Neuromuscular disease caused by qualitative or quantitative defects of dysferlin

Summary

Neuromuscular disease caused by qualitative or quantitative defects of dysferlin (MONDO:0016145) is a disease caused by DYSF (GenCC Definitive), with 1 cohort gene and 6 clinical trials. Top therapeutic interventions include bortezomib and deflazacort.

At a glance

• Causal gene: DYSF (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 3,427
• Clinical trials: 6

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	neuromuscular disease caused by qualitative or quantitative defects of dysferlin
Mondo ID	MONDO:0016145
MeSH	C537995
Orphanet	207073
UMLS	C2931687
MedGen	419874
GARD	0002003
Is cancer (heuristic)	no

Also known as: dysferlinopathy · qualitative or quantitative defects of dysferlin

Data availability: 3,427 ClinVar variants · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 4 Mondo subtypes.

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

Related subtypes (18): sarcoglycanopathy, caveolinopathy, neuromuscular disease caused by qualitative or quantitative defects of dystrophin, neuromuscular disease caused by qualitative or quantitative defects of perlecan, neuromuscular disease caused by qualitative or quantitative defects of TRIM32, neuromuscular disease caused by qualitative or quantitative defects of myofibrillar proteins, neuromuscular disease caused by qualitative or quantitative defects of titin, neuromuscular disease caused by qualitative or quantitative defects of telethonin, neuromuscular disease caused by qualitative or quantitative defects of alpha-actin, neuromuscular disease caused by qualitative or quantitative defects of nebulin, neuromuscular disease caused by qualitative or quantitative defects of beta-myosin heavy chain (MYH7), neuromuscular disease caused by qualitative or quantitative defects of selenoprotein N1, neuromuscular disease caused by qualitative or quantitative defects of plectin, neuromuscular disease caused by qualitative or quantitative defects of protein SERCA1, neuromuscular disease caused by qualitative or quantitative defects of tropomyosin, neuromuscular disease caused by qualitative or quantitative defects of alpha-dystroglycan, alpha-actinopathy, collagen 6-related myopathy

Subtypes (4): autosomal recessive limb-girdle muscular dystrophy type 2B, distal myopathy with anterior tibial onset, 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

600 retrieved; paginated sample, class counts are floors:

