ABC | Volume 113, Nº2, August 2019

Review Article Lamounier Júnior et al. Genetic and dilated cardiomyopathy Arq Bras Cardiol. 2019; 113(2):274-281 appear to have a more favorable clinical course and respond better to drug therapy than those affected by variants in the lamin ( LMNA ) gene. 31-33 Lamin : LMNA pathogenic variants produce a well- characterized DCM phenotype associated with conduction disease/malignant arrhythmias, also called cardiolaminopathies. 34 Phenotypic expression have been described as a progressive atrioventricular conduction disease which usually precedes ventricular dysfunction and/or ventricular arrhythmias, although ventricular or supraventricular arrhythmias (especially atrial fibrillation) may be identified as the first manifestation. 19,34 Diagnosis is usually established after age 20, with high penetrance (>90%) after 40 years. 35 Once the first symptoms have manifested, cardiolaminopathies can progress to advanced HF faster than primary DCMof other etiologies. 19,36 LMNA mutations prevalence ranges from 5-10% in FDCM cohorts and 2-5% in sporadic cases, accounting for up to 30% of the DCM-cases associatedwith conduction disease/arrhythmias. Their prevalence is lower in cases of isolated DCM (non‑arrhythmic). 34,35 Between 2013 and 2015, Hasselberg et al. 37 identified a 6% prevalence of LMNA gene mutations in a cohort of 79 Norwegians young with FDCM. A particularly high proportion of carriers (19%) required HTx. In another study, 122 affected LMNA carriers were followed for seven years; 27 progressed to terminal DCM or death. It is worth noting that, in this same cohort, asymptomatic carriers had a 9% annual incidence of any documented cardiac event over 4 years of follow-up. 19 These findings suggest a significant unfavorable prognosis and faster progression to HTx/death than in DCMs with other etiologies. These clinical and epidemiological profile supports the recommendations for genetic testing of patients with non-ischemic DCM. Furthermore, an early implant of a cardioverter/defibrillator (ICD) should be considered when a LMNA pathogenic variant is identified (Class of recommendation IIa, level of evidence B) in a patient with risk factors. 38 Based on the study published in 2012 that enrolled 269 patients with cardiolaminopathy, the risk of cardiac events is highest when the patient has two or more of these risk criteria at the time of diagnosis: 1) non-sustained ventricular tachycardia; 2) left ventricular ejection fraction <45%; 3) male sex; and 4) a truncating-type variant. 39 Since then, other authors have proposed that not only truncating variants but also missense-type genetic variants, would be relevant due to the potential for sudden death. 40 Finally, a new risk score for patients with DCM associated with LMNA variants should be published soon. We hope that it will increase the accuracy of risk stratification in these patients. Other genes : Some sarcomere genes more often associated with hypertrophic cardiomyopathy (HCM) may also cause DCM. 25 The beta-myosin heavy chain ( MYH7 ), troponin T ( TNNT2 ), and tropomyosin ( TPM1 ) sarcomere genes are those for which associated prognostic information is available. Depending on the location of the genetic variant in the MYH7 gene, the natural history may be particularly severe, similarly to that observed occurs in cases of DCM caused by TNNT2 mutations. 25 TPM1 variants cause less than 1% of DCM cases but account for a significant portion of pediatric forms of this disease, in which rapid progression to death or HTx is not uncommon. 25 A meta-analysis of nearly 8,100 patients evaluated genotype-phenotype correlations of DCM with the TTN and LMNA genes, as well as genes encoding sarcomere proteins such as myosin-binding protein C ( MYBPC3 ), MYH7 , TNNT2 , troponin I ( TNNI3 ), RNA‑binding protein 20 ( RBM20 ), and phospholamban ( PLN ). 41 A significantly higher frequency of HTx was observed in patients with LMNA mutations (27%) than for carriers of RBM20 and MYBPC3 mutations (~10% each). Across the different genes examined, those affected were predominantly male (79% for MYBPC3 mutations and 69% for LMNA and MYH7 variants), except for PLN mutations (46% men). More recently, the filamin C ( FLNC ) and Bcl-2-associated athanogene 3 ( BAG3 ) genes have had their role in the DCM natural history characterized in high-impact publications. 20,21,42 FLNC was associated with a more arrhythmogenic profile, and BAG3 , with a greater number of HF-related events. FLNC truncating variants were found cosegregating in 28 affected families with a particular form of arrhythmogenic/DCM. 20 The most prevalent clinical features were ventricular dilatation (68%), systolic dysfunction (46%), andmyocardial fibrosis (67%). Ventricular arrhythmias were documented in 82%of the patients, and cases of sudden death were reported in 21/28 families. Another study identified FLNC truncation variants in 2.2% of DCM-patients, 85%of whomhad ventricular arrhythmias and/or sudden death. 42 Additional right-heart involvement was reported in 38% of the cases. Thus, early ICD implantation could be considered in these patients, even when they do not meet the criteria established in current DCM guidelines. 9,20 In recent years, several isolated BAG3 reports have been described in DCM-families. 43-47 In a meaningful way, BAG3 associated phenotype was recently defined with data from a cohort of 129 carriers. 19 After a mean follow-up of 38 months, the number of carriers affected with DCM raised from 57% to 68%. It represents 26% of the carriers who initially had a negative phenotype but manifested the disease. Considering carriers over the age of 40, 80% were phenotype-positive. In this sample, the incidence of cardiac events in carriers of BAG3 variants with DCM was 5.1% per year (outcomes: sustained ventricular tachycardia, sudden death, HF death, need for ventricular assist device and HTx), with a predominance of HF-events versus a lower number of arrhythmic outcomes. Male patients, those with systolic dysfunction, or increased ventricular diameter had the highest incidence of events during the follow-up. 21 Based on these findings, variants of the BAG3 gene do not appear to be related to a need for early ICD implantation, unlike FLNC mutations. Genetic heterogeneity and overlapping phenotype Many of the genes described as disease-causing in patients with DCM are also associated with the development of other forms of PCMs (Table 1). This fact may result in the presence of more than one phenotype in the same pedigree or overlapping phenotypes in the same individual, as occurs, for example, with LVNC and DCM. 48,49 In a cohort of 95 patients with LVNC (68 unrelated individuals and 27 relatives, 23% of cases familial), a genetic variant was identified in 38% of the cases. 49 The most frequent genes were 277