Noncardiac genetic predisposition in sudden infant death syndrome

TY - JOUR

T1 - Noncardiac genetic predisposition in sudden infant death syndrome

AU - Gray, Belinda

AU - Tester, David J.

AU - Wong, Leonie Ch

AU - Chanana, Pritha

AU - Jaye, Amie

AU - Evans, Jared M.

AU - Baruteau, Alban Elouen

AU - Evans, Margaret

AU - Fleming, Peter

AU - Jeffrey, Iona

AU - Cohen, Marta

AU - Tfelt-Hansen, Jacob

AU - Simpson, Michael A.

AU - Ackerman, Michael J.

AU - Behr, Elijah R.

PY - 2019/3/1

Y1 - 2019/3/1

N2 - 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.

AB - 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.

KW - exome sequencing

KW - Genetics

KW - molecular autopsy

KW - sudden infant death syndrome

UR - http://www.scopus.com/inward/record.url?scp=85052924773&partnerID=8YFLogxK

U2 - 10.1038/s41436-018-0131-4

DO - 10.1038/s41436-018-0131-4

M3 - Journal article

C2 - 30139991

AN - SCOPUS:85052924773

SN - 1098-3600

VL - 21

SP - 641

EP - 649

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 3

ER -