Cardiac Genetic Predisposition in Sudden Infant Death Syndrome |
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| Authors: | David J Tester Leonie CH Wong Pritha Chanana Amie Jaye Jared M Evans David R FitzPatrick Margaret J Evans Peter Fleming Iona Jeffrey Marta C Cohen Jacob Tfelt-Hansen Michael A Simpson Elijah R Behr Michael J Ackerman |
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| Institution: | 1. Departments of Cardiovascular Medicine (Division of Heart Rhythm Services), Pediatrics (Division of Pediatric Cardiology), and Molecular Pharmacology & Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory), Mayo Clinic, Rochester, Minnesota;2. Molecular and Clinical Sciences Research Institute, St. George’s, University of London, London, United Kingdom;3. Cardiology Clinical Academic Group, St. George’s University Hospitals’ NHS Foundation Trust, London, United Kingdom;4. Medical and Molecular Genetics, Guy''s Hospital, King’s College London, London, United Kingdom;5. MRC Human Genetics Unit, University of Edinburgh, Edinburgh, United Kingdom;6. Royal Infirmary of Edinburgh, Edinburgh, United Kingdom;g. Centre for Child and Adolescent Health, Bristol Medical School, University of Bristol, Bristol, United Kingdom;h. Department of Cellular Pathology, St George''s, University of London, London, United Kingdom;i. Department of Cellular Pathology'', St. George''s University Hospitals'' NHS Foundation Trust, London, United Kingdom;j. Histopathology Department, Sheffield Children’s Hospital, Sheffield, United Kingdom;k. Honorary Senior Lecturer, University of Sheffield, Sheffield, United Kingdom;l. Department of Cardiology, The Heart Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark;m. Department of Forensic Medicine, Faculty of Medical Sciences, University of Copenhagen, Copenhagen, Denmark |
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| Abstract: | BackgroundSudden infant death syndrome (SIDS) is a leading cause of postneonatal mortality. Genetic heart diseases (GHDs) underlie some cases of SIDS.ObjectivesThis study aimed to determine the spectrum and prevalence of GHD-associated mutations as a potential monogenic basis for SIDS.MethodsA cohort of 419 unrelated SIDS cases (257 male; average age 2.7 ± 1.9 months) underwent whole exome sequencing and a targeted analysis of 90 GHD-susceptibility genes. The yield of “potentially informative,” ultra-rare variants (minor allele frequency <0.00005) in GHD-associated genes was assessed.ResultsOverall, 53 of 419 (12.6%) SIDS cases had ≥1 “potentially informative,” GHD-associated variant. The yield was 14.9% (21 of 141) for mixed-European ancestry cases and 11.5% (32 of 278) for European ancestry SIDS cases. Infants older than 4 months were more likely to host a “potentially informative” GHD-associated variant. There was significant overrepresentation of ultra-rare nonsynonymous variants in European SIDS cases (18 of 278 6.5%]) versus European control subjects (30 of 973 3.1%]; p = 0.013) when combining all 4 major cardiac channelopathy genes (KCNQ1, KCNH2, SCN5A, and RYR2). According to the American College of Medical Genetics guidelines, only 18 of 419 (4.3%) SIDS cases hosted a “pathogenic” or “likely pathogenic” variant.ConclusionsLess than 15% of more than 400 SIDS cases had a “potentially informative” variant in a GHD-susceptibility gene, predominantly in the 4- to 12-month age group. Only 4.3% of cases possessed immediately clinically actionable variants. Consistent with previous studies, ultra-rare, nonsynonymous variants within the major cardiac channelopathy-associated genes were overrepresented in SIDS cases in infants of European ethnicity. These findings have major implications for the investigation of SIDS cases and families. |
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| Keywords: | genetic heart diseases molecular autopsy sudden infant death syndrome whole exome sequencing GHD genetic heart disease gnomAD Genome Aggregation Database LQTS long QT syndrome MAF minor allele frequency NSV nonsynonymous variant PCA principal component analysis SIDS sudden infant death syndrome WES whole exome sequencing |
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