Lethal arthrogryposis-anterior horn cell disease syndrome

Summary

Lethal arthrogryposis-anterior horn cell disease syndrome (MONDO:0012750) is a disease caused by GLE1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GLE1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 102

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		15	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	lethal arthrogryposis-anterior horn cell disease syndrome
Mondo ID	MONDO:0012750
MeSH	C567502
OMIM	611890
Orphanet	53696
SNOMED CT	715565004
UMLS	C5193016
MedGen	1677784
GARD	0016658
Is cancer (heuristic)	no

Also known as: congenital arthrogryposis with anterior horn cell disease · LAAHD · lethal arthrogryposis with anterior horn cell disease · Vuopala disease

Data availability: 102 ClinVar variants · 2 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 › lethal arthrogryposis-anterior horn cell disease syndrome

Related subtypes (23): prenatal-onset spinal muscular atrophy with congenital bone fractures, adducted thumbs-arthrogryposis syndrome, Christian type, arthrogryposis multiplex congenita 2, neurogenic 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 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

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

102 retrieved; paginated sample, class counts are floors:

44 uncertain significance, 17 likely pathogenic, 12 conflicting classifications of pathogenicity, 9 benign, 7 pathogenic/likely pathogenic, 5 pathogenic, 5 likely benign, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1075479	NM_001003722.2(GLE1):c.357_364del (p.Gln121fs)	GLE1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1454743	NM_001003722.2(GLE1):c.1203_1204del (p.Leu402fs)	GLE1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2729696	NM_001003722.2(GLE1):c.450G>A (p.Trp150Ter)	GLE1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3014970	NM_001003722.2(GLE1):c.2028+1G>A	GLE1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
619141	NM_001003722.2(GLE1):c.1882-2A>G	GLE1	Pathogenic	criteria provided, single submitter
619142	NM_001003722.1(GLE1):c.100-7_100-3del	GLE1	Pathogenic	no assertion criteria provided
632534	NM_001003722.2(GLE1):c.397C>T (p.Arg133Ter)	GLE1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6462	NM_001003722.2(GLE1):c.433-10A>G	GLE1	Pathogenic	criteria provided, multiple submitters, no conflicts
6463	NM_001003722.2(GLE1):c.1706G>A (p.Arg569His)	GLE1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6464	NM_001003722.2(GLE1):c.1849G>A (p.Val617Met)	GLE1	Pathogenic	criteria provided, multiple submitters, no conflicts
951677	NM_001003722.2(GLE1):c.241C>T (p.Gln81Ter)	GLE1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6465	NM_001003722.2(GLE1):c.2051T>C (p.Ile684Thr)	LOC101929270	Pathogenic	criteria provided, multiple submitters, no conflicts
3897886	NM_001003722.2:c.[1807C>T];[1705C>T]		Likely pathogenic	criteria provided, single submitter
1324481	NM_001003722.2(GLE1):c.428del (p.Gly143fs)	GLE1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1522542	NM_001003722.2(GLE1):c.1881+1G>T	GLE1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3596466	NM_001003722.2(GLE1):c.266delinsAT (p.Pro89fs)	GLE1	Likely pathogenic	criteria provided, single submitter
3596467	NM_001003722.2(GLE1):c.557_561dup (p.Arg188fs)	GLE1	Likely pathogenic	criteria provided, single submitter
3596468	NM_001003722.2(GLE1):c.979C>T (p.Gln327Ter)	GLE1	Likely pathogenic	criteria provided, single submitter
3596469	NM_001003722.2(GLE1):c.1021G>T (p.Glu341Ter)	GLE1	Likely pathogenic	criteria provided, single submitter
3596470	NM_001003722.2(GLE1):c.1456-1G>A	GLE1	Likely pathogenic	criteria provided, single submitter
3596471	NM_001003722.2(GLE1):c.1675_1723del (p.Lys559fs)	GLE1	Likely pathogenic	criteria provided, single submitter
3596472	NM_001003722.2(GLE1):c.1712C>G (p.Ser571Ter)	GLE1	Likely pathogenic	criteria provided, single submitter
3596473	NM_001003722.2(GLE1):c.2015dup (p.Gln673fs)	GLE1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3596474	NM_001003722.2(GLE1):c.2029-1G>A	GLE1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3779701	NM_001003722.2(GLE1):c.553del (p.Gln185fs)	GLE1	Likely pathogenic	criteria provided, single submitter
4813419	NM_001003722.2(GLE1):c.224C>G (p.Ser75Ter)	GLE1	Likely pathogenic	criteria provided, single submitter
619144	NM_001003722.2(GLE1):c.1750C>T (p.Arg584Trp)	GLE1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3767207	NM_001003722.2(GLE1):c.1381G>A (p.Gly461Arg)	LOC101929270	Likely pathogenic	criteria provided, single submitter
3767208	NM_001003722.2(GLE1):c.1784C>A (p.Pro595His)	LOC101929270	Likely pathogenic	criteria provided, single submitter
1148496	NM_001003722.2(GLE1):c.2029-5A>G	GLE1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
GLE1	Definitive	Autosomal recessive	lethal arthrogryposis-anterior horn cell disease syndrome	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GLE1	Orphanet:1486	Lethal congenital contracture syndrome type 1
GLE1	Orphanet:53696	Arthrogryposis-anterior horn cell disease syndrome
GLE1	Orphanet:803	Amyotrophic lateral sclerosis

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
GLE1	HGNC:4315	ENSG00000119392	Q53GS7	mRNA export factor GLE1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GLE1	mRNA export factor GLE1	Required for the export of mRNAs containing poly(A) tails from the nucleus into the cytoplasm.

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)
GLE1	Other/Unknown	no		GLE1, GLE1-like_sf

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
buccal mucosa cell	1
right testis	1
tendon of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GLE1	267	ubiquitous	marker	buccal mucosa cell, tendon of biceps brachii, right testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GLE1	2,260

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GLE1	Q53GS7	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Transport of Mature mRNA derived from an Intron-Containing Transcript	1	152.3×	0.007	GLE1

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
poly(A)+ mRNA export from nucleus	1	674.1×	0.005	GLE1
nucleocytoplasmic transport	1	391.9×	0.005	GLE1
mRNA export from nucleus	1	295.6×	0.005	GLE1
protein transport	1	43.9×	0.023	GLE1

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
GLE1	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	GLE1

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)
GLE1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.