Exome-Wide Rare Variant Analyses in Sudden Infant Death Syndrome

Exome-Wide Rare Variant Analyses in Sudden Infant Death Syndrome.

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Item Type: Article
Status: Published
Official URL: https://doi.org/10.1016/j.jpeds.2018.08.011
Journal or Publication Title: The Journal of Pediatrics
Volume: 203
Page Range: 423-428.e11
Date: 2018
Divisions: Molecular Cardiology
Depositing User: General Admin
Identification Number: 10.1016/j.jpeds.2018.08.011
ISSN: 00223476
Date Deposited: 03 Jan 2021 22:54

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.

Keywords: inherited cardiac conditions; molecular autopsy; sudden infant death syndrome; whole exome sequencing.

Copyright © 2018 Elsevier Inc. All rights reserved.

Tester, David J.
Wong, Leonie C.H.
Chanana, Pritha
Gray, Belinda
Jaye, Amie
Evans, Jared M.
Evans, Margaret
Fleming, Peter
Jeffrey, Iona
Cohen, Marta
Tfelt-Hansen, Jacob
Simpson, Michael A.
Behr, Elijah R.
Ackerman, Michael J.
Last Modified: 03 Jan 2021 22:54
URI: https://eprints.centenary.org.au/id/eprint/508

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