Author + information
- Received November 8, 2017
- Revision received December 15, 2017
- Accepted January 8, 2018
- Published online March 12, 2018.
- David J. Tester, BSa,
- Leonie C.H. Wong, MBBChirb,c,
- Pritha Chanana, MSa,
- Amie Jaye, MScd,
- Jared M. Evans, MSa,
- David R. FitzPatrick, MDe,
- Margaret J. Evans, MBChBf,
- Peter Fleming, PhDg,
- Iona Jeffrey, MBChBh,i,
- Marta C. Cohen, MDj,k,
- Jacob Tfelt-Hansen, MD, DMScl,m,
- Michael A. Simpson, PhDd,
- Elijah R. Behr, MDb,c,∗ ( and )
- Michael J. Ackerman, MD, PhDa,∗∗ ()
- aDepartments 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
- bMolecular and Clinical Sciences Research Institute, St. George’s, University of London, London, United Kingdom
- cCardiology Clinical Academic Group, St. George’s University Hospitals’ NHS Foundation Trust, London, United Kingdom
- dMedical and Molecular Genetics, Guy's Hospital, King’s College London, London, United Kingdom
- eMRC Human Genetics Unit, University of Edinburgh, Edinburgh, United Kingdom
- fRoyal Infirmary of Edinburgh, Edinburgh, United Kingdom
- gCentre for Child and Adolescent Health, Bristol Medical School, University of Bristol, Bristol, United Kingdom
- hDepartment of Cellular Pathology, St George's, University of London, London, United Kingdom
- iDepartment of Cellular Pathology', St. George's University Hospitals' NHS Foundation Trust, London, United Kingdom
- jHistopathology Department, Sheffield Children’s Hospital, Sheffield, United Kingdom
- kHonorary Senior Lecturer, University of Sheffield, Sheffield, United Kingdom
- lDepartment of Cardiology, The Heart Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
- mDepartment of Forensic Medicine, Faculty of Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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 = 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 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.
This work was supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health (grant no. R01HD042569 to Dr. Ackerman) and by the British Heart Foundation (BHF Clinical Research Training Fellowship FS/13/78/30520 to Drs. Wong and Behr). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Mr. Tester is supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program. Dr. Wong is supported by additional funds from Biotronik and Cardiac Risk in the Young. Dr. Behr is supported by the Higher Education Funding Council for England; is a consultant for Medtronic; has received research funding from Biotronik; and has received funds from The Robert Lancaster Memorial Fund sponsored by McColl's RG Ltd. Dr. Ackerman is a consultant for Audentes Therapeutics, Boston Scientific, Gilead Sciences, Invitae, Medtronic, MyoKardia, and St. Jude Medical; is supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program; and the Mayo Clinic have an equity- or royalty-based relationship with AliveCor, Blue Ox Health, and StemoniX, although none of these entities were involved in this study in any way. Dr. Simpson has a part-time contract of service with Genomics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Mr. Tester and Dr. Wong contributed equally to this work and are joint first authors. Drs. Simpson, Behr, and Ackerman contributed equally to this work and are joint senior authors.
- Received November 8, 2017.
- Revision received December 15, 2017.
- Accepted January 8, 2018.
- 2018 American College of Cardiology Foundation
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