Cardiac Genetic Predisposition in Sudden€Infant Death Syndrome

ISS Fro olo Ma Lo do Hu Kin D Pa Sh Kin an wo sti Fe rep Co Yo res Dr St. Cli BACKGROUND Sudden infant death syndrome (SIDS) is a leading cause of postneonatal mortality. Genetic heart diseases (GHDs) underlie some cases of SIDS. OBJECTIVES This study aimed to determine the spectrum and prevalence of GHD-associated mutations as a potential monogenic basis for SIDS. METHODS A 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. RESULTS Overall, 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 1⁄4 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. CONCLUSIONS Less than 15% of more than 400 SIDS cases had a “potentially informative” variant in a GHD-susceptibility gene, predominantly in the 4to 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. (J Am Coll Cardiol 2018;71:1217–27) © 2018 the American College of Cardiology Foundation. Published by Elsevier. All rights reserved. N 0735-1097/$36.00 https://doi.org/10.1016/j.jacc. 2018.01. 030 m the Departments of Cardiovascular Medicine (Division of Heart Rhythm Services), Pediatrics (Division of Pediatric Cardigy), and Molecular Pharmacology & Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory), yo Clinic, Rochester, Minnesota; Molecular and Clinical Sciences Research Institute, St. George’s, University of London, ndon, United Kingdom; Cardiology Clinical Academic Group, St. George’s University Hospitals’ NHS Foundation Trust, Lonn, United Kingdom; Medical and Molecular Genetics, Guy’s Hospital, King’s College London, London, United Kingdom; MRC man Genetics Unit, University of Edinburgh, Edinburgh, United Kingdom; Royal Infirmary of Edinburgh, Edinburgh, United gdom; Centre for Child and Adolescent Health, Bristol Medical School, University of Bristol, Bristol, United Kingdom; epartment of Cellular Pathology, St George’s, University of London, London, United Kingdom; Department of Cellular thology’, St. George’s University Hospitals’ NHS Foundation Trust, London, United Kingdom; Histopathology Department, effield Children’s Hospital, Sheffield, United Kingdom; Honorary Senior Lecturer, University of Sheffield, Sheffield, United gdom; Department of Cardiology, The Heart Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; d the Department of Forensic Medicine, Faculty of Medical Sciences, University of Copenhagen, Copenhagen, Denmark. This rk was supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Intutes of Health (grant no. R01HD042569 to Dr. Ackerman) and by the British Heart Foundation (BHF Clinical Research Training llowship FS/13/78/30520 to Drs. Wong and Behr). The content is solely the responsibility of the authors and does not necessarily resent the official views of the National Institutes of Health. Mr. Tester is supported by the Mayo Clinic Windland Smith Rice mprehensive Sudden Cardiac Death Program. Dr. Wong is supported by additional funds from Biotronik and Cardiac Risk in the ung. Dr. Behr is supported by the Higher Education Funding Council for England; is a consultant for Medtronic; has received earch funding from Biotronik; and has received funds from The Robert Lancaster Memorial Fund sponsored byMcColl’s RG Ltd. . Ackerman is a consultant for Audentes Therapeutics, Boston Scientific, Gilead Sciences, Invitae, Medtronic, MyoKardia, and JudeMedical; is supportedby theMayoClinicWindlandSmithRiceComprehensiveSuddenCardiacDeathProgram;and theMayo nic have an equityor royalty-based relationship with AliveCor, Blue Ox Health, and StemoniX, although none of these entities ABBR EV I A T I ON S