Autosomal recessive myogenic arthrogryposis multiplex congenita

Summary

Autosomal recessive myogenic arthrogryposis multiplex congenita (MONDO:0017892) is a disease with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 2
• Phenotypes (HPO): 30

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

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

Signs & symptoms

Clinical features (HPO)

30 HPO clinical features (Orphanet curated; top 30 by frequency):

HPO ID	Term	Frequency
HP:0001265	Hyporeflexia	Very frequent (80-99%)
HP:0001270	Motor delay	Very frequent (80-99%)
HP:0001558	Decreased fetal movement	Very frequent (80-99%)
HP:0001776	Bilateral talipes equinovarus	Very frequent (80-99%)
HP:0002540	Inability to walk	Very frequent (80-99%)
HP:0002804	Arthrogryposis multiplex congenita	Very frequent (80-99%)
HP:0008935	Generalized neonatal hypotonia	Very frequent (80-99%)
HP:0030200	Fatiguable weakness of proximal limb muscles	Very frequent (80-99%)
HP:0430025	Bilateral facial palsy	Very frequent (80-99%)
HP:0000028	Cryptorchidism	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0000276	Long face	Occasional (5-29%)
HP:0000343	Long philtrum	Occasional (5-29%)
HP:0000400	Macrotia	Occasional (5-29%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0001181	Adducted thumb	Occasional (5-29%)
HP:0001188	Hand clenching	Occasional (5-29%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0001518	Small for gestational age	Occasional (5-29%)
HP:0003391	Gowers sign	Occasional (5-29%)
HP:0005191	Congenital knee dislocation	Occasional (5-29%)
HP:0005280	Depressed nasal bridge	Occasional (5-29%)
HP:0005469	Flat occiput	Occasional (5-29%)
HP:0008897	Postnatal growth retardation	Occasional (5-29%)
HP:0011471	Gastrostomy tube feeding in infancy	Occasional (5-29%)
HP:0012785	Flexion contracture of finger	Occasional (5-29%)
HP:0031729	Moderate hypermetropia	Occasional (5-29%)
HP:0000252	Microcephaly	Excluded (0%)
HP:0001561	Polyhydramnios	Excluded (0%)
HP:0040081	Abnormal circulating creatine kinase concentration	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive myogenic arthrogryposis multiplex congenita
Mondo ID	MONDO:0017892
Orphanet	319332
SNOMED CT	764812008
UMLS	C4707155
MedGen	1647450
GARD	0017447
Is cancer (heuristic)	no

Also known as: autosomal recessive myogenic AMC · SYNE1-related AMC · SYNE1-related arthrogryposis multiplex congenita

Data availability: 2 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › arthrogryposis multiplex congenita › autosomal recessive myogenic arthrogryposis multiplex congenita

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 arthrogryposis-anterior horn cell disease syndrome, lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome, arthrogryposis-like syndrome, 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

2 retrieved; paginated sample, class counts are floors:

1 conflicting classifications of pathogenicity, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
355857	NM_182961.4(SYNE1):c.16831C>T (p.Arg5611Trp)	LOC126859837	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
848247	NM_182961.4(SYNE1):c.20737C>T (p.Arg6913Cys)	SYNE1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 16 · 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
SYNE1	Strong	Autosomal recessive	arthrogryposis multiplex congenita 3, myogenic type	16

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SYNE1	Orphanet:319332	Autosomal recessive myogenic arthrogryposis multiplex congenita
SYNE1	Orphanet:88644	Autosomal recessive ataxia, Beauce type
SYNE1	Orphanet:98853	Autosomal dominant Emery-Dreifuss muscular dystrophy

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
SYNE1	HGNC:17089	ENSG00000131018	Q8NF91	Nesprin-1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SYNE1	Nesprin-1	Multi-isomeric modular protein which forms a linking network between organelles and the actin cytoskeleton to maintain the subcellular spatial organization.

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)
SYNE1	Other/Unknown	no		Actinin_actin-bd_CS, CH_dom, Spectrin_repeat

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
calcaneal tendon	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SYNE1	275	ubiquitous	marker	cerebellar hemisphere, right hemisphere of cerebellum, calcaneal tendon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SYNE1	2,886

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SYNE1	Q8NF91	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
Meiosis	1	285.5×	0.009	SYNE1
Reproduction	1	190.3×	0.009	SYNE1
Meiotic synapsis	1	141.0×	0.009	SYNE1
Cell Cycle	1	36.0×	0.028	SYNE1

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
nuclear matrix anchoring at nuclear membrane	1	5617.3×	9e-04	SYNE1
muscle cell differentiation	1	842.6×	0.003	SYNE1
nucleus organization	1	561.7×	0.003	SYNE1
Golgi organization	1	133.8×	0.009	SYNE1
spermatogenesis	1	35.2×	0.028	SYNE1

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
SYNE1	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	SYNE1

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)
SYNE1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.