Distal myopathy with vocal cord weakness

Summary

Distal myopathy with vocal cord weakness (MONDO:0018951) is a disease caused by MATR3 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MATR3 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 2
• Phenotypes (HPO): 30

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
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:0001260	Dysarthria	Frequent (30-79%)
HP:0001283	Bulbar palsy	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0001430	Abnormality of the calf musculature	Frequent (30-79%)
HP:0001604	Vocal cord paresis	Frequent (30-79%)
HP:0001609	Hoarse voice	Frequent (30-79%)
HP:0001611	Hypernasal speech	Frequent (30-79%)
HP:0001621	Weak voice	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0002317	Unsteady gait	Frequent (30-79%)
HP:0002460	Distal muscle weakness	Frequent (30-79%)
HP:0002747	Respiratory insufficiency due to muscle weakness	Frequent (30-79%)
HP:0002835	Aspiration	Frequent (30-79%)
HP:0003457	EMG abnormality	Frequent (30-79%)
HP:0003738	Exercise-induced myalgia	Frequent (30-79%)
HP:0003805	Rimmed vacuoles	Frequent (30-79%)
HP:0005934	Imperfect vocal cord adduction	Frequent (30-79%)
HP:0007354	Amyotrophic lateral sclerosis	Frequent (30-79%)
HP:0008180	Mildly elevated creatine kinase	Frequent (30-79%)
HP:0008756	Bowing of the vocal cords	Frequent (30-79%)
HP:0031374	Ankle weakness	Frequent (30-79%)
HP:0430015	Abnormal morphology of musculature of pharynx	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0003547	Shoulder girdle muscle weakness	Occasional (5-29%)
HP:0007149	Distal upper limb amyotrophy	Occasional (5-29%)
HP:0008049	Abnormality of the extraocular muscles	Occasional (5-29%)
HP:0009071	Inflammatory myopathy	Excluded (0%)
HP:0000726	Dementia	Very rare (<1-4%)
HP:0000762	Decreased nerve conduction velocity	Very rare (<1-4%)
HP:0002936	Distal sensory impairment	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	distal myopathy with vocal cord weakness
Mondo ID	MONDO:0018951
Orphanet	600
ICD-11	1133125258
UMLS	C1853723
MedGen	342950
GARD	0001887
Is cancer (heuristic)	no

Also known as: distal myopathy 2 · MATR3-related distal myopathy · MPD2 · VCPDM

Data availability: 2 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 › autosomal genetic disease › autosomal dominant disease › autosomal dominant distal myopathy › distal myopathy with vocal cord weakness

Related subtypes (14): tibial muscular dystrophy, myopathy, myofibrillar, 9, with early respiratory failure, distal myopathy, Welander type, myofibrillar myopathy 2, myofibrillar myopathy 3, myofibrillar myopathy 4, Finnish upper limb-onset distal myopathy, distal myopathy with posterior leg and anterior hand involvement, distal myopathy, Tateyama type, adult-onset distal myopathy due to VCP mutation, KLHL9-related early-onset distal myopathy, TARDBP-related predominantly upper-limb distal myopathy, asymetric thumb-handgrip weakness-distal myopathy, calf-predominant weakness-gastrocnemius medialis atrophy-distal myopathy

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:

2 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
859218	NM_018834.6(MATR3):c.2254GAT[1] (p.Asp753del)	MATR3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1366675	NC_000005.10:g.139276152T>A	SNHG4	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
MATR3	Definitive	Autosomal dominant	distal myopathy with vocal cord weakness	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MATR3	Orphanet:600	Vocal cord and pharyngeal distal myopathy
MATR3	Orphanet:803	Amyotrophic lateral sclerosis

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MATR3	HGNC:6912	ENSG00000015479	P43243	Matrin-3	gencc,clinvar
SNHG4	HGNC:32964	ENSG00000281398		small nucleolar RNA host gene 4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MATR3	Matrin-3	May play a role in transcription or may interact with other nuclear matrix proteins to form the internal fibrogranular network.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MATR3	Transcription factor	no		RRM_dom, Matrin/U1-C_Znf_C2H2, Matrin/U1-like-C_Znf_C2H2
SNHG4	Other/Unknown	no

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
corpus callosum	1
cortical plate	1
ganglionic eminence	1
buccal mucosa cell	1
esophagus mucosa	1
lower esophagus mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MATR3	135	ubiquitous	marker	cortical plate, corpus callosum, ganglionic eminence
SNHG4	216	ubiquitous	marker	buccal mucosa cell, lower esophagus mucosa, esophagus mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MATR3	3,804
SNHG4	0

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MATR3	P43243	57.64

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 2 evidence-associated genes (0 with Reactome annotation).

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
heart valve development	1	1532.0×	0.002	MATR3
blastocyst formation	1	766.0×	0.002	MATR3
post-transcriptional regulation of gene expression	1	648.1×	0.002	MATR3
ventricular septum development	1	495.6×	0.002	MATR3
activation of innate immune response	1	481.5×	0.002	MATR3
innate immune response	1	33.6×	0.030	MATR3

Therapeutics

Drug target analysis

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

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
MATR3	1	2
SNHG4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	MATR3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
MATR3	7	Binding:7

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

1 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.

Compound	Max phase	Cohort target (bioactivity)
MOLIBRESIB	2	MATR3

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	1	MATR3
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SNHG4

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)
SNHG4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.