Incidentally identified genetic variants in arrhythmogenic right ventricular cardiomyopathy-associated genes among children undergoing exome sequencing reflect healthy population variation.

Journal Article (Journal Article)

BACKGROUND: With expanding use of clinical whole exome sequencing (WES), genetic variants of uncertain significance are increasingly identified. As pathologic mutations in genes associated with arrhythmogenic right ventricular cardiomyopathy (ARVC) carry a risk of sudden death, determining the diagnostic relevance of incidentally identified variants associated with these genes is critical. METHODS: WES variants from a large, predominantly pediatric cohort (N = 7,066 probands) were obtained for nine ARVC-associated genes (Baylor Miraca). For comparison, a control cohort was derived from the gnomAD database and an ARVC case cohort (N = 1,379 probands) was established from ARVC cases in the literature. Topologic mapping was performed and signal-to-noise analysis was conducted normalizing WES, or case variants, against control variant frequencies. Retrospective chart review was performed of WES cases evaluated clinically (Texas Children's Hospital). RESULTS: Incidentally identified variants occurred in 14% of WES referrals and localized to genes which were rare among ARVC cases yet similar to controls. Amino acid-level signal-to-noise analysis of cases demonstrated "pathologic hotspots" localizing to critical domains of PKP2 and DSG2 while WES variants did not. PKP2 ARM7 and ARM8 domains and DSG2 N-terminal cadherin-repeat domains demonstrated high pathogenicity while normalized WES variant frequency was low. Review of clinical data available on WES referrals demonstrated none with evidence of ARVC among variant-positive individuals. CONCLUSIONS: Incidentally identified variants are common among pediatric WES testing with gene frequencies similar to "background" variants. Incidentally identified variants are unlikely to be pathologic.

Full Text

Duke Authors

Cited Authors

  • Headrick, AT; Rosenfeld, JA; Yang, Y; Tunuguntla, H; Allen, HD; Penny, DJ; Kim, JJ; Landstrom, AP

Published Date

  • June 2019

Published In

Volume / Issue

  • 7 / 6

Start / End Page

  • e593 -

PubMed ID

  • 30985088

Pubmed Central ID

  • PMC6565596

Electronic International Standard Serial Number (EISSN)

  • 2324-9269

Digital Object Identifier (DOI)

  • 10.1002/mgg3.593


  • eng

Conference Location

  • United States