315 likely benign, 167 uncertain significance, 59 pathogenic, 27 conflicting classifications of pathogenicity, 14 pathogenic/likely pathogenic, 13 likely pathogenic, 5 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1068079	NM_001130987.2(DYSF):c.345+2T>C	DYSF	Pathogenic	criteria provided, single submitter
1068508	NM_001130987.2(DYSF):c.3018_3019delinsAA (p.Cys1006_Pro1007delinsTer)	DYSF	Pathogenic	criteria provided, single submitter
1068645	NM_001130987.2(DYSF):c.4434_4435insTTTTTTTTNNNNNNNNNNTTTAGCCGGGATGGTCTCGATCTCCTGACCTCGTGATCCGCCCGCCTCGGCCTCCCAAAGTGCTGGGATTACAGGCGTGAGCCACCGCGCCCGGCCAACTCATCGACATT (p.Asp1479delinsPhePheXaaXaaXaaXaaPheSerArgAspGlyLeuAspLeuLeuThrSerTer)	DYSF	Pathogenic	criteria provided, single submitter
1069223	NM_001130987.2(DYSF):c.5514_5515insA (p.Pro1839fs)	DYSF	Pathogenic	criteria provided, single submitter
1069450	NM_001130987.2(DYSF):c.1271del (p.Pro424fs)	DYSF	Pathogenic	criteria provided, single submitter
1069589	NM_001130987.2(DYSF):c.1276_1276+7del	DYSF	Pathogenic	criteria provided, multiple submitters, no conflicts
1069667	NM_001130987.2(DYSF):c.4848del (p.Glu1616fs)	DYSF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070532	NM_001130987.2(DYSF):c.1258del (p.Ala420fs)	DYSF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071301	NM_001130987.2(DYSF):c.179del (p.Leu60fs)	DYSF	Pathogenic	criteria provided, multiple submitters, no conflicts
1071822	NM_001130987.2(DYSF):c.4177del (p.Arg1393fs)	DYSF	Pathogenic	criteria provided, single submitter
1072189	NM_001130987.2(DYSF):c.2624G>A (p.Trp875Ter)	DYSF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072386	NM_001130987.2(DYSF):c.4954del (p.Ser1652fs)	DYSF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073503	NM_001130987.2(DYSF):c.1380+1G>C	DYSF	Pathogenic	criteria provided, single submitter
1073586	NM_001130987.2(DYSF):c.1778_1782dup (p.Ala595fs)	DYSF	Pathogenic	criteria provided, single submitter
1074366	NM_001130987.2(DYSF):c.1984+2T>C	DYSF	Pathogenic	criteria provided, single submitter
1075046	NM_003494.4(DYSF):c.24T>G (p.Tyr8Ter)	DYSF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075165	NM_001130987.2(DYSF):c.1501del (p.Arg500_Leu501insTer)	DYSF	Pathogenic	criteria provided, single submitter
1075368	NM_001130987.2(DYSF):c.3251dup (p.Glu1085fs)	DYSF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075637	NM_001130987.2(DYSF):c.2605C>T (p.Gln869Ter)	DYSF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076980	NC_000002.11:g.(?71783085)(71913729_?)del	DYSF	Pathogenic	criteria provided, single submitter
1184483	NM_001130987.2(DYSF):c.5718C>G (p.Phe1906Leu)	DYSF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1321153	NM_001130987.2(DYSF):c.3931C>T (p.Gln1311Ter)	DYSF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1322803	NM_001130987.2(DYSF):c.2149C>T (p.Gln717Ter)	DYSF	Pathogenic	criteria provided, multiple submitters, no conflicts
1322807	NM_001130987.2(DYSF):c.923del (p.Glu308fs)	DYSF	Pathogenic	criteria provided, multiple submitters, no conflicts
1322810	NM_001130987.2(DYSF):c.1985-1G>T	DYSF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1322813	NM_001130987.2(DYSF):c.1494G>A (p.Trp498Ter)	DYSF	Pathogenic	criteria provided, multiple submitters, no conflicts
1350242	NM_001130987.2(DYSF):c.5718C>A (p.Phe1906Leu)	DYSF	Pathogenic	criteria provided, single submitter
1350474	NM_001130987.2(DYSF):c.6057dup (p.Leu2020fs)	DYSF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1350756	NM_001130987.2(DYSF):c.2697+5G>A	DYSF	Pathogenic	reviewed by expert panel
1361687	NM_001130987.2(DYSF):c.5251_5258del (p.Lys1751fs)	DYSF	Pathogenic	criteria provided, single submitter

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	Definitive	Autosomal recessive	neuromuscular disease caused by qualitative or quantitative defects of dysferlin	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: 6.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3
PHASE1	2
PHASE2/PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00527228	PHASE2/PHASE3	COMPLETED	Deflazacort in Dysferlinopathies
NCT01863004	PHASE1	TERMINATED	Proteasomal Inhibition for Patients With Mis-sense Mutated Dysferlin
NCT02710500	PHASE1	COMPLETED	rAAVrh74.MHCK7.DYSF.DV for Treatment of Dysferlinopathies
NCT04824040	Not specified	ENROLLING_BY_INVITATION	Clinical, Immunological, Morphological and Genetic Characteristics of Patients With Dysferlinopathy (LGMD R2) in the RF
NCT01676077	Not specified	UNKNOWN	Clinical Outcome Study for Dysferlinopathy
NCT07035145	Not specified	COMPLETED	Observational Cohort Study of Dysferlinopathy in China

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
BORTEZOMIB	4	1
DEFLAZACORT	4	1