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Exome-Wide Rare Variant Analyses in Sudden Infant Death Syndrome

Research output: Contribution to journalArticle

  • David J. Tester
  • Leonie C.H. Wong
  • Pritha Chanana
  • Belinda Gray
  • Amie Jaye
  • Jared M. Evans
  • Margaret Evans
  • Peter Fleming
  • Iona Jeffrey
  • Marta Cohen
  • Jacob Tfelt-Hansen
  • Michael A. Simpson
  • Elijah R. Behr
  • Michael J. Ackerman
Original languageEnglish
Pages (from-to)423-428.e11
Number of pages17
JournalJournal of Pediatrics
Volume203
Early online date26 Sep 2018
DOIs
DateAccepted/In press - 8 Aug 2018
DateE-pub ahead of print - 26 Sep 2018
DatePublished (current) - Dec 2018

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.

    Research areas

  • inherited cardiac conditions, molecular autopsy, sudden infant death syndrome, whole exome sequencing

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  • Full-text PDF (accepted author manuscript)

    Rights statement: This is the author accepted manuscript (AAM). The final published version (version of record) is available online via Elsevier at https://www.sciencedirect.com/science/article/pii/S0022347618311211 . Please refer to any applicable terms of use of the publisher.

    Accepted author manuscript, 450 KB, PDF document

    Licence: CC BY-NC-ND

  • Supplementary information PDF

    Rights statement: This is the author accepted manuscript (AAM). The final published version (version of record) is available online via Elsevier at https://www.sciencedirect.com/science/article/pii/S0022347618311211 . Please refer to any applicable terms of use of the publisher.

    Accepted author manuscript, 1 MB, PDF document

    Licence: CC BY-NC-ND

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