Clinical and Genomic Evaluation of 207 Genetic Myopathies in the Indian Subcontinent

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.

Keywords: India; LGMD; exome sequencing; inherited myopathies; molecular diagnostics; next generation sequencing; subcontinent.

Figure 1

Molecular diagnosis with different genetic myopathy subtypes. Molecular diagnosis using exome sequencing has been established in 49% of the patients with the majority having pathogenic variants identified in one of the following genes: GNE (31%), DYSF (27%), CAPN3 (19%), indicating that these genes are likely the major contributors to genetic myopathy-like phenotype.

Figure 2

Unique pathogenic variants and percent homozygosity identified in major myopathy genes. (A) Number of unique pathogenic variants identified in major myopathy genes. (B) The percentage of homozygosity observed in the major myopathy subtypes. Among the three major myopathy subtypes, 96% of the limb-girdle muscular dystrophy R2 (LGMDR2) patients caused by variants in DYSF gene were identified with homozygous variants. (C) Mutation spectrum of CAPN3 gene: CAPN3 variants identified in the current study are distributed throughout the gene. There is no specific mutation hot spot region but 3 variants are located in exon 10 indicating it as more unstable region prone to genetic variation. (D) Two common variants in GNE gene: The two common variants in GNE gene were detected in exome sequencing with high confidence and also further confirmed by Sanger sequencing. Left side panel indicates the variants confirmation by exome sequencing. Right side panel indicates the variants confirmation by Sanger sequencing.

Figure 3

Classical features of common subtypes identified. GNE myopathy (A–C): Tibialis anterior (TA) muscle wasting, normal quadriceps, and first dorsal interossei (FDI) muscle wasting identified, respectively. Dysferlinopathy (D,E): Gastrocnemius wasting and biceps lump. Calpainopathy (F,G): Scapular winging and ankle contracture. Sarcoglycanopathy (H): Calf hypertrophy. Collagenopathy (I–K): Long finger flexor and ankle contractures.