Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies

Gene: DYSF

Green List (high evidence)

Comment on mode of inheritance: There are at least 6 unrelated families with heterozygous carrier individuals presenting with a limb-girdle muscular dystrophy/ myopathy phenotype despite it being milder and later-onset than individuals with biallelic variants. There is also evidence of some heterozygous carriers from two of the families not displaying phenotype suggesting reduced penetrance.

As there are six unrelated families with monoalellic phenotype, the MOI should be updated to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal' in the next GMS update.

Created: 25 Jun 2026, 10:41 a.m. | Last Modified: 25 Jun 2026, 10:41 a.m.

Panel Version: 6.10

PMID:17287450 (2007) reported two unrelated patuients, one with limb girdle weakness and the other with distal weakness, who presented with elecvated CK, patholgical MRI and reduced dysferlin expression in a muscle biopsy specimen. First patient was the sister of an autosomal recessive limb-girdle muscular dystrophy patient and patient 2 was the father of two offspring with Miyoshi myopathy. The two patients wer identified with variant in one allele (patient 1: p.Asp625Tyr; patient 2: p.Gly519Arg) of DYSF gene, whereas as family members with AR disease harboured compund heterozygous or homozygous variants.

PMID:21658164 (2011) reported two unrelated patients identified with a heterozygous variant in DYSF gene (p.Glu1763Asp). First patient had proximal weakness of the lower limbs and was unable to walk on her toes and heels since the age of 18 years and her brother had asymptomatic hyperCKemia. Second patient, who was previously active in sports presented in late adolescence with distal myopathy. Both patients had high CK activity and electromyography showed myopathic changes. The parents of neither patients had muscle weakness. The variant was found in heterozygous state in mother, grandfather and brother of patient 1, while it is not detected in father of patient 2 and mother's DNA wasn't available.

PMID:29879922 (2018) reported a South African family of mixed descent in which all affetced first generation (G1) members presented with a predominant distal ‘posterior calf’ myopathy starting in early adulthood. Their offspring (G2) experienced severe unexpected symptoms of myalgia and cramps since adolescence. All affected G1 individuals were homozygous for a novel truncating p.Tyr1433Ter DYSF variant, with their asymptomatic sibling and pauci-symptomatic G2 offspring carrying only a single variant allele.

PMID:35962550 (2022) reported a large family with progressive muscular dystrophy and hyperCKaemia and was identified with a monoallelic novel DYSF variant (p.Tyr2070Metfs*4). Skeletal muscle involvement was milder and later onset than typical dysferlinopathy presentations; these clinical signs manifested in four individuals, all between the fourth and sixth decades of life. The study showed a consistent dysferlinopathy phenotype across three generations, with dystrophic muscle changes and fatty replacement, reduced dysferlin protein expression, but no evidence that the C‑terminal DYSF variant triggers mRNA decay.

Monoallelic DYSF variants are not yet associated with any phenotypes in OMIM.

Created: 25 Jun 2026, 10:33 a.m. | Last Modified: 25 Jun 2026, 2:52 p.m.

Panel Version: 6.11

Comment on phenotypes: Biallelic variants in DYSF gene are associated with relevant phenotypes in OMIM (MIMs #253601, #254130 & #606768) and the records were last accessed 11 June 2026.

Biallelic DYSF variants are also associated with AR limb-girdle muscular dystrophy with 'Definitive' rating by the Muscular Dystrophies and Myopathies GCEP in ClinGen (https://search.clinicalgenome.org/CCID:004715)

Created: 11 Jun 2026, 4:59 p.m. | Last Modified: 11 Jun 2026, 4:59 p.m.

Panel Version: 6.4

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Phenotypes
Muscular dystrophy, limb-girdle, autosomal recessive 2, OMIM:253601; Miyoshi muscular dystrophy 1, OMIM:254130; Myopathy, distal, with anterior tibial onset, OMIM:606768

Publications

• 17287450
• 21658164
• 29879922
• 35962550

I don't know

Amber rating relevant to monoallelic mode of inheritance

PMID: 35962550 - Single family reported with a heterozygous frameshift variant in the last exon segregating with a later onset dysferlinopathy. mRNA produced from the allele carrying the variant shown not to undergo nonsense mediated decay. Study of muscle biopsy from affected members show reduction in dysferlin. Speculated a dominant negative mechanism

Created: 2 Jun 2026, 7:36 p.m. | Last Modified: 2 Jun 2026, 7:36 p.m.

Panel Version: 6.1

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Publications

• PMID: 35962550
• 39511170

Green List (high evidence)

Listed as associated with Limb Girdle Muscular Dystrophy by Gene Advisor (June 2016), Steve Abbs

Created: 27 Jul 2016, 8:22 a.m.