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Genetic analysis of patients with Arrhythmogenic Right Ventricular Dysplasia (ARVD) and functional characterization of differentiated cardiomyocytes (iPSC-CM)

Grant number: 17/16399-0
Support type:Scholarships abroad - Research Internship - Doctorate (Direct)
Effective date (Start): February 08, 2018
Effective date (End): February 07, 2019
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Alexandre da Costa Pereira
Grantee:Fanny Wulkan
Supervisor abroad: Michael Alan Laflamme
Home 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
Local de pesquisa : 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


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 youngpeople, athletes and males. The clinical diagnosis is based on the International TaskForce Criteria which takes into account several types of criteria. Currently, multiplemutations in 12 key genes associated with the disease have been described. Nextgeneration sequencing (NGS) as a tool for the molecular diagnosis of the disease allowsan advance in the correlation between genotypic and phenotypic changes andconsequently in the prevention of this disease in familial cases and has contributedpotential benefits that grow along with the challenges in their interpretation. In addition, theuse of hiPSCs as an in vitro model of certain heart diseases allows to specifically evaluatethe relationship between the genotype and the different cellular phenotypic consequencesof the ARVC. However, the molecular mechanisms of the disease are still unclear andthere are no studies in the literature that encompass both the mutational profile (with anextensive panel of genes) and functional studies with the use of hiPSC-CMs. This studyaims to standardize the application of next-generation sequencing platforms in moleculardiagnosis of ARVC in the Brazilian population and to characterize, from a functional pointof view, hiPSC-derived cardiomyocytes (hiPSC-CMs) from patients with identifiedmutations in order to associate the mutational profile with the cellular phenotypicexpression. Approximately 40 individuals with a clinical diagnosis of ARVC from the HeartInstitute arrhythmia outpatient clinic will be subject to a genetic evaluation by a sequencingmethod according to Ion Torrent PGM and Miseq platforms and functional evaluations willbe performed, according to various phenotypic analysis of iPSC-derived cardiomyocytesfrom these patients. This work has a potential contribution in the area since it is the first toassociate different mutations in genes not yet studied in models that use hiPSCs-CMsderived from ARVC patients.