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.
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.
Authors: Satish V Khadilkar; Chetan R Chaudhari; Rashna S Dastur; Pradnya S Gaitonde; Jayendra G Yadav Journal: Ann Indian Acad Neurol Date: 2016 Jan-Mar Impact factor: 1.383
Authors: Mats I Nilsson; Lauren G Macneil; Yu Kitaoka; Fatimah Alqarni; Rahul Suri; Mahmood Akhtar; Maria E Haikalis; Pavneet Dhaliwal; Munim Saeed; Mark A Tarnopolsky Journal: PLoS One Date: 2014-07-31 Impact factor: 3.240
Authors: Rashna Sam Dastur; Pradnya Satish Gaitonde; Munira Kachwala; Babi R R Nallamilli; Arunkanth Ankala; Satish V Khadilkar; Nalini Atchayaram; N Gayathri; A K Meena; Laura Rufibach; Sarah Shira; Madhuri Hegde Journal: Ann Indian Acad Neurol Date: 2017 Jul-Sep Impact factor: 1.383