Ancestral founder mutations in calpain-3 in the Indian Agarwal community: Historical, clinical, and molecular perspective
Research output: Contribution to journal › Article
- Emory University
- Institute for Advanced Training and Research in Interdisciplinary Sciences
- Sir J.J. Group of Hospitals
Introduction: Clinical heterogeneity of limb-girdle muscular dystrophies (LGMDs, 24 known subtypes), which includes overlapping phenotypes and varying ages of onset and morbidity, adds complexity to clinical and molecular diagnoses. Methods: To diagnose LGMD subtype, protein analysis, using immunohistochemistry (IHC) and immunoblotting, was followed by gene sequencing through a panel approach (simultaneous sequencing of known LGMD genes) in 9 patients from unrelated families of the Indian Agarwal community. Haplotype studies were performed by targeted SNP genotyping to establish mutation segregation. Results: We identified 2 founder mutations in CAPN3, a missense (c.2338G>C; p.D780H) and a splice-site (c.2099-1G>T) mutation, on 2 different haplotype backgrounds. The patients were either heterozygous for both or homozygous for either of these mutations. Conclusions: Founder mutations have immediate clinical application, at least in selected population groups. Clinically available gene panels may provide a definitive molecular diagnosis for heterogeneous disorders such as LGMD.
- CAPN3, Founder mutation, Gene panel, LGMD2A, Limb-girdle muscular dystrophy, Splice-site mutation