ABC | Volume 113, Nº2, August 2019

Review Article Lamounier Júnior et al. Genetic and dilated cardiomyopathy Arq Bras Cardiol. 2019; 113(2):274-281 TTN , LMNA , and MYBPC3 ; one family was affected by a RBM20 mutation. In this family, three generations were affected on the maternal side, and the index case underwent to HTx at the age of 21 (3 years after diagnosis). The number of major cardiovascular events in this cohort was significantly higher in patients with LVNC than those probands with non‑ischemic DCM of known etiology. Approximately 10% of the patients with LVNC required HTx vs. 2.8% in the non‑ischemic DCM group. 49 One of the families with LVNC in this cohort was found carrying a MYH7 gene variant which has been associated in different studies with malignant-HCM. Although the affected individuals did not meet definitive criteria for HCM, several had an appreciable increase in myocardial wall thickness. 49 This should draw the attention of cardiologists to the phenotypic heterogeneity of PCMs, as well as to the need to bear in mind what an etiological diagnosis can represent in terms of the natural history of the disease. Genes usually related to arrhythmogenic cardiomyopathy (ACM) may produce indistinguishable clinical phenotype from those with DCM. Patients affected by desmoplakin ( DSP ) or FLNC truncating variants, for instance, may be affected by a form of ACM with exclusive left ventricle involvement. 20,50,51 There are several reports of DCM-patients affected by mutations in desmosomal genes that do not fulfil any (or only some) of the arrhythmogenic right ventricular dysplasia diagnostic criteria. 50-52 In a study of 89 unrelated end-stage DCM patients requiring HTx, screening of the five most common desmosomal genes ( PKP2 , DSP , JUP , DSC2 , DSG2 ) identified genetic variants in 18% of the probands. 51 Genetic testing in relatives identified additionally 38 carriers, including some with subclinical DCM. Histopathological analysis of explanted hearts was heterogeneous; some cases showed fibro-fatty infiltration of the right ventricle, some of the left ventricle, and some had no observable fibro-fatty replacement. 52 Final considerations In view of the foregoing, we conclude that the PCMs, particularly the dilated form (DCM), reflect a complex, highly heterogeneous syndrome of challenging diagnosis, prognosis, and treatment. In this scenario, molecular NGS diagnosis can be a very useful tool for clinical cardiologists practice. Although still incipient in Brazil, the use of genetic testing in DCM and HTx services should be considered, since etiological diagnosis often allows a more assertive clinical management and risk stratification. Moreover, clinical and genetic screening of patients' relatives with these conditions is somewhat neglected, although it is a recommended approach. In this way, cardiomyopathy units and HTx services, as well as correlated research groups, should address this topic more incisively and focus on disseminating knowledge among health professionals and in the society as a whole. Despite its potential benefits, the limitations of genetic testing should not be overlooked. The possible psychological impact of the genetic testing results on patients and their families should be anticipated and discussed. In addition, genetic testing cannot determine whether the proband will develop symptoms, as well as the severity of these potential symptoms. 53 Finally, we illustrate the present article with a clinical case from our practice in which genetic testing was part of the clinical evaluation. Clinical case: A 30-year-old male was hospitalized due to congestive HF (NYHA functional class III). After 1 year of occasional palpitations, a diagnosis of DCM was established. Cardiac magnetic resonance imaging, which revealed diffuse hypokinesis, left ventricular dysfunction (left ventricular ejection fraction, 46%), and diffuse mesoepicardial fibrosis (Figure 1). Comparison with a previous echocardiogram performed two years latter suggested a rapid clinical progression (left ventricular ejection fraction, 32%); systolic and diastolic diameters, 49 and 58 mm, respectively; left atrial diameter, 44 mm. Echocardiogram showed atrial fibrillation and the coronary angiography did not reveal any evidence of coronary heart disease. Taking into consideration, the severity of the case and a positive family history of sudden death (Figure 2), genetic testing was performed (NGS panel for DCM). A LMNA p.Leu176Pro variant was identified, providing etiological confirmation for familial DCM. Based on these findings an ICD was implanted for primary prevention, despite of the left ventricular ejection fraction > 30%. Consistent with descriptions in the literature, cardiolaminopathy of the patient did not respond adequately to optimized clinical treatment and progressed rapidly to HTx. One year later, the patient developed anasarca and was hospitalized again, requiring positive inotropic supporting with intravenous agents. HTx was performed 2 months later. The patient’s children (both under 10 years of age) were apparently healthy. As the mean age of diagnosis of LMNA gene carriers is from the third decade of life onward, ethical recommendations for genetic testing in underage relatives were followed, respecting the appropriate age for genetic counseling. 54 However, it is important to mention that cases of children affected by LMNA cardiomyopathy have been reported rarely, which should call into question the current expectant management of young children of patients with cardiolaminopathies. 55 Author contributions Conception and design of the research: Lamounier Júnior A, Stein R; Acquisition of data and Analysis and interpretation of the data: Lamounier Júnior A, Ferrari F, Stein R; Obtaining financing: Stein R; Writing of the manuscript and Critical revision of the manuscript for intellectual content: Lamounier Júnior A, Ferrari F, Max R, Ritt LEF, Stein R. Potential Conflict of Interest No potential conflict of interest relevant to this article was reported. Sources of Funding There were no external funding sources for this study. 278