Abstract 16066: Genomic Autopsy of 103 Sudden Deaths in the Young Reveals the Importance of Cardiomyopathy Genes and Non-Mendelian Risk

Abstract

Introduction: Genetic testing after sudden death in the young can identify pathogenic cardiac gene variants. Hypothesis: Genomic methods, coupled with phenotype evaluation, reveal non-Mendalian risks. Methods: We conducted clinical analysis and whole genome sequencing on 103 decedents aged 1-40 (mean age at death 23.7 years) accrued prospectively from 2015 to 2019 across 22 states. Postmortem pathological findings were classified as: known cardiac disorders, findings of uncertain significance (FUS), or sudden unexplained death (SUD, indicating no postmortem pathological diagnosis). Parental DNA and clinical data were obtained where possible. Variants were classified by an independent clinical genetic laboratory. Results: Among the 103 decedents, 34 had a postmortem clinical diagnosis, 23 had FUS, and 46 were classified as SUD. Pathogenic/likely pathogenic (P/LP) variants in arrhythmia or cardiomyopathy genes were identified in 17 (16.5%) decedents. The distribution of P/LP variants was not associated with age at death (OR 1.01 [0.97, 1.05], p=0.54); however, a multivariable analysis including decedent phenotype, ancestry and sex demonstrated that younger decedents had a higher burden of curated P/LP/VUS variants (effect size -1.5, p=0.0019). DNA from 31 parent-decedent trios and 14 parent-decedent dyads revealed 9 transmitted P/LP variants and 1 de novo P/LP variant. More than half of parents transmitting a P/LP variant (5/9) did not have clinical findings associated with the genotype. Conclusions: Whole genome sequencing effectively revealed P/LP variants in cases of sudden death in the young, implicating both arrhythmia and cardiomyopathy genes. In addition, both genotype and phenotype analyses suggest additional non-Mendelian risk mechanisms.