[17] DSG2 Mutations in ARVC: A Molecular Autopsy Study

Jonathan Young, Mingchang Zhang, Fabio Tavora, Joao B Oliveira, Allen Burke. University of Maryland Medical Center, Baltimore, MD; Shanghai Medical College, Fudan University, Shanghai, China; National Institutes of Health, Bethesda, MD; Messejana Heart and Lung Hospital, Fortaleza, Brazil

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a disease of the cardiac muscle that causes severe arrhythmias and sudden death. It has been linked to mutations in several desmosmal related proteins including plakophilin-2 (most prevalent), desmoglein-2, (DSG2), desmocollin-2, desmoplakin, and plakoglobin. Clinical series of ARVC patients report mutations of any type in approximately 50% of patients, and DSG2 mutations in approximately 10% of patients. However, the diagnosis of ARVC is clinically variable and can be challenging in living patients. In this study, to determine the role of DSG2 mutations in ARVC, we sequenced DSG2 in autopsy cases with definitive histologic diagnoses of ARVC.
Design: DNA was extracted from the post-mortem tissues of 25 patients dying suddenly with ARVC, and the 15 exons of DSG2 were sequenced. The primers were designed using Primer Express 3.0 software. Direct sequencing for both sense and antisense strands was performed with a BigDye Terminator DNA sequencing kit on a 3130 Genetic Analyzer with SeqScape software.
Results: DSG2 mutations were identified in 2 of 25 ARVC patients, both of which were novel. One of the mutations (3075_3076 ins C) is an insertion in exon 15 and is considered to be damaging, while the other (2092G>A), a missense mutation in exon 14, was determined to be 'possibly damaging' by PolyPhen and 'benign' by Mutation Taster and SIFT software.
Conclusions: There have been few molecular autopsy series of ARVC patients that looked for mutations in desmosomal related proteins. Here we report two novel DSG2 mutations in patients dying suddenly with histologically diagnosed ARVC. In this small autopsy series, we observed a DSG2 mutation prevalence of 8% in ARVC patients, which corresponds to the approximately 10% seen in clinical ARVC series. This study establishes the usefulness of molecular autopsy studies in patients with sudden death.
Category: Autopsy

Wednesday, March 21, 2012 9:30 AM

Poster Session V # 1, Wednesday Morning


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