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

Garrett W. Shanks, David J. Tester, Jaeger P. Ackerman, Michael A. Simpson, Elijah R. Behr, Steven M. White, Michael John Ackerman

Research output: Contribution to journalArticle

9 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2705-2715
Number of pages11
JournalCirculation
Volume137
Issue number25
DOIs
StatePublished - Jun 19 2018

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Exome
Sudden Death
Autopsy
Population
Cardiomyopathies
Channelopathies
Guidelines
Genetic Testing
Genes
Virulence

Keywords

  • cardiomyopathies
  • channelopathies
  • genetics
  • sudden death

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Shanks, G. W., Tester, D. J., Ackerman, J. P., Simpson, M. A., Behr, E. R., White, S. M., & Ackerman, M. J. (2018). Importance of Variant Interpretation in Whole-Exome Molecular Autopsy: Population-Based Case Series. Circulation, 137(25), 2705-2715. https://doi.org/10.1161/CIRCULATIONAHA.117.031053

Importance of Variant Interpretation in Whole-Exome Molecular Autopsy : Population-Based Case Series. / Shanks, Garrett W.; Tester, David J.; Ackerman, Jaeger P.; Simpson, Michael A.; Behr, Elijah R.; White, Steven M.; Ackerman, Michael John.

In: Circulation, Vol. 137, No. 25, 19.06.2018, p. 2705-2715.

Research output: Contribution to journalArticle

Shanks, GW, Tester, DJ, Ackerman, JP, Simpson, MA, Behr, ER, White, SM & Ackerman, MJ 2018, 'Importance of Variant Interpretation in Whole-Exome Molecular Autopsy: Population-Based Case Series', Circulation, vol. 137, no. 25, pp. 2705-2715. https://doi.org/10.1161/CIRCULATIONAHA.117.031053
Shanks GW, Tester DJ, Ackerman JP, Simpson MA, Behr ER, White SM et al. Importance of Variant Interpretation in Whole-Exome Molecular Autopsy: Population-Based Case Series. Circulation. 2018 Jun 19;137(25):2705-2715. https://doi.org/10.1161/CIRCULATIONAHA.117.031053
Shanks, Garrett W. ; Tester, David J. ; Ackerman, Jaeger P. ; Simpson, Michael A. ; Behr, Elijah R. ; White, Steven M. ; Ackerman, Michael John. / Importance of Variant Interpretation in Whole-Exome Molecular Autopsy : Population-Based Case Series. In: Circulation. 2018 ; Vol. 137, No. 25. pp. 2705-2715.
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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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