Arrhythmogenic Right Ventricular Cardiomyopathy: Growing Evidence for Complex Inheritance

Abstract

The identification of the genetic underpinnings of the rare Mendelian cardiac diseases associated with sudden cardiac death (SCD) in the young has led to an improvement in the management of patients with some of these disorders.1 For example, genetic testing in the long-QT syndrome (LQTS) provides an important means of confirming the clinical diagnosis and allows for cascade familial screening in affected families. Moreover, in this disorder, numerous genotype–phenotype relationships have been uncovered, such as the relation between the affected gene and arrhythmogenic triggers, and genotype-specific response to pharmacotherapy. In the LQTS, genetic testing, which identifies a (putative) mutation in ≈70% of probands, has joined traditional risk factors, such as sex and the extent of QTc-interval prolongation, as an independent prognostic risk factor.1 This contrasts sharply with other disorders associated with SCD in the young, 1 of which is arrhythmogenic right ventricular cardiomyopathy (ARVC), where the role of genotype as a prognostic factor is unclear.1 Article see p 533 ARVC2 is a progressive disease of the myocardium, which leads to cardiomyopathic changes involving pathological fatty infiltration and cardiomyocyte loss and SCD from ventricular arrhythmias at a young age. Although it has classically been considered to affect the right ventricle (hence the name), the increasing awareness of the disease has led to the recognition of forms that present left ventricular or biventricular involvement.2 Genetic studies have identified a number of genes for the disorder; most of these encode components of the cardiac desmosome ( DSC2 , DSG2 , DSP , JUP , and PKP2 ), although other genes have also been implicated (eg, TMEM43 and PLN ). About 50% to 70% of probands harbor a causal or possibly causal mutation in a desmosomal gene.2 However, although gene identification has provided important molecular insight for initiation of mechanistic studies …