Noncardiac genetic predisposition in sudden infant death syndrome

Belinda Gray, David J. Tester, Leonie Ch Wong, Pritha Chanana, Amie Jaye, Jared M. Evans, Alban Elouen Baruteau, Margaret Evans, Peter Fleming, Iona Jeffrey, Marta Cohen, Jacob Tfelt-Hansen, Michael A. Simpson, Michael John Ackerman, Elijah R. Behr

Research output: Contribution to journalArticle

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Abstract

Purpose: Sudden infant death syndrome (SIDS) is the commonest cause of sudden death of an infant; however, the genetic basis remains poorly understood. We aimed to identify noncardiac genes underpinning SIDS and determine their prevalence compared with ethnically matched controls. Methods: Using exome sequencing we assessed the yield of ultrarare nonsynonymous variants (minor allele frequency [MAF] ≤0.00005, dominant model; MAF ≤0.01, recessive model) in 278 European SIDS cases (62% male; average age =2.7 ± 2 months) versus 973 European controls across 61 noncardiac SIDS-susceptibility genes. The variants were classified according to American College of Medical Genetics and Genomics criteria. Case-control, gene-collapsing analysis was performed in eight candidate biological pathways previously implicated in SIDS pathogenesis. Results: Overall 43/278 SIDS cases harbored an ultrarare single-nucleotide variant compared with 114/973 controls (15.5 vs. 11.7%, p=0.10). Only 2/61 noncardiac genes were significantly overrepresented in cases compared with controls (ECE1, 3/278 [1%] vs. 1/973 [0.1%] p=0.036; SLC6A4, 2/278 [0.7%] vs. 1/973 [0.1%] p=0.049). There was no difference in yield of pathogenic or likely pathogenic variants between cases and controls (1/278 [0.36%] vs. 4/973 [0.41%]; p=1.0). Gene-collapsing analysis did not identify any specific biological pathways to be significantly associated with SIDS. Conclusions: A monogenic basis for SIDS amongst the previously implicated noncardiac genes and their encoded biological pathways is negligible.

Original languageEnglish (US)
JournalGenetics in Medicine
DOIs
StateAccepted/In press - Jan 1 2018

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Keywords

  • exome sequencing
  • Genetics
  • molecular autopsy
  • sudden infant death syndrome

ASJC Scopus subject areas

  • Genetics(clinical)

Cite this

Gray, B., Tester, D. J., Wong, L. C., Chanana, P., Jaye, A., Evans, J. M., Baruteau, A. E., Evans, M., Fleming, P., Jeffrey, I., Cohen, M., Tfelt-Hansen, J., Simpson, M. A., Ackerman, M. J., & Behr, E. R. (Accepted/In press). Noncardiac genetic predisposition in sudden infant death syndrome. Genetics in Medicine. https://doi.org/10.1038/s41436-018-0131-4