ABC | Volume 113, Nº2, August 2019

Review Article Lamounier Júnior et al. Genetic and dilated cardiomyopathy Arq Bras Cardiol. 2019; 113(2):274-281 Methods for genetic diagnosis in dilated cardiomyopathy The use of next-generation sequencing (NGS) platforms has enabled two approaches for the genetic diagnosis of DCM: 1. Whole-exome sequencing: this approach covers “all” exons and flanking regions of the human genome (in practice, it considers only those genes for which correlated clinical information already exists). Exome sequencing has been more used in applied clinical research, resulting in the discovery of new genes potentially associated with DCM. 13,14 These “new” genes are also called candidate genes because the level of evidence supporting its pathogenic potential is still low or uncertain. It would result in a greater number of unknown clinical significance variants; 2. Targeted NGS: NGS panels sequence a certain number of genes for which there is higher evidence of a causal association with DCM (Table 1). 15,16 The large volume of cases already described in carriers of pathogenic/ likely pathogenic variants in these genes raised useful information for clinical decision-making; 17 it is important to emphasize that most of the mutations reported in DCM are exclusive to a single family, which leads to barriers in the interpretation of the genetic data. Therefore, integration of clinical manifestations and family history is essential in the decision-making process. 17 There are around a hundred genes associated with DCM, with different levels of evidence for their associations. Furthermore, it bears stressing that the presence of a genetic mutation does not always mean that the disease will develop. 18 The best-documented genes are listed in Table 1. In recent years, the increasingly widespread use of NGS panels has allowed the identification of a significant number of individuals with variants in the same gene. This population has been enabling relevant clinical descriptions in DCM, as in the most recent studies addressing different genes ( TTN , LMNA , FLNC , or BAG3 ). 19-21 Cosegregation of variants in these genes has been demonstrated as disease-causing in multiple DCM-families, and the ever-increasing number of identified carriers has enabled genotype-phenotype correlation analyses on the prognosis of the disease. 22,23 Briefly, genetic testing through the aforementioned techniques can help cardiologists in three important clinical scenarios: 8-10,24,25 1. familial management; 2. etiological definition and; 3. assertive risk stratification. Importance of family screening in dilated cardiomyopathy A cohort study with advanced HF patients waiting in the transplant list shows that the diagnosis of familial DCM (FDCM) was systematically neglected. 26 The mere use of the pedigree tool increased the prevalence of this diagnosis from 4.1%to 26%. Prospective cohorts have since found that 25 to 40% of non‑ischemic DCM cases are in fact familial, 9,24 drawing attention to the hereditary component of this syndrome, as well as to the importance of early detection and treatment of affected relatives. In this context, pedigree with at least three generations and the use of genetic testing is strongly recommended. 9 The identification of a pathogenic or a likely pathogenic variant in an index case (proband) allows the entire family of the patient may benefit from genetic screening. 4,9 This is particularly useful in cases where clinical evaluation alone has not been able to establish the diagnosis in a relative. 2,4 In addition, the early identification of a family member carrier who is asymptomatic, or in the subclinical phase of the disease, may be particularly relevant when genetic testing reveals etiologies with greater arrhythmogenic potential or known to evolve faster. 19,20 Moreover, in this scenario, it would be possible to apply measures to delay disease progression or even avert a fulminant outcome. On the other hand, regular follow-up of the index case's relatives that are identified as non-carriers of a pathogenic variant is not recommended; 9 this avoids unnecessary health expenditures and prevents additional psychological stress to the patient/family. Etiological definition and associated prognosis TTN truncating variants : amilestone in knowledge about the role of genetics in DCM was a study by Herman et al. 11 In this publication, titin-truncating variants (TTNtv) were identified in 25% of cases of FDCM and in 18% of sporadic DCM-cases. These prevalence were obtained across three different cohorts, with a frequency of TTNtv between 8 and 40%. It is worth noting that higher frequencies were observed in subjects undergoing HTx or with severe systolic dysfunction. Since then, other studies have sought to ascertain the natural history of DCM by assessing TTNtv patients. 24,27,28 No differencewas observed in the incidence of outcomes among affected carriers vs. non‑carriers, 27 as there was no difference inmesocardial fibrosis between these groups. 28 However, males with TTNtv manifested the disease at younger ages than female carries (78% vs. 30% of women at age 40). 27 Other authors have identified that affected TTNtv carriers would have an earlier outcome event (death fromany cause, waiting for HTx, or requiring a ventricular-assist device) than non-carriers. 28 In this same line, male carriers had a lower survival rate (28% of men had a cardiovascular event vs. 8% of women before age 50), considering the outcomes death by HF, HTx, or use of a ventricular assist device. 27 In a robust sample (n = 558), a high incidence of cardiovascular death starting at age 40 years was observed in patients with TTNtv. 29 In this cohort, the incidence of cardiovascular events was again higher in men than in women “(1.25% vs. 0.75%/year between the ages of 40-60), with sudden cardiac death being the most frequent outcome. In addition, several publications have described a high incidence of atrial fibrillation, as well as sustained and non‑sustained ventricular tachycardia, in these patients. 24,25,28,30 Although according to the literature, the presence of TTNtv is associated with early onset of arrhythmic manifestations, it has not yet been possible to define a characteristic phenotype for these patients, unlike for patients with mutations in other DCM-related genes. Moreover, it has been proposed that TTNtv may be acting as a susceptibility genetic substrate to different DCM-types (anthracycline-induced, peripartum, and alcoholic). 27-29 Finally, patients with titin cardiomyopathy 276