ABC | Volume 113, Nº2, August 2019

Review Article Keywords Cardiomyopathy, Dilated/genetics; Ventricular Dysfunction, Left; Heart Failure; Genetic Testing/methods; Heart Transplantation. Mailing Address: Ricardo Stein • Universidade Federal do Rio Grande do Sul - Rua João Caetano, 20 Apt 402. Postal Code 90040-060, Porto Alegre, RS – Brazil E-mail: rstein@cardiol.br Manuscript received January 13, 2019, revised manuscript March 13, 2019, accepted April 10, 2019 DOI: 10.5935/abc.20190144 Importance of Genetic Testing in Dilated Cardiomyopathy: Applications and Challenges in Clinical Practice Arsonval Lamounier Júnior, 1,2 Filipe Ferrari, 3, 4 R enato Max, 5 Luiz Eduardo Fonteles Ritt, 6, 7 Ricardo Stein 3, 4 Health in Code S.L., Scientific Department, 1 A Coruña – Spain Universidade da Coruña, GRINCAR (Cardiovascular Research Group), 2 A Coruña – Spain Graduate Program in Cardiology and Cardiovascular Sciences, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, 3 Porto Alegre, RS – Brazil Exercise Cardiology Research Group (CardioEx), Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, 4 Porto Alegre, RS – Brazil Hospital Universitário Onofre Lopes, 5 Natal, RN – Brazil Escola Bahiana de Medicina e Saúde Pública, 6 Salvador, BA – Brazil Hospital Cárdio Pulmonar, 7 Salvador, BA – Brazil Abstract Dilated cardiomyopathy (DCM) is a clinical syndrome characterized by left ventricular dilatation and contractile dysfunction. It is the most common cause of heart failure in young adults. The advent of next-generation sequencing has contributed to the discovery of a large amount of genomic data related to DCM. Mutations involving genes that encode cytoskeletal proteins, the sarcomere, and ion channels account for approximately 40% of cases previously classified as idiopathic DCM. In this scenario, geneticists and cardiovascular genetics specialists have begun to work together, building knowledge and establishing more accurate diagnoses. However, proper interpretation of genetic results is essential and multidisciplinary teams dedicated to the management and analysis of the obtained information should be considered. In this review, we approach genetic factors associated with DCM and their prognostic relevance and discuss how the use of genetic testing, when well recommended, can help cardiologists in the decision-making process. Introduction Primary cardiomyopathies (PCMs) are a heterogeneous group composed predominantly by genetic diseases associated with pathological alterations of myocardial structure and function. 1-3 These diseases often progress to heart failure (HF), with dilated cardiomyopathy (DCM) being the main indication for heart transplantation (HTx). 3 Currently, the prevalence of idiopathic DCM is estimated at around 1 case per 2,500 population, but authors such as Hershberger et al. 4 describe a frequency ten times greater. 4 Particularly in the last two decades, a greater understanding on the etiology and clinical course of many of these diseases has been achieved. 5,6 This has been possible by substantial advances in the use of genetic diagnosis at cardiomyopathy clinics and research centers around the world. Traditionally, DCM is defined as dilatation of the left ventricle or both ventricles, with consequent impairment in myocardial contractility, in the absence of abnormal overload and/or ischemic heart disease. 4-6 However, this syndrome can encompass a wide range of genetic and acquired disorders that can be expressed to a greater or lesser impact over the patient’s life course. Some individuals with specific mutations detected in the early DCM-stages may present intermediate phenotypes that do not meet the classical definition of the disease. 2,4 For this reason, the formulation of some concepts that define subgroups of patients with this syndrome would be relevant, such as the case of hypokinetic non-DCM, 2 where systolic dysfunction may occur without left ventricular dilatation. In fact, the observed clinical heterogeneity is the partial reflex of the various genes related to sarcomere proteins, cytoskeleton, intercellular connections, the cell membrane, and ion channels (Table 1), 2,4,7,8 which have been implicated in DCM. Many of these genes have been also associated with other forms of cardiomyopathies (left ventricle non-compaction [LVNC], arrhythmogenic, hypertrophic, and restrictive), and the prevalence of pathogenic variants in each of these genes is distinct for each disorder. 4,7 Mutations with pathogenic potential are identified in up to 40% of cases described as idiopathic DCM, depending on the cohort. 9,10 Indeed, it has been suggested that genetic testing would have a higher yield (up to 70%) in cohorts of patients with idiopathic DCM already waitlisted for HTx. 11,12 In the last decade, recommendations for the use of genetic testing in familial DCM have been established by respective guidelines. 9 Genetic testing can help in the management of patients and their relatives, as well as optimize the risk stratification. Careful clinical evaluation, a thorough family history, and the results of genetic testing are the cornerstones of this approach. Considering the incipient use of genetics in DCM management in Brazil, the aim of this review is to present and discuss the importance of molecular testing in the DCM spectrum. 274