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

Headrick, Andrew T

Rosenfeld, Jill A

Yang, Yaping

Tunuguntla, Hari

Allen, Hugh D

Penny, Daniel J

Kim, Jeffrey J

Landstrom, Andrew P

2020-04-01T13:27:15Z

2020-04-01T13:27:15Z

2019-06

2020-04-01T13:27:13Z

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.

2324-9269

2324-9269

https://hdl.handle.net/10161/20294

eng

Wiley

Molecular Genetics & Genomic Medicine

10.1002/mgg3.593

arrhythmogenic right ventricular cardiomyopathy

genetic testing

genetics

incidental finding

secondary finding

variant of undetermined significance

whole exome sequencing

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

Journal article

Landstrom, Andrew P|0000-0002-1878-9631

e593

6

School of Medicine

Cell Biology

Pediatrics, Cardiology

Duke

Basic Science Departments

Pediatrics

Clinical Science Departments

Published

7