👤 Sumita Danda

Genetic cardiomyopathies (CM) are disorders that affect morphology and function of cardiac muscle. Significant number of genes have been implicated in causing the phenotype. It is one of the leading genetic causes of death in young. We performed a study to understand the genetic variants in primary cardiomyopathies in an Indian cohort. Study comprised of 22 probands (13 with family history) representing hypertrophic (n = 10), dilated (n = 7), restrictive (n = 2) and arrhythmogenic ventricular(n = 3) cardiomyopathies. Genomic DNA was target captured with a panel of 46 genes and libraries sequenced on Illumina platform. Analysis identified, reported pathogenic as well as novel pathogenic (n = 6) variants in 16 probands. Of the 10 HCM patients, candidate variants were identified in nine of them involving sarcomere genes (62%, MYBPC3, MYH6, MYH7, MYL3, TTN), Z-disc (10%, ACTN2, LDB3, NEXN,), desmosome (10%, DSG2, DSP, PKP2) cytoskeletal (4%, DTNA) and ion channel (10% RYR2). In four DCM patients, variants were identified in genes NEXN, LMNA and TTN. Three arrhythmogenic right ventricular cardiomyopathy (ARVD) patients carried mutations in desmosome genes. Rare TTN variants were identified in multiple patients. Targeted capture and sequencing resulted in identification of candidate variants in about 70% of the samples which will help in management of disease in affected individual as well as in screening and early diagnosis in asymptomatic family members. Amongst the analysed cases, 22% were inconclusive without any significant variant identified. Study illustrates the utility of next-generation multi-gene panel as a cost-effective genetic testing to screen all forms of primary cardiomyopathies. Show less

Systemic sclerosis is a fibrotic disease that initiates in the skin and progresses to internal organs, leading to a poor prognosis. Unraveling the etiology of a chronic, multifactorial disease such as systemic sclerosis has been aided by various animal models that recapitulate certain aspects of the human pathology. We found that the transcription factor SNAI1 is overexpressed in the epidermis of patients with systemic sclerosis, and a transgenic mouse recapitulating this expression pattern is sufficient to induce many clinical features of the human disease. Using this mouse model as a discovery platform, we have uncovered a critical role for the matricellular protein Mindin (SPON2) in fibrogenesis. Mindin is produced by SNAI1 transgenic skin keratinocytes and aids fibrogenesis by inducing early inflammatory cytokine production and collagen secretion in resident dermal fibroblasts. Given the dispensability of Mindin in normal tissue physiology, targeting this protein holds promise as an effective therapy for fibrosis. Show less

To investigate the mutational spectrum and genotype-phenotype correlation in Indian patients with congenital myasthenic syndrome (CMS), using next-generation sequencing of 5 genes. CHRNE, COLQ, DOK7, RAPSN, and GFPT1 were sequenced in 25 affected patients. We found clinically significant variants in 18 patients, of which variants in CHRNE were the most common, and 9 were novel. A common pathogenic COLQ variant was also detected in 4 patients with isolated limb-girdle congenital myasthenia. Targeted screening of 5 genes is an effective alternate test for CMS, and an affordable one even in a developing country such as India. In addition, we recommend that patients with isolated limb-girdle congenital myasthenia be screened initially for the common COLQ pathogenic variant. This study throws the first light on the genetic landscape of CMSs in India. Show less