Whole genome sequencing in the 100,000 Genomes project identifies a RYR2 variant associating with dilated cardiomyopathy and sudden unexpected death in the young

Abstract Funding Acknowledgements Type of funding sources: None. Background Previous studies have shown genetic testing in sudden unexpected death the young (SUDY) cases identify a pathogenic variant 13-27% cases. This diagnostic yield increased up to 39% when was combined with family evaluation. The 100,000 Genomes Project launched investigate role whole genome sequencing (WGS) as tool for cancers and rare diseases national health care system. Young victims no finding on postmortem were enrolled SUDY cohort. Purpose We aimed analyse WGS data cohort panel analysis trio order examine this population. Methods Sudden victims, aged 40 or younger, without pre-existing condition that would explain event diagnosis established examination between 2017 2019 at different Genomic Medicine Centres (GMCs) across UK. Parents recruited all paediatric DNA performed by Illumina. platform's automated pipeline used calling. Panel based hypothesis free approaches analysis. Variant focus variants annotation-dependent depletion (CADD) score >15 American College Medical Genetics Genomics (ACMG) classification (P), likely (LP), unknown significance (VUS). Results A total 15 participants, including 6 trios, included study. Participants had median age 18 [IQR 1-29.5] two thirds male. Following assessment protein coding intronic identified, only missense RYR2:c.10046C>T (p.Ser3349Leu) thought be suitable investigation upgrade pathogenic, giving 6.67% detected 24-year-old victim. Family evaluation led dilated cardiomyopathy (DCM) four members segregation confirmed affected harboured variant. Further Project, laboratory data, our inherited cardiac conditions database well previous publications, identified additional association DCM (see table figure). Conclusion targeted gene can an effective SUDY. study’s findings show importance large population databases collaboration research community, allowing reclassification RYR2 VUS LP variant, strongest so far associate familial risk SCD. made possible through access generated Project.