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:

Digenic Variants in the TTN and TRAPPC11 Genes Co-segregating With a Limb-Girdle Muscular Dystrophy in a Han Chinese Family

“…TTN gene variants have previously been implicated with variants in other genes as the basis for familial hypertrophic cardiomyopathy, left-ventricular non-compaction cardiomyopathy, and dilated cardiomyopathy ( Waldmüller et al, 2015 ). Double heterozygous mutations in two genes were identified in several patients with genetic myopathies ( Trabelsi et al, 2008 ; Peddareddygari et al, 2018 ; Chakravorty et al, 2020 ). The bioinformatics analysis revealed possible interactions and common pathways in desmin and calpain 3, which supported the two heterozygous variants leading to the patient’s LGMD in a digenic mechanism ( Peddareddygari et al, 2018 ).…”

“…The interrelationship and synergy between the two proteins await further functional experiments. Though with the application of appropriate approaches for diagnosis, some LGMD cases remain undiagnosed in genetics, and monogenic variants may not be accountable for all cases ( Magri et al, 2017 ; Yu et al, 2017 ; Chakravorty et al, 2020 ). Although the possibility of complex rearrangement, deletion, and duplication involving one or a few exons, or deep pathogenic point variants in introns cannot be fully ruled out, our study provides the clue of a possible digenic mechanism or enhanced susceptibility responsible for the phenotype in this LGMD family.…”

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

“…In a series of 207 individuals with suspected inherited myopathy from the Indian subcontinent, 13 cases (6.28%) had pathogenic variants in >1 gene, suggesting a high incidence of synergistic heterozygosity in genetic myopathies. 3 While in some of these cases, both the genes were expressed phenotypically (viz dual diagnosis); in some instances the 'synergism' of > 1 genetic mutations resulted in a net-amplified expression of one trait preferentially over the other (i.e facilitation). 3 Immunohistochemistry studies assessing the laminin α2 and collagen VI expression of the dermal fibroblasts through skin biopsy could not be obtained in this case, but could potentially further clarify the impact of the COL6A2 variant in the future.…”

“…3 While in some of these cases, both the genes were expressed phenotypically (viz dual diagnosis); in some instances the 'synergism' of > 1 genetic mutations resulted in a net-amplified expression of one trait preferentially over the other (i.e facilitation). 3 Immunohistochemistry studies assessing the laminin α2 and collagen VI expression of the dermal fibroblasts through skin biopsy could not be obtained in this case, but could potentially further clarify the impact of the COL6A2 variant in the future. 12,13 Despite overlapping features, a future musculoskeletal MRI in the child and her mother may help to establish the phenotype; fatty infiltration of the muscles is relatively more common in LAMA2-MD, while a "central-cloud phenomenon" in rectus femoris is classic for BM (►Table 1).…”

“…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 COL6A2related Bethlem myopathy (BM).…”