Gray, B;
Tester, DJ;
Wong, LC;
Chanana, P;
Jaye, A;
Evans, JM;
Baruteau, A-E;
Evans, M;
Fleming, P;
Jeffrey, I;
et al.
Gray, B; Tester, DJ; Wong, LC; Chanana, P; Jaye, A; Evans, JM; Baruteau, A-E; Evans, M; Fleming, P; Jeffrey, I; Cohen, M; Tfelt-Hansen, J; Simpson, MA; Ackerman, MJ; Behr, ER
(2019)
Noncardiac genetic predisposition in sudden infant death syndrome.
Genet Med, 21 (3).
pp. 641-649.
ISSN 1530-0366
https://doi.org/10.1038/s41436-018-0131-4
SGUL Authors: Behr, Elijah Raphael Gray, Belinda Ruth
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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.
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