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.

Abstract

BACKGROUND:

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.

METHODS AND RESULTS:

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).

CONCLUSIONS:

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.

• Authors: Moniek G P J Cox, Paul A van der Zwaag, Christian van der Werf, Jasper J van der Smagt, Maartje Noorman, Zahir A Bhuiyan, Ans C P Wiesfeld, Paul G A Volders, Irene M van Langen, Douwe E Atsma, Dennis Dooijes, Arthur van den Wijngaard, Arjan C Houweling, Jan D H Jongbloed, Luc Jordaens, Maarten J Cramer, Pieter A Doevendans, Jacques M T de Bakker, Arthur A M Wilde, J Peter van Tintelen, Richard N W Hauer
• Journal: Circulation (Circulation) Vol. 123 Issue 23 Pg. 2690-700 (Jun 14 2011) ISSN: 1524-4539 [Electronic] United States
• PMID: 21606396 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Topics

• Adolescent
• Adult
• Arrhythmogenic Right Ventricular Dysplasia (genetics, mortality, pathology)
• Asymptomatic Diseases (mortality)
• Death, Sudden, Cardiac (epidemiology)
• Desmosomes (pathology)
• Family
• Female
• Follow-Up Studies
• Genotype
• Humans
• Male
• Middle Aged
• Netherlands (epidemiology)
• Phenotype
• Predictive Value of Tests
• Risk Factors
• Tachycardia, Ventricular (genetics, mortality, pathology)
• Ventricular Fibrillation (genetics, mortality, pathology)
• Young Adult