Arrhythmogenic Right Ventricular Dysplasia, Familial, 13

A number sign (#) is used with this entry because of evidence that arrhythmogenic right ventricular dysplasia-13 (ARVD13) is caused by heterozygous mutation in the CTNNA3 gene (607667) on chromosome 10q21.

For a discussion of genetic heterogeneity of ARVD, see ARVD1 (107970).

Description

Arrhythmogenic right ventricular cardiomyopathy/dysplasia is characterized by progressive fibrofatty myocardial replacement, primarily of the right ventricle. The main clinical features are structural and functional abnormalities of the ventricles, electrocardiographic depolarization/repolarization changes, reentrant arrhythmias, and sudden death (summary by van Hengel et al., 2013).

Clinical Features

Van Hengel et al. (2013) studied an Italian man with ARVD who was diagnosed at 14 years of age during a screening for participation in sports activities, at which time his baseline electrocardiogram (ECG) showed first-degree atrioventricular block and negative T-waves in V1 to V4 in the absence of complete right bundle branch block (RBBB). He had several episodes of sustained ventricular tachycardia with left bundle branch block (LBBB) morphology and superior axis deviation, and late potentials were detected in the absence of QRS greater than 110 ms. Echocardiography showed severe dilation of the right ventricle with marked hypokinesia of the free wall, reduced right ventricular ejection fraction (RVEF), and anterior, apical, and subtricuspid akinesia. MRI confirmed marked dilation of the right ventricle, with apical sacculation and regional right ventricle akinesia with an RVEF of 30%. After 3 transcatheter ablations, the patient received an implantable cardioverter-defibrillator at 36 years of age. Van Hengel et al. (2013) also studied an Italian female ARVD proband who was evaluated at 15 years of age due to a syncopal episode. Holter ECG showed nonsustained ventricular tachycardia with LBBB morphology and superior axis, and late potentials were present in the absence of QRS duration greater than 110 ms. Echocardiography in the female patient showed mild right ventricular dilation with kinetic abnormalities in the apical region, which was confirmed by MRI. Her father also exhibited mild right ventricular dilation on echocardiography, although he did not fulfill the diagnostic criteria for ARVD. Contrast-enhanced MRI in an asymptomatic paternal aunt showed increased trabeculations in the right ventricular apex and intramural and epicardial fibrosis in the left ventricular posterolateral and basal inferior walls. Her paternal grandmother died at 83 years of age due to heart failure, without a history of valvular or ischemic heart disease.

Molecular Genetics

In 76 Italian probands with ARVD who were negative for mutation in 5 known ARVD-associated genes, van Hengel et al. (2013) analyzed the candidate gene CTNNA3 and identified different heterozygous mutations in 2 of the probands, a missense mutation (V94D; 607667.0001) and an in-frame 3-bp deletion (607667.0002). Neither mutation was found in 250 ethnically matched controls or in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases.