Submission Details

DES: Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) HGNC: 2770 http://purl.obolibrary.org/obo/MONDO_0016587 Mode of Inheritance: Autosomal dominant inheritance (HP:0000006) Expert Panel: Arrhythmogenic Right Ventricular Cardiomyopathy SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 6

Calculated Classification (date) Moderate 09/11/2018 Evidence Summary: The first publication that associated DES variants with ARVC was published in 2009 and reported a missense variant (p.Ser13Phe) in 27 individuals in five families with a severe cardiac phenotype characterized by conduction disease and right ventricular involvement (19879535). Further studies in families with ARVC have identified additional missense variants: the p.Asn342Asp variant was reported in two pedigrees (20423733); p.His326Arg in one family (24200904); p.Pro419Ser in a large Swedish pedigree (22395865) and p.Glu401Asp was detected in a family with 23 affected individuals showing predominant left ventricular arrhythmogenic cardiomyopathy with a high incidence of adverse clinical events (29212896). Two cohort studies of 91 and 22 ARVC index cases respectively have performed genetic screening of DES and identified a total of three missense variants (23168288, 20829228). Immunohistochemistry analysis of cardiac specimens from affected individuals with the p.Arg454Trp or p.Asn116Ser variant has shown severe disruption of desmin distribution at the intercalated discs and formation of cytoplasmic and perinuclear aggregates in cardiomyocytes (20423733, 20829228). Experimental data from three studies support the causative role of DES variants in ARVC (20829228, 22403400, 29212896). In particular, Klauke B et al. characterized the p.Asn116Ser variant in in vitro expression systems using a variety of methods including viscosity analysis of desmin mutant protein and atomic force microscopic imaging. Data from these experiments confirmed the presence of fibrous protein aggregates in mutant cultured cells and were consistent with histological examinations of skeletal and cardiac muscle of ARVC cases carrying the same DES variants (20829228). Similarly, functional studies on the p.Glu401Asp variant in transfected cells showed disruption of cellular adhesion and intermediate filament structure and formation of desmin cytoplasmic aggregates (29212896). Finally, the deleterious structural effects of five heterozygous DES mutations on filament formation in vitro and in living cells were investigated in a study that utilized dual color photoactivation localization microscopy (22403400). In summary, there is moderate evidence to support this gene-disease association. Desmin mutations associated with ARVC appear to be very rare and the observed phenotypes frequently overlap with dilated cardiomyopathy with conduction system abnormalities and occasionally skeletal myopathy.