Importance of Variant Interpretation in Whole-Exome Molecular Autopsy

• DOI: 10.1161/circulationaha.117.031053
• Publication Date: 2018-06-18T18:05:38Z
• Authors: Garrett W. Shanks; David J. Tester; Jaeger P. Ackerman; Michael A. Simpson; Elijah R. Behr; Steven M. White; Michael J. Ackerman
• Keywords: Nonsynonymous substitution; Exome

Potentially lethal cardiac channelopathies/cardiomyopathies may underlie a substantial portion of sudden unexplained death in the young (SUDY). The whole-exome molecular autopsy represents latest approach to postmortem genetic testing for SUDY. However, proper variant adjudication setting SUDY can be challenging.From January 2012 through December 2013, 25 consecutive cases from 1 40 years age (average at 27±5.7 years; 13 white, 12 black) Cook County, Illinois, were referred after negative (n=16) or equivocal (n=9) conventional autopsy. A with analysis 99 death-susceptibility genes was performed. predicted pathogenicity ultrarare, nonsynonymous variants determined using American College Medical Genetics guidelines.Overall, 27 ultrarare seen 16/25 (64%) victims Among black individuals, 9/12 (75%) had an compared 7/13 (54%) white individuals. Of variants, 10 considered pathogenic likely 7/25 (28%) individuals accordance guidelines. Pathogenic/likely identified 5/16 (31%) autopsy-negative and 2/6 (33%) findings cardiomyopathy. Overall, 6 pathogenic/likely 4/25 (16%) congruent phenotypic therefore clinically actionable.Whole-exome gene-specific surveillance is effective detection potential cases. systematic crucial ensure accurate care surviving family members.