Genetic analysis of patients with arrhythmogenic right ventricular dysplasia (ARVD) and functional characterization of differentiated cardiomyocytes (iPSC-CM).

• Grant number: 17/16399-0
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• Start date: February 08, 2018
• End date: February 07, 2019
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Alexandre da Costa Pereira
• Grantee: Fanny Wulkan
• Supervisor: Michael Alan Laflamme
• Host Institution: Instituto do Coração Professor Euryclides de Jesus Zerbini (INCOR). Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
• Institution abroad: University Health Network (UHN), Canada
• Associated to the scholarship: 16/23858-9 - Genetic analysis of patients with arrhythmogenic right ventricular dysplasia (ARVD) and functional characterization of differentiated cardiomyocytes (iPSC-CM), BP.DD

Abstract

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic cardiomyopathy characterized by the replacement of myocardial cells by fibro-fatty tissue.The disease has a prevalence of approximately 1: 3500, and is more common in young people, athletes and males. The clinical diagnosis is based on the International Task Force Criteria which takes into account several types of criteria. Currently, multiple mutations in 12 key genes associated with the disease have been described. Next generation sequencing (NGS) as a tool for the molecular diagnosis of the disease allows an advance in the correlation between genotypic and phenotypic changes and consequently in the prevention of this disease in familial cases and has contributed potential benefits that grow along with the challenges in their interpretation. In addition, the use of hiPSCs as an in vitro model of certain heart diseases allows to specifically evaluate the relationship between the genotype and the different cellular phenotypic consequences of the ARVC. However, the molecular mechanisms of the disease are still unclear and there are no studies in the literature that encompass both the mutational profile (with an extensive panel of genes) and functional studies with the use of hiPSC-CMs. This study aims to standardize the application of next-generation sequencing platforms in molecular diagnosis of ARVC in the Brazilian population and to characterize, from a functional point of view, hiPSC-derived cardiomyocytes (hiPSC-CMs) from patients with identified mutations in order to associate the mutational profile with the cellular phenotypic expression. Approximately 40 individuals with a clinical diagnosis of ARVC from the Heart Institute arrhythmia outpatient clinic will be subject to a genetic evaluation by a sequencing method according to Ion Torrent PGM and Miseq platforms and functional evaluations will be performed, according to various phenotypic analysis of iPSC-derived cardiomyocytes from these patients. This work has a potential contribution in the area since it is the first to associate different mutations in genes not yet studied in models that use hiPSCs-CMsderived from ARVC patients. (AU)