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Noncardiac genetic predisposition in sudden infant death syndrome

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  • 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 J Ackerman
  • Elijah R Behr
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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
JournalGenetics in medicine : official journal of the American College of Medical Genetics
Issue number3
Pages (from-to)641-649
Publication statusPublished - Mar 2019

    Research areas

  • Genetics, exome sequencing, molecular autopsy, sudden infant death syndrome, European Continental Ancestry Group/genetics, United States, Humans, Genetic Predisposition to Disease/genetics, Infant, Male, United Kingdom, Genetic Variation/genetics, Case-Control Studies, Gene Frequency/genetics, Whole Exome Sequencing, Exome, Ethnic Groups/genetics, Sudden Infant Death/genetics, Autopsy, Alleles, Female, Mutation, Infant, Newborn

ID: 56383227