SGCD – Limb-Girdle Muscular Dystrophy Type 2F

Limb-Girdle Muscular Dystrophy Type 2F (LGMD2F; Limb-Girdle Muscular Dystrophy Type 2F) is an autosomal recessive myopathy caused by biallelic mutations in the δ-sarcoglycan gene SGCD. Clinical hallmarks include progressive weakness of pelvic and shoulder girdle muscles, elevated serum creatine kinase, and a dystrophic pattern on muscle biopsy. Onset ranges from childhood to adolescence with marked variability in disease progression. Cardiac involvement is reported but less frequent than in other sarcoglycanopathies.

A European multicenter retrospective study of 439 genetically confirmed sarcoglycanopathy patients identified seven unrelated individuals with LGMD2F, confirming the role of SGCD in this subtype (PMID:32875335). All seven probands presented with early onset limb-girdle weakness, and loss of ambulation occurred variably in the second decade. Segregation analysis demonstrated biallelic inheritance consistent with autosomal recessive transmission without additional affected relatives.

The SGCD variant spectrum in LGMD2F encompasses missense and predicted loss-of-function changes. A representative allele is c.451T>G (p.Ser151Ala), which alters a conserved serine in exon 6 and impairs δ-sarcoglycan stability and function in vivo. No recurrent or founder SGCD mutations have been reported in European cohorts to date.

Functional evidence from a heterozygous Sgcd knock-in mouse carrying the p.Ser151Ala mutation revealed a mild cardiomyopathy with preserved cardiac function at one year and subtle histopathological changes (PMID:23695275). AAV9-mediated transfer of wild-type Sgcd cDNA into Sgcd-null mice fully rescued cardiac function, supporting a loss-of-function mechanism for SGCD variants.

Contrasting human data indicate that heterozygous p.Ser151Ala carriers in a large consanguineous family exhibit no overt cardiac or skeletal muscle phenotype, suggesting reduced penetrance or context-dependent effects. This highlights the need to integrate animal model findings with comprehensive human segregation studies.

Overall, seven unrelated LGMD2F probands with biallelic SGCD variants, consistent recessive segregation, and supportive functional models fulfill Moderate clinical validity for SGCD–LGMD2F. Further natural history studies and variant-specific functional assays will refine genotype-phenotype correlations. Key Take-home: Biallelic SGCD mutations cause autosomal recessive Limb-Girdle Muscular Dystrophy Type 2F, providing a clear target for emerging gene replacement therapies.

References

• Brain • 2020 • New genotype-phenotype correlations in a large European cohort of patients with sarcoglycanopathy. PMID:32875335
• European Journal of Human Genetics • 2014 • S151A α-sarcoglycan mutation causes a mild phenotype of cardiomyopathy in mice PMID:23695275

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