Miyoshi Muscular Dystrophy Due to Novel Splice Site Variants in DYSF Gene

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Dysferlinopathies encompass a range of muscle disorders stemming from mutations in the DYSF gene, encoding the protein dysferlin.
• The clinical manifestations are diverse, including Miyoshi muscular dystrophy (MMD), limb-girdle muscular dystrophy type R2, and distal myopathy.
• A clear genotype-phenotype correlation is often lacking in dysferlinopathies.

Observation:

• A 15-year-old female presented with symptoms aligning with MMD, initially misdiagnosed and treated as polymyositis.
• Despite initial misdiagnosis, genetic analysis identified two previously undocumented variants in the DYSF gene: c.3225dup (p.Gly1076Trpfs*38) and c.3349-2A>G (Splice acceptor).

Findings:

• Immunohistochemistry and western blot analyses of muscle biopsy samples revealed a complete absence of dysferlin.
• The identified novel DYSF variants were confirmed to be pathogenic, explaining the observed lack of dysferlin protein.

Implications:

• This case highlights the importance of genetic testing in diagnosing heterogeneous neuromuscular disorders like dysferlinopathies.
• The discovery of novel DYSF variants expands the known mutational landscape of dysferlinopathies and aids in understanding disease mechanisms.
• Accurate genetic diagnosis is crucial for appropriate patient management and counseling, especially when initial clinical presentations are atypical.