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 have a high prevalence of 1 in 6000 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. 78% 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). 13 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.

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

“…genomicsengland.co.uk/about-genomics-england/the-100000genomes-project/), NIH All of US Genomics program (https:// allofus.nih.gov/), and others for faster and more accurate variant classification, faster enhanced diagnostics, and the understanding of genotype-phenotype correlations. available online as a preprint (156). We thank Dr. Arunkanth Ankala of Emory University Department of Human Genetics, Mrs. Khanjan K. Gandhi of Emory University Winship Cancer Center, and Dr. Lora Bean of PerkinElmer Genomics for assisting with data management.…”

Exome Sequencing Reveals Diagnosis of LAMA2-Muscular Dystrophy and Possibility of Coexisting Bethlem Myopathy in a Neonate

“…18 Lately, adding to the diagnostic prowess of NGS is its ability to diagnose dual and supernumerary genetic diagnoses, as highlighted by the series on Indian myopathies above. 3 In a large retrospective analysis of 7,374 adults undergoing NGS tests, a definite diagnosis was established in 2,076 (DR: 28.1%), with 101 individuals (4.9% of those with a diagnosis, 1.4% of all patients) harboring multiple genetic diagnoses. 2 While 97 among those had dual genetic diagnoses, three patients had three genetic disorders each, and one had four distinct molecular diagnoses.…”

“…[11][12][13][14][15] (4.6% of those with a diagnosis, 1.4% of all patients) received dual genetic diagnoses. 3 With increasing application of NGS in clinical practice, we expect more cases with similar results to emerge, thereby guiding future research in understanding complex disease inheritances, interactions, and pathophysiology.…”

“…Next-generation sequencing (NGS) is enabling new insights into the under-recognized prevalence of dual/multiple genetic diagnoses, 1 2 and outlining cases of complex oligogenic/multigenic inheritances due to synergism of pathogenic variants in >1 gene, in the same individual. 3 We present a newborn with a diagnosis of LAMA2-muscular dystrophy (LAMA2-MD) and possibly coexisting COL6A2-related Bethlem myopathy (BM).…”

Clinical Features, Diagnosis and Treatment Strategies of Limb Girdle Muscular Dystrophy: An Observational Study from South India

“…Serum Creatinine Kinase activity, muscle biopsy specimens, immuno histochemical analysis of alpha sarco-glycan were included in the study. The demographic data was expressed using descriptive statistics mean ± standard deviation [SD] [10]. Primary outcome is expressed as the number and percentage of patients with age as mean ± SD (range).…”