Key result
CAPN3 sequencing identifies mutations in ~88% of Indian LGMDR1 patients, enabling targeted genetic diagnosis.
Why the study?
Despite the significant burden of muscular dystrophy and LGMDR1 in India, its genetic characterization and phenotypic manifestations remained unidentified.
Observational (n=95)
This study characterizes the genetic framework of LGMDR1 in the Indian population, identifying nine priority CAPN3 exons for targeted genetic diagnosis.
May support targeted CAPN3 exon testing in Indian LGMDR1 patients; leaves open broader validation and prospective diagnostic utility.
BACKGROUND: Limb girdle muscular dystrophy recessive type 1 (LGMDR1, Previously LGMD2A) is characterized by inactivating mutations in CAPN3. Despite the significant burden of muscular dystrophy in India, and particularly of LGMDR1, its genetic characterization and possible phenotypic manifestations are yet unidentified. MATERIAL AND METHODS: We performed bidirectional CAPN3 sequencing in 95 LGMDR1 patient samples characterized by calpain-3 protein analysis, and these findings were correlated with clinical, biochemical and histopathological features. RESULTS: We identified 84 (88.4%) cases of LGMDR1 harboring 103 CAPN3 mutations (71 novel and 32 known). At least two mutant alleles were identified in 79 (94.2%) of patients. Notably, 76% exonic variations were enriched in nine CAPN3 exons and overall, 41 variations (40%) correspond to only eight exonic and intronic mutations. Patients with two nonsense/out of frame/splice-site mutations showed significant loss of calpain-3 protein as compared to those with two missense/inframe mutations (P = 0.04). We observed a slow progression of disease and less severity in our patients compared to European population. Rarely, presenting clinical features were atypical, and mimicked other muscle diseases like FSHMD, distal myopathy and metabolic myopathies. CONCLUSION: This is first systematic study to characterize the genetic framework of LGMDR1 in the Indian population. Preliminary calpain-3 immunoblot screening serves well to direct genetic testing. Our findings prioritized nine CAPN3 exons for LGMDR1 diagnosis in our population; therefore, a targeted-sequencing panel of nine exons could serve well for genetic diagnosis, carrier testing, counseling and clinical trial feasibility study in LGMDR1 patients in India.
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Pathak et al. (2020) conducted an observational in Limb girdle muscular dystrophy recessive type 1 (LGMDR1) (n=95). Bidirectional CAPN3 sequencing was evaluated on Identification of CAPN3 mutations. Bidirectional CAPN3 sequencing identified 103 mutations (71 novel) in 88.4% of 95 Indian LGMDR1 patients, with 76% of exonic variations enriched in nine exons, enabling targeted genetic diagnosis.
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