Distal myopathy with anterior tibial onset

Summary

Distal myopathy with anterior tibial onset (MONDO:0011721) is a disease caused by DYSF (GenCC Strong), with 1 cohort gene and 2 clinical trials.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: DYSF (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 305
• Phenotypes (HPO): 13
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

13 HPO clinical features (Orphanet curated; top 13 by frequency):

HPO ID	Term	Frequency
HP:0030114	Absent muscle fiber dysferlin	Very frequent (80-99%)
HP:0040081	Abnormal circulating creatine kinase concentration	Very frequent (80-99%)
HP:0003738	Exercise-induced myalgia	Frequent (30-79%)
HP:0008963	Tibialis muscle weakness	Frequent (30-79%)
HP:0009073	Progressive proximal muscle weakness	Frequent (30-79%)
HP:0003325	Limb-girdle muscle weakness	Occasional (5-29%)
HP:0003438	Absent Achilles reflex	Occasional (5-29%)
HP:0008954	Intrinsic hand muscle atrophy	Occasional (5-29%)
HP:0009005	Weakness of the intrinsic hand muscles	Occasional (5-29%)
HP:0000467	Neck muscle weakness	Excluded (0%)
HP:0003474	Somatic sensory dysfunction	Excluded (0%)
HP:0003805	Rimmed vacuoles	Excluded (0%)
HP:0031177	Finger flexor weakness	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	distal myopathy with anterior tibial onset
Mondo ID	MONDO:0011721
MeSH	C564664
OMIM	606768
Orphanet	178400
DOID	DOID:0111187
ICD-11	651559966
UMLS	C1847532
MedGen	335706
GARD	0017080
Is cancer (heuristic)	no

Also known as: distal anterior compartment myopathy · DMAT · myopathy, distal, with anterior tibial onset

Data availability: 305 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › qualitative or quantitative protein defects in neuromuscular diseases › neuromuscular disease caused by qualitative or quantitative defects of dysferlin › distal myopathy with anterior tibial onset

Related subtypes (3): autosomal recessive limb-girdle muscular dystrophy type 2B, congenital myopathy, Paradas type, Miyoshi muscular dystrophy 1

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

305 retrieved; paginated sample, class counts are floors:

108 likely pathogenic, 76 pathogenic, 33 conflicting classifications of pathogenicity, 33 pathogenic/likely pathogenic, 30 uncertain significance, 17 benign, 6 benign/likely benign, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1072386	NM_001130987.2(DYSF):c.4954del (p.Ser1652fs)	DYSF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1300185	NM_001130987.2(DYSF):c.4989del (p.Glu1663fs)	DYSF	Pathogenic	reviewed by expert panel
1389207	NM_001130987.2(DYSF):c.5188C>T (p.Gln1730Ter)	DYSF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1448346	NM_001130987.2(DYSF):c.2955dup (p.Met986fs)	DYSF	Pathogenic	criteria provided, multiple submitters, no conflicts
167025	NM_001130987.2(DYSF):c.3886C>T (p.Gln1296Ter)	DYSF	Pathogenic	reviewed by expert panel
167030	NM_001130987.2(DYSF):c.5642+1G>A	DYSF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1708551	NM_001130987.2(DYSF):c.2472C>A (p.Tyr824Ter)	DYSF	Pathogenic	criteria provided, single submitter
1724499	NM_001130987.2(DYSF):c.4923C>A (p.Tyr1641Ter)	DYSF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1724791	NM_001130987.2(DYSF):c.2832G>A (p.Trp944Ter)	DYSF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1724930	NM_001130987.2(DYSF):c.1597del (p.Leu533fs)	DYSF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1725487	NM_001130987.2(DYSF):c.561del (p.Gly188fs)	DYSF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1802250	NM_001130987.2(DYSF):c.5680_5681insC (p.Asp1894fs)	DYSF	Pathogenic	criteria provided, single submitter
18443	NM_001130987.2(DYSF):c.5546G>A (p.Arg1849Lys)	DYSF	Pathogenic	reviewed by expert panel
195490	NM_001130987.2(DYSF):c.1906G>A (p.Gly636Arg)	DYSF	Pathogenic	reviewed by expert panel
197433	NM_001130987.2(DYSF):c.4551G>A (p.Trp1517Ter)	DYSF	Pathogenic	criteria provided, multiple submitters, no conflicts
198495	NM_001130987.2(DYSF):c.797G>A (p.Gly266Glu)	DYSF	Pathogenic	reviewed by expert panel
217223	NM_001130987.2(DYSF):c.1888C>T (p.Gln630Ter)	DYSF	Pathogenic	reviewed by expert panel
217226	NM_001130987.2(DYSF):c.3570_3571del (p.Phe1190_Ser1191insTer)	DYSF	Pathogenic	criteria provided, multiple submitters, no conflicts
217227	NM_001130987.2(DYSF):c.5194C>T (p.Arg1732Trp)	DYSF	Pathogenic	reviewed by expert panel
2203093	NM_001130987.2(DYSF):c.4078C>G (p.Arg1360Gly)	DYSF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
242418	NM_001130987.2(DYSF):c.3167G>A (p.Arg1056Gln)	DYSF	Pathogenic	reviewed by expert panel
265108	NM_001130987.2(DYSF):c.334C>T (p.Gln112Ter)	DYSF	Pathogenic	reviewed by expert panel
265487	NM_001130987.2(DYSF):c.1225C>T (p.Arg409Ter)	DYSF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2674961	NM_001130987.2(DYSF):c.959dup (p.Asp320fs)	DYSF	Pathogenic	reviewed by expert panel
2734212	NM_001130987.2(DYSF):c.1417C>T (p.Gln473Ter)	DYSF	Pathogenic	criteria provided, multiple submitters, no conflicts
2796264	NM_001130987.2(DYSF):c.2888del (p.Gly963fs)	DYSF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
281063	NM_001130987.2(DYSF):c.3532C>T (p.Gln1178Ter)	DYSF	Pathogenic	criteria provided, multiple submitters, no conflicts
281140	NM_001130987.2(DYSF):c.460+2T>G	DYSF	Pathogenic	reviewed by expert panel
281197	NM_001130987.2(DYSF):c.5003+1249G>T	DYSF	Pathogenic	reviewed by expert panel
281954	NM_001130987.2(DYSF):c.1276+5G>C	DYSF	Pathogenic	reviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 4 · 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
DYSF	Strong	Autosomal recessive	distal myopathy with anterior tibial onset	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DYSF	Orphanet:178400	Distal myopathy with anterior tibial onset
DYSF	Orphanet:199329	Congenital myopathy, Paradas type
DYSF	Orphanet:268	Dysferlin-related limb-girdle muscular dystrophy R2
DYSF	Orphanet:45448	Miyoshi myopathy

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
DYSF	HGNC:3097	ENSG00000135636	O75923	Dysferlin	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DYSF	Dysferlin	Key calcium ion sensor involved in the Ca(2+)-triggered synaptic vesicle-plasma membrane fusion.

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)
DYSF	Other/Unknown	no		C2_dom, Peroxin/Ferlin, Ferlin_A-domain

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
blood	1
hindlimb stylopod muscle	1
skeletal muscle tissue of rectus abdominis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DYSF	257	ubiquitous	marker	blood, hindlimb stylopod muscle, skeletal muscle tissue of rectus abdominis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DYSF	1,776

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DYSF	O75923	11

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
Smooth Muscle Contraction	1	265.6×	0.004	DYSF

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
monocyte activation involved in immune response	1	16852.0×	2e-04	DYSF
macrophage activation involved in immune response	1	1123.5×	0.001	DYSF
negative regulation of phagocytosis	1	991.3×	0.001	DYSF
regulation of neurotransmitter secretion	1	766.0×	0.001	DYSF

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
DYSF	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	DYSF

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)
DYSF	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04824040	Not specified	ENROLLING_BY_INVITATION	Clinical, Immunological, Morphological and Genetic Characteristics of Patients With Dysferlinopathy (LGMD R2) in the RF
NCT06507215	Not specified	COMPLETED	Dysferlinopathy Protein in Peripheral Blood Monocytes.