David J Tester1, Leonie C H Wong2, Pritha Chanana3, Belinda Gray4, Amie Jaye5, Jared M Evans3, Margaret Evans6, Peter Fleming7, Iona Jeffrey8, Marta Cohen9, Jacob Tfelt-Hansen10, Michael A Simpson5, Elijah R Behr2, Michael J Ackerman11. 1. Department of Cardiovascular Medicine (Division of Heart Rhythm Services), Pediatrics (Division of Pediatric Cardiology), Molecular Pharmacology & Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory), Mayo Clinic, Rochester, MN. 2. Molecular and Clinical Sciences Research Institute, St George's University of London, London, United Kingdom; Cardiology Clinical Academic Group, St George's University Hospitals' National Health Service (NHS) Foundation Trust, London, United Kingdom. 3. Department of Health Sciences Research, Mayo Clinic, Rochester, MN. 4. Molecular and Clinical Sciences Research Institute, St George's University of London, London, United Kingdom; Cardiology Clinical Academic Group, St George's University Hospitals' National Health Service (NHS) Foundation Trust, London, United Kingdom; Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, Australia; Sydney Medical School, University of Sydney, Sydney, Australia. 5. Medical and Molecular Genetics, Guy's Hospital, King's College London, London, United Kingdom. 6. Department of Pathology, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom. 7. Centre for Child and Adolescent Health, Bristol Medical School, University of Bristol, Bristol, United Kingdom. 8. Department of Cellular Pathology, St George's University of London, London, United Kingdom; Department of Cellular Pathology, St George's University Hospitals NHS Foundation Trust, London, United Kingdom. 9. Histopathology Department, Sheffield Children's Hospital NHS FT, Sheffield, United Kingdom. 10. Department of Cardiology, The Heart Centre, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Department of Forensic Medicine, Faculty of Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 11. Department of Cardiovascular Medicine (Division of Heart Rhythm Services), Pediatrics (Division of Pediatric Cardiology), Molecular Pharmacology & Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory), Mayo Clinic, Rochester, MN. Electronic address: ackerman.michael@mayo.edu.
Abstract
OBJECTIVE: To determine whether a monogenic basis explains sudden infant death syndrome (SIDS) using an exome-wide focus. STUDY DESIGN: A cohort of 427 unrelated cases of SIDS (257 male; average age = 2.7 ± 1.9 months) underwent whole-exome sequencing. Exome-wide rare variant analyses were carried out with 278 SIDS cases of European ancestry (173 male; average age = 2.7 ± 1.98 months) and 973 ethnic-matched controls based on 6 genetic models. Ingenuity Pathway Analysis also was performed. The cohort was collected in collaboration with coroners, medical examiners, and pathologists by St George's University of London, United Kingdom, and Mayo Clinic, Rochester, Minnesota. Whole-exome sequencing was performed at the Genomic Laboratory, Kings College London, United Kingdom, or Mayo Clinic's Medical Genome Facility, Rochester, Minnesota. RESULTS: Although no exome-wide significant (P < 2.5 × 10-6) difference in burden of ultra-rare variants was detected for any gene, 405 genes had a greater prevalence (P < .05) of ultra-rare nonsynonymous variants among cases with 17 genes at P < .005. Some of these potentially overrepresented genes may represent biologically plausible novel candidate genes for a monogenic basis for a portion of patients with SIDS. The top canonical pathway identified was glucocorticoid biosynthesis (P = .01). CONCLUSIONS: The lack of exome-wide significant genetic associations indicates an extreme heterogeneity of etiologies underlying SIDS. Our approach to understanding the genetic mechanisms of SIDS has far reaching implications for the SIDS research community as a whole and may catalyze new evidence-based SIDS research across multiple disciplines. Perturbations in glucocorticoid biosynthesis may represent a novel SIDS-associated biological pathway for future SIDS investigative research.
OBJECTIVE: To determine whether a monogenic basis explains sudden infant death syndrome (SIDS) using an exome-wide focus. STUDY DESIGN: A cohort of 427 unrelated cases of SIDS (257 male; average age = 2.7 ± 1.9 months) underwent whole-exome sequencing. Exome-wide rare variant analyses were carried out with 278 SIDS cases of European ancestry (173 male; average age = 2.7 ± 1.98 months) and 973 ethnic-matched controls based on 6 genetic models. Ingenuity Pathway Analysis also was performed. The cohort was collected in collaboration with coroners, medical examiners, and pathologists by St George's University of London, United Kingdom, and Mayo Clinic, Rochester, Minnesota. Whole-exome sequencing was performed at the Genomic Laboratory, Kings College London, United Kingdom, or Mayo Clinic's Medical Genome Facility, Rochester, Minnesota. RESULTS: Although no exome-wide significant (P < 2.5 × 10-6) difference in burden of ultra-rare variants was detected for any gene, 405 genes had a greater prevalence (P < .05) of ultra-rare nonsynonymous variants among cases with 17 genes at P < .005. Some of these potentially overrepresented genes may represent biologically plausible novel candidate genes for a monogenic basis for a portion of patients with SIDS. The top canonical pathway identified was glucocorticoid biosynthesis (P = .01). CONCLUSIONS: The lack of exome-wide significant genetic associations indicates an extreme heterogeneity of etiologies underlying SIDS. Our approach to understanding the genetic mechanisms of SIDS has far reaching implications for the SIDS research community as a whole and may catalyze new evidence-based SIDS research across multiple disciplines. Perturbations in glucocorticoid biosynthesis may represent a novel SIDS-associated biological pathway for future SIDS investigative research.
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