Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy

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 Ϸ50% 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, 49Ϯ13 years) according to 2010 Task Force criteria and 302 relatives from 93 families (282 asymptomatic; 135 male patients; age, 44Ϯ13 years) were clinically and genetically characterized. DNA analysis comprised sequencing of plakophilin-2 (PKP2), desmocollin-2, desmoglein-2, desmoplakin, and plakoglobin and multiplex ligationdependent 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 Ͻ20 years of age. In 45% of screened families, Ն1 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. A rrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is histopathologically characterized by progressive fibrofatty replacement of myocardium, primarily of the right ventricle (RV). 1-3 Although familial occurrence was recognized in the first report, only in the last decade has the genetic substrate been identified in genes encoding desmosomal proteins. 1,4 -9 Desmosomes are protein complexes in the intercalated disk, among others responsible for mechanical coupling of cardiac myocytes. Their impairment leads to both mechanical and electric uncoupling of cardiomyocytes, followed by cell death with fibrofatty replacement. 10 -13 Both uncoupling and altered architecture result in activation delay, which is the pivotal mechanism for reentry and thus ventricular tachycardia (VT). 14 -16 Editorial see p 2661 Clinical Perspective on p 2700Arrhythmogenic right ventricular dysplasia/cardiomyopathy usually shows an autosomal dominant inheritance pattern, w...

Clinical utility gene card for: arrhythmogenic right ventricular cardiomyopathy (ARVC)

“…Nevertheless, because carriership of multiple pathogenic mutations in more than one gene has been reported, 5,13,17,18 this mutation-negative family member may carry an yet unidentified ARVC-related mutation.…”

“…4 Less frequently, other types of mutations including large deletions/ duplications, are detected. 5,6 1.6 Analytical methods Sanger sequencing of coding regions and their flanking intronic sequences is used in combination with pre-screening methods, such as DGGE, DHPLC, CSCE and so on. The multiplex ligation-dependent probe amplification (MLPA) technique is being used to identify large deletions/duplications.…”

“…[14][15][16] ARVC patients carrying more than one disease-associated mutation often show a more severe phenotype, characterized by a younger age of onset and worse prognosis, suggesting a gene-dosage effect. 5,13,17,18 It is to be expected that the use of NGS techniques will result in the identification of an increasing number of patients with such complex genotypes.…”

“…On average, the mutation detection rate for the most common ARVC-related genes are: PKP2 11-51%, DSG2 3-20%, DSC2 1-7%, JUP 0.5-16% and DSP 1-7%. 5,12,13,[17][18][19][20][21] …”

“…However, as carriership of multiple disease-causing or -modifying mutations in one or more genes has been reported, it cannot be excluded that this mutation-negative family member carries a still unidentified ARVCrelated mutation. 5,13,17,18 Index case in that family had not been tested: ARVC is believed to be familial in B30-50% of cases. 1,8,9,20 Therefore, when an index patient has been clinically diagnosed with ARVC, and no genetic test has been performed, the chance for a firstdegree relative to develop ARVC may reach up to 15-25%.…”