Expanding DYSF Mutational Landscape: Identification of Novel Variants associated with Limb-Girdle Muscular Dystrophy Type R2
Abstract
Abstract Background Dysferlinopathy is a clinically and genetically heterogeneous group of muscular dystrophies caused by pathogenic variants in the DYSF gene, most commonly presenting as limb-girdle muscular dystrophy type R2. Given the marked phenotypic variability, molecular genetic testing is essential for accurate diagnosis. Methods Two unrelated consanguineous families with adult-onset, progressive proximal muscle weakness and markedly elevated serum creatine kinase levels were clinically evaluated. Whole-exome sequencing was performed to identify the underlying genetic cause. Results WES revealed two novel homozygous truncating DYSF variants. A nonsense variant (c.5404G > T; p.Glu1802*) in exon 47 was identified in the first family, while a frameshift insertion (c.2755_2756insC; p.Tyr919Serfs*6) in exon 26 was detected in the second family. Both variants were absent from population databases, showed complete co-segregation with disease, and were classified as pathogenic according to ACMG criteria. In silico and structural analyses predicted severe disruption of dysferlin protein function. Conclusion These findings expand the mutational spectrum of DYSF and highlight the value of WES for diagnosing dysferlinopathy, particularly in consanguineous populations, with important implications for genetic counselling.
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