Tester, DJ;
Wong, LCH;
Chanana, P;
Gray, B;
Jaye, A;
Evans, JM;
Evans, M;
Fleming, P;
Jeffrey, I;
Cohen, M;
et al.
Tester, DJ; Wong, LCH; Chanana, P; Gray, B; Jaye, A; Evans, JM; Evans, M; Fleming, P; Jeffrey, I; Cohen, M; Tfelt-Hansen, J; Simpson, MA; Behr, ER; Ackerman, MJ
(2018)
Exome-Wide Rare Variant Analyses in Sudden Infant Death Syndrome.
J Pediatr, 203.
423-428.e11.
ISSN 1097-6833
https://doi.org/10.1016/j.jpeds.2018.08.011
SGUL Authors: Behr, Elijah Raphael Wong, Leonie Cheok Heng Gray, Belinda Ruth
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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.
Item Type: | Article | ||||||||||||
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Additional Information: | © 2018. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/ | ||||||||||||
Keywords: | inherited cardiac conditions, molecular autopsy, sudden infant death syndrome, whole exome sequencing, inherited cardiac conditions, molecular autopsy, sudden infant death syndrome, whole exome sequencing, 1114 Paediatrics And Reproductive Medicine, 1106 Human Movement And Sports Science, Pediatrics | ||||||||||||
SGUL Research Institute / Research Centre: | Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) > Cardiac (INCCCA) |
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Journal or Publication Title: | J Pediatr | ||||||||||||
ISSN: | 1097-6833 | ||||||||||||
Language: | eng | ||||||||||||
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Publisher License: | Creative Commons: Attribution-Noncommercial-No Derivative Works 4.0 | ||||||||||||
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PubMed ID: | 30268395 | ||||||||||||
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URI: | https://openaccess.sgul.ac.uk/id/eprint/110335 | ||||||||||||
Publisher's version: | https://doi.org/10.1016/j.jpeds.2018.08.011 |
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