Enter Note Done


Keywords: Exome sequencing; Mendelian disorder; Genetic testing; Variant calling11; Rare variants

E. Salfati 1; E. Spencer 1; S. Topol 1; E. Muse 1,2; J. Lucas 3; G. Wagner 4; S. Campman 4; E. Topol 1,2; A. Torkamani 1

1) Scripps Research, La Jolla, California; 2) Division of Cardiology, Scripps Clinic, La Jolla, California; 3) Los Angeles County Department of Medical Examiner-Coroner, Los Angeles, California; 4) San Diego County Medical Examiner’s Office, San Diego, California

Around 10% of natural death cases remain unexplained each year and are subsequently classified as sudden unexpected deaths (SUD). The use of exome sequencing-based (WES) molecular autopsy protocol has recently proven its potential to improve this yield. As genomic sequencing expands and knowledge of gene?disease and variant?disease associations increase, reanalysis of initial WES data may facilitate new discovery and maximize the accuracy of clinical sequencing.

We tested this hypothesis in the Scripps Molecular Autopsy study, where in 2017 we reported a diagnostic yield of 16% through WES of 50 sudden-death cases. We re-assessed these post-mortem genetic data ~2 years later using an improved variant classification methodology and updated variant annotation pipeline.

Reanalysis yielded one pathogenic variant that was not initially reported in one individual, comprising an 18% increase in P/LP yield. We also reclassified variants of uncertain significance (VUS) to benign due to updated population frequency data. Explanatory variants have been discovered in 9 of 50 previously SUD cases. Our re-annotation efforts also classified another 30 (60%) cases with uncertain clinical significance finding (VUS), an almost 10% increase from our original study. These new genetic diagnoses are mainly due to improved variant prioritization, newly available clinical information since our original publication and highly accurate annotation database.

Iterative reanalysis of negative WES data may prove useful, as knowledge of genetic etiologies grows. In addition, these findings underline the importance of systematic molecular autopsy to cases with an undetermined manner of death, with implications for screening of relatives.