Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy: Pathogenic Desmosome Mutations in Index-Patients Predict Outcome of Family Screening: Dutch Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Genotype-Phenotype Follow-Up Study

• Published in: Circulation (New York, N.Y.) Vol. 123; no. 23; pp. 2690 - 2700
• Main Authors: COX, Moniek G. P. J, VAN DER ZWAAG, Paul A, DOOIJES, Dennis, VAN DEN WIJNGAARD, Arthur, HOUWELING, Arjan C, JONGBLOED, Jan D. H, JORDAENS, Luc, CRAMER, Maarten J, DOEVENDANS, Pieter A, DE BAKKER, Jacques M. T, WILDE, Arthur A. M, VAN TINTELEN, J. Peter, VAN DER WERF, Christian, HAUER, Richard N. W, VAN DER SMAGT, Jasper J, NOORMAN, Maartje, BHUIYAN, Zahir A, WIESFELD, Ans C. P, VOLDERS, Paul G. A, VAN LANGEN, Irene M, ATSMA, Douwe E
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 14.06.2011
• Subjects: Adolescent; Adult; Arrhythmogenic Right Ventricular Dysplasia - genetics; Arrhythmogenic Right Ventricular Dysplasia - mortality; Arrhythmogenic Right Ventricular Dysplasia - pathology; Asymptomatic Diseases - mortality; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cardiovascular system; Death, Sudden, Cardiac - epidemiology; Desmosomes - pathology; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Family; Female; Follow-Up Studies; Genotype; Humans; Male; Medical sciences; Middle Aged; Netherlands - epidemiology; Pharmacology. Drug treatments; Phenotype; Predictive Value of Tests; Risk Factors; Tachycardia, Ventricular - genetics; Tachycardia, Ventricular - mortality; Tachycardia, Ventricular - pathology; Vasodilator agents. Cerebral vasodilators; Ventricular Fibrillation - genetics; Ventricular Fibrillation - mortality; Ventricular Fibrillation - pathology; Young Adult; Netherlands; Human; Prognosis; Arrhythmia; Cardiomyopathy; Genotype; Cardiovascular disease; Medical screening; Myocardial disease; Phenotype; follow-up studies; genetics; Arrhythmogenic right ventricular dysplasia; Follow up study; Heart disease; desmosome; Mutation
• DOI: 10.1161/CIRCULATIONAHA.110.988287
• ISSN: 0009-7322

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an autosomal dominant inherited disease with incomplete penetrance and variable expression. Causative mutations in genes encoding 5 desmosomal proteins are found in ≈50% of ARVD/C index patients. Previous genotype-phenotype relation studies involved mainly overt ARVD/C index patients, so follow-up data on relatives are scarce. One hundred forty-nine ARVD/C index patients (111 male patients; age, 49±13 years) according to 2010 Task Force criteria and 302 relatives from 93 families (282 asymptomatic; 135 male patients; age, 44±13 years) were clinically and genetically characterized. DNA analysis comprised sequencing of plakophilin-2 (PKP2), desmocollin-2, desmoglein-2, desmoplakin, and plakoglobin and multiplex ligation-dependent probe amplification to identify large deletions in PKP2. Pathogenic mutations were found in 87 index patients (58%), mainly truncating PKP2 mutations, including 3 cases with multiple mutations. Multiplex ligation-dependent probe amplification revealed 3 PKP2 exon deletions. ARVD/C was diagnosed in 31% of initially asymptomatic mutation-carrying relatives and 5% of initially asymptomatic relatives of index patients without mutation. Prolonged terminal activation duration was observed more than negative T waves in V(1) to V(3), especially in mutation-carrying relatives <20 years of age. In 45% of screened families, ≥1 affected relatives were identified (90% with mutations). Pathogenic desmosomal gene mutations, mainly truncating PKP2 mutations, underlie ARVD/C in the majority (58%) of Dutch index patients and even 90% of familial cases. Additional multiplex ligation-dependent probe amplification analysis contributed to discovering pathogenic mutations underlying ARVD/C. Discovering pathogenic mutations in index patients enables those relatives who have a 6-fold increased risk of ARVD/C diagnosis to be identified. Prolonged terminal activation duration seems to be a first sign of ARVD/C in young asymptomatic relatives.