Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia via the DSC2 Gene

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a heart disease primarily affecting the right ventricle. It is characterized by myocardial atrophy, fibrofatty replacement of the ventricular myocardium and inflammatory infiltrates (McNally et al. GeneReviews, 2009). With disease progression and occasional left ventricle involvement, heart failure may result. The most common symptoms include ventricular arrhythmias, recurrent syncope, seizures and sudden death after physical or emotional stress. ARVC/D is present in ~20% of young sudden cardiac death victims (Corrado et al. N Engl J Med 339:364-369, 1998). ARVC/D affects between 1/1000 and 1/5000 people worldwide with a higher prevalence in men compared to women (Corrado and Thiene Circulation 113:1634-1637, 2006).

ARVC/D is a heterogeneous disease that is inherited in about 50% of the cases (Basso et al. Eur Heart J 25:531-534, 2004). The mode of inheritance is most often autosomal dominant with age- and gender-dependent penetrance. Autosomal recessive variants of ARVC/D with hair and skin abnormalities have also been described (Protonotarios et al. Br Heart J 56:321-326, 1986). To date, eight genes, including DSC2, have been implicated in autosomal dominant ARVC/D (Heuser et al. Am J Hum Genet 79:1081-1088, 2006). Mutations in four genes encoding desmosomal proteins, PKP2, DSP, DSG2 and DSC2 account for the majority of known genetic causes of ARVC/D (Bhuiyan et al. Circ Cardiovasc Genet 2:418-427, 2009; den Haan et al. Circ Cardiovasc Genet 2:428-435, 2009). More than half of all documented causative mutations in DSC2 are missense mutations. A homozygous single base deletion, c.1841delG, predicted to result in a truncated protein, has been detected in a consanguineous family of Pakistani origin. Affected siblings presented with autosomal recessive ARVC/D with left ventricular involvement, mild palmoplantar keratoderma and woolly hair (Simpson et al. Cardiology 113:28-34, 2009).

The DSC2 gene encodes the desmocollin-2 protein.

This test will detect causative mutations in ~2% of patients with a clinical diagnosis of ARVC/D (Bhuiyan et al. Circ Cardiovasc Genet 2:418-427, 2009).

This test provides full coverage of all coding exons of the DSC2 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).