Abstract 15841: Whole Exome Sequencing and Analysis for Sudden Unexplained Death in the Young: A Case Series
Introduction: Annually, thousands of sudden deaths in individuals under the age of 35 years remain unexplained following a medico-legal autopsy and are termed autopsy negative sudden unexplained death in the young (SUDY). Cardiomyopathies, channelopathies, and metabolic disorders may underlie a significant number of SUDY cases. Previously, we demonstrated that 25% of autopsy-negative SUDY cases had mutations in the 4 major cardiac ion channel genes (KCNQ1, KCNH2, SCN5A, and RYR2). However, over 100 sudden death-susceptibility genes have been discovered and may be implicated in SUDY.
Objective: We explored the utility of whole exome sequencing (WES) followed by gene-specific surveillance as an efficient and effective means of performing post-mortem genetic testing in SUDY.
Methods: Postmortem WES was performed on 14 consecutively-referred white SUDY victims (57% men; average age at death 17.4 ± 8.6 years) using the Agilent SureSelect Human All Exon V4+UTR capture kit and an Illumina HiSeq 2000 sequencer. Following variant alignment (hg19) and annotation, 117 cardiac channelopathy-, cardiomyopathy-, and metabolic disorder-susceptibility genes were surveyed to identify putative SUDY-associated mutations. Potentially pathogenic variants had to be non-synonymous and ultra-rare [i.e. absent in all 3 evaluated exome databases (1,000 Genome Project, the NHLBI GO Exome Sequencing Project, and Exome Chip Design)].
Results: On average, each SUDY case had 12,758 ± 2016 non-synonymous variants, of which 79 ± 15 localized to the 117 evaluated genes. Overall, 8 unique, ultra-rare variants (7 missense, 1 in-frame insertion) identified in 6 genes (3 in TTN; 1 each in CACNA1C, JPH2, MYH7, VCL, RYR2) were detected in 7 of 14 cases (50%). Of the 7 missense alterations, 2 (T171M-CACNA1C, I22160T-TTN) were predicted damaging by 3 in-silico tools.
Conclusions: Although WES and gene-specific surveillance is an efficient and effective strategy to detect rare, potentially lethal, genetic variants, the accurate interpretation of each variant is daunting. Importantly, rarity, even ultra-rarity, does not equal pathogenicity even when the ultra-rare variant resides within a so-called sudden death-susceptibility gene.
Author Disclosures: N. Narula: None. D.J. Tester: Other; Modest; Intellectual Property/Royalties- Transgenomic. A. Paulmichl: None. J.J. Maleszewski: None. M.J. Ackerman: Consultant/Advisory Board; Modest; Boston Scientific, Gilead Sciences, Medtronic, St. Jude Medical. Other; Significant; Intellectual Property/Royalties- Transgenomic.
- © 2014 by American Heart Association, Inc.