Molecular Genetic Studies in Families with Life Threatening Cardiac Arrhythmias

Abstract

Introduction: Cardiac Arrhythmias have a prevalence of about 1:2000-2500 in different populations worldwide. Individuals affected with life threatening arrhythmias typically exhibit episodes of syncope, palpitations, abnormal ECG pattern that can lead to sudden cardiac death. These are autosomal dominant disorders. The two common syndromes are Long QT (LQT) and Brugada (BrS) syndrome. Mutations identified in three genes (KCNQ1, KCNH2 and SCN5A) account for majority of the cases. newlineAim: To identify causative variations responsible for cardiac arrhythmias in Indian patients, perform genotype phenotype correlation and identify founder mutation, if any. newlineMaterials and Methods: Forty patients who fulfilled the inclusion criteria of the study were enrolled. Mutation analysis was performed in three common genes by direct sequencing. If a mutation was not identified, NGS was performed to identify mutations in other genes or uncover potential new genetic variations in probands. Novel mutations were evaluated for pathogenicity using bioinformatics and molecular modeling softwares. The genotype phenotype correlation was performed between: patients and their family members, patients of different LQTS groups or BrS groups. newlineResults: Sanger sequencing identified mutations in twenty-three patients, twenty had LQTS and three were affected with BrS. Among the LQT syndromes, mutations were identified in seventeen in KCNQ1 (LQTS1), one in KCNH2 (LQTS2) and two in SCN5A (LQTS3). The three BrS patients had mutations in SCN5A, a gene responsible for BrS1. Ten of 23 mutations were novel. NGS identified mutation in nine of the remaining seventeen patients. Of which, seven had LQTS and two had BrS. Of these nine mutations, seven were novel. Genotypephenotype correlation on factors including ECG pattern, QTc, age, sex, symptoms and triggers was performed on different forms of LQTS and BrS. newlineConclusion: Identification of mutations helps in confirming the clinical diagnosis, screening family members and correlating the genotype with phenotype...