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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

Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands.
Circulation (Impact Factor: 14.95). 06/2011; 123(23):2690-700. DOI: 10.1161/CIRCULATIONAHA.110.988287
Source: PubMed

ABSTRACT 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.

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    • "The latter resides next to a potential phosphorylation site at Ser864 [69] [91] [93]. Hence, the frequency and types of mutations roughly mirrors those found in DSG2, consistent with their similar roles and orientations in cardiac desmosomes. "
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    • ") have also been linked to the ARVC phenotype [ Basso et al . , 2011 ; van der Zwaag et al . , 2009 ] . Mutations in the desmoglein - 2 gene ( DSG2 ) have been identified in ARVC patients with a variable frequency ranging from 5% to 25% in cohorts of Italian , Dutch , British , and US patients , respectively [ Bauce et al . , 2010 ; Cox et al . , 2011 ; Quarta et al . , 2011 ; Tan et al . , 2010 ] . The DSG2 protein forms part of desmosomes that help to maintain mechanical integrity in the myocardium as well as in the epidermis [ Desai et al . , 2009 ] . The desmosomal junctions of the my - ocardium are situated within the intercalated discs and constitute a functional unit with adhe"
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    • "To facilitate diagnosis in clinical practice, an international Task Force defined in 1994 a set of criteria (TFC) based on electrocardiographic, functional and morphologic features , and family history (McKenna et al., 1994). Data of growing numbers of index cases and their family members, combined with molecular genetic data, increased insight in development and behavior of the disease process importantly (Hulot et al., 2004; Dalal et al., 2006; Cox et al., 2011). Therefore, recently a new Task Force introduced modifications to the 1994 TFC by implementation of these new insights (Marcus et al., 2010). "
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