:0000316	Hypertelorism	Occasional (5-29%)
HP:0000347	Micrognathia	Occasional (5-29%)
HP:0001357	Plagiocephaly	Occasional (5-29%)
HP:0001558	Decreased fetal movement	Occasional (5-29%)
HP:0001562	Oligohydramnios	Occasional (5-29%)
HP:0001623	Breech presentation	Occasional (5-29%)
HP:0001627	Abnormal heart morphology	Occasional (5-29%)
HP:0001838	Rocker bottom foot	Occasional (5-29%)
HP:0002058	Myopathic facies	Occasional (5-29%)
HP:0002098	Respiratory distress	Occasional (5-29%)
HP:0002380	Fasciculations	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0002747	Respiratory insufficiency due to muscle weakness	Occasional (5-29%)
HP:0002827	Hip dislocation	Occasional (5-29%)
HP:0003273	Hip contracture	Occasional (5-29%)
HP:0007477	Abnormal dermatoglyphics	Occasional (5-29%)
HP:0008110	Equinovarus deformity	Occasional (5-29%)
HP:0008807	Acetabular dysplasia	Occasional (5-29%)
HP:0010781	Skin dimple	Occasional (5-29%)
HP:0011968	Feeding difficulties	Occasional (5-29%)
HP:0030799	Scaphocephaly	Occasional (5-29%)
HP:0410263	Brain imaging abnormality	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	arthrogryposis multiplex congenita 2, neurogenic type
Mondo ID	MONDO:0008823
MeSH	C536614
OMIM	208100
Orphanet	1143
DOID	DOID:0090124
SNOMED CT	715316005
UMLS	C5435650
MedGen	1725686
GARD	0000790
Is cancer (heuristic)	no

Also known as: AMCN · arthrogryposis multiplex congenita, neurogenic type · neurogenic arthrogryposis multiplex congenita · neurogenic type of AMC

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

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › arthrogryposis multiplex congenita › arthrogryposis multiplex congenita 2, neurogenic type

Related subtypes (23): prenatal-onset spinal muscular atrophy with congenital bone fractures, adducted thumbs-arthrogryposis syndrome, Christian type, fetal akinesia deformation sequence, arthrogryposis multiplex congenita-whistling face syndrome, arthrogryposis-hyperkeratosis syndrome, lethal form, multiple pterygium-malignant hyperthermia syndrome, Marden-Walker syndrome, arthrogryposis due to muscular dystrophy, infantile-onset X-linked spinal muscular atrophy, van den Ende-Gupta syndrome, lethal arthrogryposis-anterior horn cell disease syndrome, lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome, arthrogryposis-like syndrome, autosomal recessive myogenic arthrogryposis multiplex congenita, Wieacker-Wolff syndrome (spectrum), arthrogryposis multiplex congenita 6, arthrogryposis multiplex congenita 3, myogenic type, arthrogryposis multiplex congenita 4, neurogenic, with agenesis of the corpus callosum, microphthalmia microtia fetal akinesia, MYBPC1-related autosomal recessive non-lethal arthrogryposis multiplex congenita syndrome, arthrogryposis multiplex congenita 5, hypomyelination neuropathy-arthrogryposis syndrome, arthrogryposis multiplex congenita 7, X-linked

Subtypes (1): arthrogryposis-renal dysfunction-cholestasis syndrome

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

3 retrieved; paginated sample, class counts are floors:

2 pathogenic, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
523093	NM_001031711.3(ERGIC1):c.293T>A (p.Val98Glu)	ERGIC1	Pathogenic	no assertion criteria provided
585241	NM_139284.3(LGI4):c.2T>C (p.Met1Thr)	LGI4	Pathogenic	criteria provided, single submitter
3367130	NM_001031711.3(ERGIC1):c.155+1G>A	ERGIC1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
ERGIC1	Strong	Autosomal recessive	arthrogryposis multiplex congenita 2, neurogenic type	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ERGIC1	Orphanet:1143	Neurogenic arthrogryposis multiplex congenita
LGI4	Orphanet:2680	Hypomyelination neuropathy-arthrogryposis 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
ERGIC1	HGNC:29205	ENSG00000113719	Q969X5	Endoplasmic reticulum-Golgi intermediate compartment protein 1	gencc,clinvar
LGI4	HGNC:18712	ENSG00000153902	Q8N135	Leucine-rich repeat LGI family member 4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ERGIC1	Endoplasmic reticulum-Golgi intermediate compartment protein 1	Possible role in transport between endoplasmic reticulum and Golgi.
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: 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)
ERGIC1	Other/Unknown	no		Erv_C, Erv_N, Erv
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.

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
oviduct epithelium	1
right adrenal gland cortex	1
stromal cell of endometrium	1
nerve	1
peripheral nervous system	1
tibial nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ERGIC1	253	ubiquitous	marker	stromal cell of endometrium, oviduct epithelium, right adrenal gland cortex
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
ERGIC1	2,515
LGI4	879

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LGI4	Q8N135	92.80
ERGIC1	Q969X5	88.96

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
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 2 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	443.5×	0.004	LGI4
myelination in peripheral nervous system	1	443.5×	0.004	LGI4
regulation of myelination	1	443.5×	0.004	LGI4
neuron maturation	1	401.2×	0.004	LGI4
retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum	1	168.5×	0.008	ERGIC1
adult locomotory behavior	1	150.5×	0.008	LGI4
endoplasmic reticulum to Golgi vesicle-mediated transport	1	68.0×	0.015	ERGIC1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

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
ERGIC1	0	0
LGI4	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
ERGIC1	1	Binding:1

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

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	2	ERGIC1, LGI4

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ERGIC1	1	—
LGI4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.