Prospective use of genomics in the evaluation of sudden cardiac death: results from a national health service population pathway

<h4>Background</h4>Sudden cardiac death (SCD) is a major cause of premature and potentially avoidable mortality. Determining whether a SCD was caused by an inherited cardiac condition (ICC) enables identification and appropriate clinical management of at-risk relatives. We report findings from the NHS and Coronial Service Sudden Unexpected Death programme, which established a national pathway aimed at reducing population risk of SCD in England.<h4>Methods</h4>Cases of SCD were included where a coroner's autopsy raised suspicion of an ICC (ages 1-60) or was unable to determine a cause of death (sudden arrhythmic death syndrome [SADS]) (ages 1-40). Decedent tissue was retained for post-mortem genetic testing, and their relatives were signposted to a new ICC pathway. Where a decedent harboured a pathogenic (P) or likely pathogenic (LP) genetic variant associated with an ICC, relatives were offered predictive genetic testing for that variant. A negative genetic result enabled appropriate discharge, while a positive result triggered clinical evaluation for cardiac disease phenotype. Where no ICC associated P or LP variants were identified in decedents, their relatives underwent clinical evaluation.<h4>Findings</h4>Of 107 SCD cases, the most common findings were SADS (35%) and arrhythmogenic cardiomyopathy (15%), while 17% of those tested were found to have P or LP variants. Three-hundred-and-seven relatives subsequently entered the ICC clinic for further evaluation. Diagnostic yield for relatives of decedents with P or LP variants was 47%. Of the 235 relatives who completed ICC evaluation, 28% were provided with a new genetic and/or clinical diagnosis and subsequently managed appropriately. One notable family cluster (n = 24) included 13 individuals (57%) with the KCNH2:c2775dup variant causative of long QT syndrome.<h4>Interpretation</h4>Integration of coronial, pathology, genomic, and cardiac services in a prospective population pathway enabled efficient capture and use of genetic and clinical information to reduce population risk of SCD.<h4>Funding</h4>British Heart Foundation, Cardiac Risk in the Young, NHS England, NIHR.