Amitabh Biswas1, Soumi Das2, Mitali Kapoor2, Karuthedath Vellarikkal Shamsudheen3, Rijith Jayarajan3, Ankit Verma3, Sandeep Seth4, Balram Bhargava4, Vinod Scaria3, Sridhar Sivasubbu3, V R Rao5. 1. Dept. of Anthropology, Delhi University, Delhi, India; College of Natural Sciences, Arba Minch University, Ethiopia. 2. Dept. of Anthropology, Delhi University, Delhi, India. 3. CSIR-Institute of Genomics & Integrative Biology (IGIB), New Delhi, India. 4. Dept. of Cardiology, All India Institute of Medical Sciences (AIIMS), New Delhi, India. 5. Dept. of Anthropology, Delhi University, Delhi, India; Genome Foundation, Hyderabad, India; Dept. of Genetics, Osmania University, Hyderabad, India. Electronic address: profvrrao@gmail.com.
Abstract
BACKGROUND: Hypertrophic Cardiomyopathy (HCM) with variable clinical presentations and heterogeneity is the common cause of sudden cardiac death. Genetic diagnosis is challenging in these complex diseases but exome sequencing as a genetic diagnostic tool provides explainable results. METHODS: In a familial Hypertrophic Cardiomyopathy with multigenerational inheritance with apparent phenotype, had a history of sudden death and severe arrhythmia followed by implantation of Implantable cardioverter defibrillator (ICD). Exome sequencing (100×) trailed by effective filtering steps for exome variants on the basis of different parameters, segregated variants are prioritized for the disease and further clinical relevance are evaluated for the variants. RESULTS: A rare causal variant in troponin-T gene (TNNT2, NM_000364.3;c.274C > T;p.Arg92Trp) is identified, shared by only affected members, absent in unaffected members and also in 200 unrelated control chromosomes. TNNT2 mutation act as a driver mutation but mutations in other disease-related genes, KCNMB1, LPL, APOE and other biochemical factors provides risk stratification within affected family members. CONCLUSION: This study contributes to the role of "rare variants" in complex disease phenotypes and heterogeneity within family and the necessity of whole exome targeted approaches in complex cardiomyopathy, which are known to harbor private mutations.
BACKGROUND:Hypertrophic Cardiomyopathy (HCM) with variable clinical presentations and heterogeneity is the common cause of sudden cardiac death. Genetic diagnosis is challenging in these complex diseases but exome sequencing as a genetic diagnostic tool provides explainable results. METHODS: In a familial Hypertrophic Cardiomyopathy with multigenerational inheritance with apparent phenotype, had a history of sudden death and severe arrhythmia followed by implantation of Implantable cardioverter defibrillator (ICD). Exome sequencing (100×) trailed by effective filtering steps for exome variants on the basis of different parameters, segregated variants are prioritized for the disease and further clinical relevance are evaluated for the variants. RESULTS: A rare causal variant in troponin-T gene (TNNT2, NM_000364.3;c.274C > T;p.Arg92Trp) is identified, shared by only affected members, absent in unaffected members and also in 200 unrelated control chromosomes. TNNT2 mutation act as a driver mutation but mutations in other disease-related genes, KCNMB1, LPL, APOE and other biochemical factors provides risk stratification within affected family members. CONCLUSION: This study contributes to the role of "rare variants" in complex disease phenotypes and heterogeneity within family and the necessity of whole exome targeted approaches in complex cardiomyopathy, which are known to harbor private mutations.
Authors: Ândrea Chaves-Markman; Manuel Markman; Marcelo Antônio O Santos-Veloso; Lucas S Bezerra; Dário C Sobral Filho; Brivaldo Markman Filho Journal: Cureus Date: 2020-01-01