Genetic Determinants of Sudden Unexpected Death in Pediatrics |
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Authors: | Hyun Yong Koh Alireza Haghighi Christine Keywan Sanda Alexandrescu Erin Plews-Ogan Elisabeth A Haas Catherine A Brownstein Sara O Vargas Robin L Haynes Gerard T Berry Ingrid A Holm Annapurna H Poduri Richard D Goldstein |
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Institution: | 1. Robert’s Program for Sudden Unexpected Death in Pediatrics, Boston Children’s Hospital, Boston, MA;2. F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA;3. Epilepsy Genetics Program, Department of Neurology, Boston Children’s Hospital and Harvard Medical School, Boston, MA;4. Division of Genetics and Genomics, Department of Pediatrics and Manton Center for Orphan Diseases Research, Boston Children’s Hospital, MA;5. Department of Genetics, Harvard Medical School, Boston, MA;6. Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA;7. Broad Institute of MIT and Harvard, Cambridge, MA;8. Departments of Pathology, Boston Children’s Hospital and Harvard Medical School, Boston, MA;9. Harvard Medical School, Boston, MA;10. Department of Research, Rady Children’s Hospital-San Diego, San Diego, CA;11. Department of Pediatrics, Harvard Medical School, Boston, MA;12. Department of Neurology, Harvard Medical School, Boston, MA;13. Division of General Pediatrics, Department of Pediatrics, Boston Children’s Hospital, Boston, MA |
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Abstract: | PurposeThis study aimed to evaluate genetic contributions to sudden unexpected death in pediatrics (SUDP).MethodsWe phenotyped and performed exome sequencing for 352 SUDP cases. We analyzed variants in 294 "SUDP genes" with mechanisms plausibly related to sudden death. In a subset of 73 cases with parental data (trios), we performed exome-wide analyses and conducted cohort-wide burden analyses.ResultsIn total, we identified likely contributory variants in 37 of 352 probands (11%). Analysis of SUDP genes identified pathogenic/likely pathogenic variants in 12 of 352 cases (SCN1A, DEPDC5 2], GABRG2, SCN5A 2], TTN 2], MYBPC3, PLN, TNNI3, and PDHA1) and variants of unknown significance–favor-pathogenic in 17 of 352 cases. Exome-wide analyses of the 73 cases with family data additionally identified 4 de novo pathogenic/likely pathogenic variants (SCN1A 2], ANKRD1, and BRPF1) and 4 de novo variants of unknown significance–favor-pathogenic. Comparing cases with controls, we demonstrated an excess burden of rare damaging SUDP gene variants (odds ratio, 2.94; 95% confidence interval, 2.37-4.21) and of exome-wide de novo variants in the subset of 73 with trio data (odds ratio, 3.13; 95% confidence interval, 1.91-5.16).ConclusionWe provide strong evidence for a role of genetic factors in SUDP, involving both candidate genes and novel genes for SUDP and expanding phenotypes of disease genes not previously associated with sudden death. |
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Keywords: | Intrinsic vulnerability Sudden infant death syndrome Sudden unexpected death in pediatrics Sudden unexpected infant death Sudden unexplained death in childhood |
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