A Homozygous Founder Mutation in Desmocollin-2 (DSC2) Causes Arrhythmogenic Cardiomyopathy in the Hutterite Population.
ABSTRACT -Dominant mutations in cellular junction proteins are the major cause of arrhythmogenic cardiomyopathy, whereas recessive mutations in those proteins cause cardiocutaneous syndromes such as Naxos and Carvajal syndrome. The Hutterites are distinct genetic isolates who settled in North America in 1874. Descended from fewer than 100 founders, they trace their origins to the 16(th) century Europe.
-We clinically and genetically evaluated two large families of the Alberta Hutterite population with a history of sudden death and found several individuals with severe forms of biventricular cardiomyopathy characterized by mainly left-sided localized aneurysms, regions of wall thinning with segmental akinesis in addition to typical electrical and histological features known for arrhythmogenic right ventricular cardiomyopathy (ARVC). We identified a homozygous truncation mutation, c.1660C>T (p.Q554X) in desmocollin-2 (DSC2) in affected individuals, and determined a carrier frequency of this mutation of 9.4% (1 in 10.6) among 1,535 Schmiedeleut Hutterites, suggesting a common founder in that subgroup. Immunohistochemistry of endomyocardial biopsy samples revealed altered expression of the truncated DSC2 protein at the intercalated discs, but only minor changes in immunoreactivity of other desmosomal proteins. Recombinant expressed mutant DSC2 protein in cells confirmed a stable, partially processed truncated protein with cytoplasmic and membrane localization.
-A homozygous truncation mutation in DSC2 leads to a cardiac restricted phenotype of an early onset biventricular arrhythmogenic cardiomyopathy. The truncated protein remains partially stable and localized at the intercalated discs. These data suggest that the processed DSC2 protein plays a role in maintaining desmosome integrity and function.
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ABSTRACT: Arrhythmogenic right ventricular cardiomyopathy is an inherited cardiac entity characterized by right ventricular, or biventricular, fibrofatty replacement of myocardium. Structural alterations may lead to sudden cardiac death, mainly in young males during exercise. Autosomal dominant pattern of inheritance is reported in most parts of pathogenic genetic variations identified. Currently, 13 genes have been associated with the disease but nearly 40 % of clinically diagnosed cases remain without a genetic diagnosis. New genetic technologies allow further genetic analysis, generating a significant amount of genetic data in novel genes, which is often classified as of ambiguous significance. We focus on genetic advances of arrhythmogenic right ventricular cardiomyopathy, helping clinicians to interpret and translate genetic data into clinical practice.Clinical Research in Cardiology 11/2014; · 4.17 Impact Factor
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ABSTRACT: There is currently extensive discussion and debate in the literature on how, when, and to whom genetic research results should be returned (see Genetics in Medicine, April 2012 issue). Here, we describe our experience in disclosing genetic information on Mendelian disorders discovered during the course of our research in the Hutterites. We first assessed attitudes toward the disclosure of carrier results, which revealed that many individuals wanted carrier information and that many intended to use the information in family planning. Based on this information, we developed a pilot study to test and disclose cystic fibrosis (CF) carrier status. Next, a larger scale project was developed in order to disclose genetic research results for 14 diseases to those interested in receiving the information. We developed brochures, offered a live interactive educational program, conducted a consent process, and disclosed results in letters mailed to the consented individuals. Overall, ~80 % of individuals who participated in the educational program signed consent forms for the release of their results for 14 diseases. We describe our experience with returning individual genetic research results to participants in a population-based research study.Journal of Genetic Counseling 04/2014; · 1.75 Impact Factor
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ABSTRACT: Arrhythmogenic right ventricular cardiomyopathy/dysplasia is an inherited cardiomyopathy that is transmitted in autosomal dominant and autosomal recessive forms and involves mutations in desmosomal and extradesmosomal genes. We present a case of arrhythmogenic right ventricular cardiomyopathy that cosegregates in a Lebanese family with a previously unreported desmocollin-2 mutation (c.712_714delGAT). We believe this newly described genetic variant displays autosomal recessive inheritance without the cutaneous manifestations expected in recessive genotypes, and represents the latest addition to the compendium of desmosomal mutations with pathogenic potential.The Canadian journal of cardiology 01/2014; · 3.12 Impact Factor