TY - JOUR
T1 - Exome-Wide Rare Variant Analyses in Sudden Infant Death Syndrome
AU - Tester, David J.
AU - Wong, Leonie C.H.
AU - Chanana, Pritha
AU - Gray, Belinda
AU - Jaye, Amie
AU - Evans, Jared M.
AU - Evans, Margaret
AU - Fleming, Peter
AU - Jeffrey, Iona
AU - Cohen, Marta
AU - Tfelt-Hansen, Jacob
AU - Simpson, Michael A.
AU - Behr, Elijah R.
AU - Ackerman, Michael J.
N1 - Funding Information:
Supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health ( R01HD042569 [to M.A.]) and by the British Heart Foundation (BHF Clinical Research Training Fellowship FS/13/78/30520 [to L.W. and E.B.]). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work is also supported by the UK Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy's and St Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London and King's College Hospital NHS Foundation Trust and Newlife research funding for the establishment of the Edinburgh SIDS DNA cohort. D.T. and M.A. receive research support from the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program . L.W. received research support from Biotronik and Cardiac Risk in the Young . B.G. is the recipient of a National Health and Medical Research Council, Australia (NHMRC) Early Career Fellowship (# 1122330 ). E.B. receives research support from the Higher Education Funding Council for England and receives funds from the Robert Lancaster Memorial Fund sponsored by McColl's Retail Group Ltd . M.A. serves as a consultant for Audentes Therapeutics, Boston Scientific, Gilead Sciences, Invitae, Medtronic, MyoKardia, and St Jude Medical. M.A. and the Mayo Clinic have potential equity/royalty relationships (without remuneration so far) with AliveCor, Blue Ox Health, and StemoniX. The authors declare no conflicts of interest.
Funding Information:
Supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health (R01HD042569 [to M.A.]) and by the British Heart Foundation (BHF Clinical Research Training Fellowship FS/13/78/30520 [to L.W. and E.B.]). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work is also supported by the UK Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy's and St Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London and King's College Hospital NHS Foundation Trust and Newlife research funding for the establishment of the Edinburgh SIDS DNA cohort. D.T. and M.A. receive research support from the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program. L.W. received research support from Biotronik and Cardiac Risk in the Young. B.G. is the recipient of a National Health and Medical Research Council, Australia (NHMRC) Early Career Fellowship (#1122330). E.B. receives research support from the Higher Education Funding Council for England and receives funds from the Robert Lancaster Memorial Fund sponsored by McColl's Retail Group Ltd. M.A. serves as a consultant for Audentes Therapeutics, Boston Scientific, Gilead Sciences, Invitae, Medtronic, MyoKardia, and St Jude Medical. M.A. and the Mayo Clinic have potential equity/royalty relationships (without remuneration so far) with AliveCor, Blue Ox Health, and StemoniX. The authors declare no conflicts of interest.
Publisher Copyright:
© 2018 Elsevier Inc.
PY - 2018/12
Y1 - 2018/12
N2 - 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.
AB - 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.
KW - inherited cardiac conditions
KW - molecular autopsy
KW - sudden infant death syndrome
KW - whole exome sequencing
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U2 - 10.1016/j.jpeds.2018.08.011
DO - 10.1016/j.jpeds.2018.08.011
M3 - Article
C2 - 30268395
AN - SCOPUS:85053932297
VL - 203
SP - 423-428.e11
JO - Journal of Pediatrics
JF - Journal of Pediatrics
SN - 0022-3476
ER -