Abstract 15872: A Founder Mutation in Desmocollin-2 Causes a Predominant Left Ventricular Arrhythmogenic Cardiomyopathy in Homozygous Carriers in a Hutterite Population
Background: Heterozygous mutations in desmosomal proteins have been shown to cause arrhythmogenic right ventricular cardiomyopathy (ARVC). The disease predominantly affects the right ventricle and is diagnosed using recently revised Task Force Criteria (TFC). The Hutterite brethren are an isolated population who trace their origins to 16th century Europe. The modern Hutterites are descendants of fewer than 100 common founders.
Methods and Results: Here we report a large Hutterite family with a history of sudden death in children aged 8 and 14 years. Further clinical assessment identified three individuals in the early twenties with a severe form of left ventricular arrhythmogenic cardiomyopathy requiring an ICD. All three fulfilled the recently revised TFC for ARVC based on findings from ECG, Holter-ECG, SAECG and family history, but none of them have had remarkable structural alterations of the right ventricle by various imaging techniques. However the left ventricles were very abnormal showing localized aneurysms and additional regions of wall thinning with segmental akinesis. Contrast uptakes in the late Gd enhancement images were consistent with transmural fibrosis. Genetic screening identified a homozygous truncation mutation in desmocollin-2 (DSC2): c.1660C>T (p.Q554X) in all three patients; two are siblings and the parents are heterozygous carriers. One young male is from another branch of the family, his mother carries the heterozygous mutation, but his father died suddenly at the age of 54. Furthermore we evaluated to date 15 heterozygous mutation carriers who were mildly affected or unaffected according to the TFC, but the CMR demonstrated supportive findings of an apical, left sided true aneurysm in several cases. The p.Q554X mutation is located within the cadherin domains of DSC2. Western blot analysis and immunostaining of a cardiac biopsy sample revealed a truncated protein, which unexpectedly showed its proper localization at the intercalated discs. Recombinant expressed mutant DSC2 protein in cell-lines also confirmed a stable truncated protein at a size of 75KD.
Conclusions: A homozygous truncation mutation in DSC2 leads to a cardiac restricted phenotype of a severe early onset left ventricular arrhythmogenic cardiomyopathy.
- © 2011 by American Heart Association, Inc.