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Importance of Variant Interpretation in Whole-Exome Molecular Autopsy: Population-Based Case Series. | LitMetric

Importance of Variant Interpretation in Whole-Exome Molecular Autopsy: Population-Based Case Series.

Circulation

Department of Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory (G.W.S., D.J.T., J.P.A., M.J.A.)

Published: June 2018

AI Article Synopsis

  • Sudden unexplained death in the young (SUDY) is often linked to serious heart conditions, and whole-exome molecular autopsies can help identify genetic causes after conventional autopsies fail.
  • In a study of 25 SUDY cases, researchers found ultrarare genetic variants in 64% of victims, with a higher prevalence in black individuals compared to white individuals.
  • Among the identified variants, 10 were classified as pathogenic or likely pathogenic, leading to actionable results for some families, highlighting the need for careful review of genetic findings for proper follow-up care.

Article Abstract

Background: Potentially lethal cardiac channelopathies/cardiomyopathies may underlie a substantial portion of sudden unexplained death in the young (SUDY). The whole-exome molecular autopsy represents the latest approach to postmortem genetic testing for SUDY. However, proper variant adjudication in the setting of SUDY can be challenging.

Methods: From January 2012 through December 2013, 25 consecutive cases of SUDY from 1 to 40 years of age (average age at death 27±5.7 years; 13 white, 12 black) from Cook County, Illinois, were referred after a negative (n=16) or equivocal (n=9) conventional autopsy. A whole-exome molecular autopsy with analysis of 99 sudden death-susceptibility genes was performed. The predicted pathogenicity of ultrarare, nonsynonymous variants was determined using the American College of Medical Genetics guidelines.

Results: Overall, 27 ultrarare nonsynonymous variants were seen in 16/25 (64%) victims of SUDY. Among black individuals, 9/12 (75%) had an ultrarare nonsynonymous variant compared with 7/13 (54%) white individuals. Of the 27 variants, 10 were considered pathogenic or likely pathogenic in 7/25 (28%) individuals in accordance with the American College of Medical Genetics guidelines. Pathogenic/likely pathogenic variants were identified in 5/16 (31%) of autopsy-negative cases and in 2/6 (33%) victims of SUDY with equivocal findings of cardiomyopathy. Overall, 6 pathogenic/likely pathogenic variants in 4/25 (16%) cases were congruent with the phenotypic findings at autopsy and therefore considered clinically actionable.

Conclusions: Whole-exome molecular autopsy with gene-specific surveillance is an effective approach for the detection of potential pathogenic variants in SUDY cases. However, systematic variant adjudication is crucial to ensure accurate and proper care for surviving family members.

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Source
http://dx.doi.org/10.1161/CIRCULATIONAHA.117.031053DOI Listing

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