Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia via the DSG2 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 DSG2, have been implicated in autosomal dominant ARVC/D (Pilichou et al. Circulation 113:1171-9, 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). Over 60 heterozygous DSG2 causative mutations, distributed throughout the entire coding region, have been reported. The majority of causative variants are missense mutations, however, nonsense, small insertions or deletions, and splicing mutations have also been reported. ARVC/D patients with compound heterozygous mutations in the DSG2 gene or digenic mutations in the DSG2 and DSC2 genes have been reported (Awad et al. Am J Hum Genet 79:136-142, 2006). In addition to ARVC/D, a heterozygous deletion in DSG2 has also been found in a patient with dilated cardiomyopathy (Garcia-Pavia et al. Heart 97:1744-52, 2011).

The DSG2 gene encodes the desmoglein-2 protein, an important component of the cardiac desmosome that is expressed only in the myocardium.

This test will detect causative mutations in ~10% of patients with clinical diagnosis of ARVC/D (Pilichou et al. Circulation 113:1171-1179, 2006; Syrris et al. Eur Heart J 28:581-588, 2007).

This test provides full coverage of all coding exons of the DSG2 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).