Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)/Dysplasia Panel

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. With disease progression and frequent left ventricle involvement (32-88%), heart failure may result. The most common symptoms include ventricular arrhythmias, recurrent syncope, seizures and sudden death after physical or emotional stress (Marcus et al. 2010. PubMed ID: 20172911). ARVC/D is present in ~20% of young sudden cardiac death victims (Corrado et al. 1998. PubMed ID: 9691102). ARVC/D affects between 1/2,000 and 1/5,000 people worldwide with a higher prevalence in men compared to women and typically presents in the 2^nd-4^th decade of life (Peters. 2006. PubMed ID: 16737750; Corrado and Thiene. 2006. PubMed ID: 16585401). For more information, see McNally et al. 2014 (PubMed ID: 20301310).

ARVC/D is a heterogeneous disease that is inherited in roughly 50% of the cases (Basso et al. 2004. PubMed ID: 15039134). The mode of inheritance is most often autosomal dominant (AD) with age- and gender-dependent penetrance. Pathogenic variants in three genes encoding desmosomal proteins, PKP2, DSP, and DSG2, account for the great majority of known genetic causes of ARVC/D (McNally et al. 2014. PubMed ID: 20301310). Pathogenic variants in the DSC2 gene account for ~2% of patients with a clinical diagnosis of ARVC/D (Bhuiyan et al. 2009. PubMed ID: 20031616). The remaining genes are rare causes (<1-2% each) of ARVC/D. This panel includes 16 genes associated with ARVC/D: CDH2, CTNNA3, DES, DSC2, DSG2, DSP, FLNC, JUP, LDB3, LMNA, PKP2, PLN, RYR2, SCN5A, TGFB3, and TMEM43. A wide variety of causative variants (missense, nonsense, splicing, small deletions and insertions) have been reported. Large deletions/duplications and complex genomic rearrangements have also been reported in a few genes (DES, DSP, PKP2) (Human Gene Mutation Database). See individual gene test descriptions for information on molecular biology of gene products.

Genetic testing of individuals that meet the revised diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) (Marcus et al. 2010. PubMed ID: 20172911) found pathogenic variants in 58% of families (Quarta et al. 2011. PubMed ID: 21606390), however, this study only included the 6 most common genes involved in ARVC/D. The inclusion of additional genes is expected to improve the yield of this panel.

The proportion of ARVC/D cases attributed to gross deletions and duplications is unknown, but presumed to be low. Gross deletions and insertions in PKP2 have been reported to cause ARVC/D (Roberts et al. 2013. PubMed ID: 22889254; Kapplinger et al. 2011. PubMed ID: 21636032). Gross deletions in DES have been observed in patients with myopathy (Muñoz-Mármol et al. 1998. PubMed ID: 9736733; Piñol-Ripoll et al. 2009. PubMed ID: 19433360).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 97.9% coverage of all coding exons of the genes 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 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).