Garrett W Shanks1, David J Tester1, Jaeger P Ackerman1, Michael A Simpson2, Elijah R Behr3,4, Steven M White5,6, Michael J Ackerman7,8,9. 1. 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.). 2. King's College London, United Kingdom (M.A.S.). 3. Molecular and Clinical Sciences Research Institute, St George's University of London, London, United Kingdom (E.R.B.). 4. Cardiology Clinical Academic Group, St George's University Hospitals' NHS Foundation Trust, London, United Kingdom (E.R.B.). 5. Office of the Medical Examiner, County of Cook, Chicago, IL (S.M.W.). 6. Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL (S.M.W.). 7. 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.) ackerman.michael@mayo.edu. 8. Department of Cardiovascular Diseases, Division of Heart Rhythm Service (M.J.A.). 9. Department of Pediatric and Adolescent Medicine, Division of Pediatric Cardiology (M.J.A.), Mayo Clinic, Rochester, MN.
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.
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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