Abstract
Objective: Inherited myopathies comprise more than 200 different individually rare disease-subtypes, but when combined together they have a high prevalence of 1 in 6,000 individuals across the world. Our goal was to determine for the first time the clinical- and gene-variant spectrum of genetic myopathies in a substantial cohort study of the Indian subcontinent.Methods: In this cohort study, we performed the first large clinical exome sequencing (ES) study with phenotype correlation on 207 clinically well-characterized inherited myopathy-suspected patients from the Indian subcontinent with diverse ethnicities.Results: Clinical-correlation driven definitive molecular diagnosis was established in 49% (101 cases; 95% CI, 42–56%) of patients with the major contributing pathogenicity in either of three genes, GNE (28%; GNE-myopathy), DYSF (25%; Dysferlinopathy), and CAPN3 (19%; Calpainopathy). We identified 65 variant alleles comprising 37 unique variants in these three major genes. Seventy-eight percent of the DYSF patients were homozygous for the detected pathogenic variant, suggesting the need for carrier-testing for autosomal-recessive disorders like Dysferlinopathy that are common in India. We describe the observed clinical spectrum of myopathies including uncommon and rare subtypes in India: Sarcoglycanopathies (SGCA/B/D/G), Collagenopathy (COL6A1/2/3), Anoctaminopathy (ANO5), telethoninopathy (TCAP), Pompe-disease (GAA), Myoadenylate-deaminase-deficiency-myopathy (AMPD1), myotilinopathy (MYOT), laminopathy (LMNA), HSP40-proteinopathy (DNAJB6), Emery-Dreifuss-muscular-dystrophy (EMD), Filaminopathy (FLNC), TRIM32-proteinopathy (TRIM32), POMT1-proteinopathy (POMT1), and Merosin-deficiency-congenital-muscular-dystrophy-type-1 (LAMA2). Thirteen patients harbored pathogenic variants in >1 gene and had unusual clinical features suggesting a possible role of synergistic-heterozygosity/digenic-contribution to disease presentation and progression.Conclusions: Application of clinically correlated ES to myopathy diagnosis has improved our understanding of the clinical and genetic spectrum of different subtypes and their overlaps in Indian patients. This, in turn, will enhance the global gene-variant-disease databases by including data from developing countries/continents for more efficient clinically driven molecular diagnostics.
Highlights
To date, >250 genes are associated with various inherited neuromuscular disorders (NMDs) (1–4) comprising a broad heterogeneous group of genetic myopathies
Molecular diagnosis was established in 49% (101/207; 95% CI, 42–56%) of the patients with the majority having pathogenic variants identified in one of the following genes, GNE (31%; 31/101), DYSF (27%; 27/101), or CAPN3 (19%; 19/101), indicating that these genes are the major contributors to genetic myopathy in India (Figure 1)
Autosomal-dominant-subtypes were less common with 3 laminopathies (EDMD2; 3%), 1 myotilinopathy (Myofibrillar Myopathy; 1%), and 1 HSP40-proteinopathy (LGMDD1 DNAJB6-related; 1%)
Summary
To date, >250 genes are associated with various inherited neuromuscular disorders (NMDs) (1–4) comprising a broad heterogeneous group of genetic myopathies. Significant numbers of affected patients remain without a definitive molecular diagnosis due to novel gene or multiple gene associations with disease (5, 6). The autosomal-dominant forms represent
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