Cardiac Genetic Predisposition in Sudden Infant Death Syndrome

David J. Tester, Leonie C.H. Wong, Pritha Chanana, Amie Jaye, Jared M. Evans, David R. FitzPatrick, Margaret J. Evans, Peter Fleming, Iona Jeffrey, Marta C. Cohen, Jacob Tfelt-Hansen, Michael A. Simpson, Elijah R. Behr, Michael John Ackerman

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Background: Sudden infant death syndrome (SIDS) is a leading cause of postneonatal mortality. Genetic heart diseases (GHDs) underlie some cases of SIDS. Objectives: This study aimed to determine the spectrum and prevalence of GHD-associated mutations as a potential monogenic basis for SIDS. Methods: A cohort of 419 unrelated SIDS cases (257 male; average age 2.7 ± 1.9 months) underwent whole exome sequencing and a targeted analysis of 90 GHD-susceptibility genes. The yield of “potentially informative,” ultra-rare variants (minor allele frequency <0.00005) in GHD-associated genes was assessed. Results: Overall, 53 of 419 (12.6%) SIDS cases had ≥1 “potentially informative,” GHD-associated variant. The yield was 14.9% (21 of 141) for mixed-European ancestry cases and 11.5% (32 of 278) for European ancestry SIDS cases. Infants older than 4 months were more likely to host a “potentially informative” GHD-associated variant. There was significant overrepresentation of ultra-rare nonsynonymous variants in European SIDS cases (18 of 278 [6.5%]) versus European control subjects (30 of 973 [3.1%]; p = 0.013) when combining all 4 major cardiac channelopathy genes (KCNQ1, KCNH2, SCN5A, and RYR2). According to the American College of Medical Genetics guidelines, only 18 of 419 (4.3%) SIDS cases hosted a “pathogenic” or “likely pathogenic” variant. Conclusions: Less than 15% of more than 400 SIDS cases had a “potentially informative” variant in a GHD-susceptibility gene, predominantly in the 4- to 12-month age group. Only 4.3% of cases possessed immediately clinically actionable variants. Consistent with previous studies, ultra-rare, nonsynonymous variants within the major cardiac channelopathy-associated genes were overrepresented in SIDS cases in infants of European ethnicity. These findings have major implications for the investigation of SIDS cases and families.

Original languageEnglish (US)
Pages (from-to)1217-1227
Number of pages11
JournalJournal of the American College of Cardiology
Volume71
Issue number11
DOIs
StatePublished - Mar 20 2018

Fingerprint

Sudden Infant Death
Genetic Predisposition to Disease
Inborn Genetic Diseases
Heart Diseases
Channelopathies
Genes
Disease Susceptibility
Exome
Infant Mortality
Gene Frequency
Age Groups
Guidelines

Keywords

  • genetic heart diseases
  • molecular autopsy
  • sudden infant death syndrome
  • whole exome sequencing

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Tester, D. J., Wong, L. C. H., Chanana, P., Jaye, A., Evans, J. M., FitzPatrick, D. R., ... Ackerman, M. J. (2018). Cardiac Genetic Predisposition in Sudden Infant Death Syndrome. Journal of the American College of Cardiology, 71(11), 1217-1227. https://doi.org/10.1016/j.jacc.2018.01.030

Cardiac Genetic Predisposition in Sudden Infant Death Syndrome. / Tester, David J.; Wong, Leonie C.H.; Chanana, Pritha; Jaye, Amie; Evans, Jared M.; FitzPatrick, David R.; Evans, Margaret J.; Fleming, Peter; Jeffrey, Iona; Cohen, Marta C.; Tfelt-Hansen, Jacob; Simpson, Michael A.; Behr, Elijah R.; Ackerman, Michael John.

In: Journal of the American College of Cardiology, Vol. 71, No. 11, 20.03.2018, p. 1217-1227.

Research output: Contribution to journalArticle

Tester, DJ, Wong, LCH, Chanana, P, Jaye, A, Evans, JM, FitzPatrick, DR, Evans, MJ, Fleming, P, Jeffrey, I, Cohen, MC, Tfelt-Hansen, J, Simpson, MA, Behr, ER & Ackerman, MJ 2018, 'Cardiac Genetic Predisposition in Sudden Infant Death Syndrome', Journal of the American College of Cardiology, vol. 71, no. 11, pp. 1217-1227. https://doi.org/10.1016/j.jacc.2018.01.030
Tester DJ, Wong LCH, Chanana P, Jaye A, Evans JM, FitzPatrick DR et al. Cardiac Genetic Predisposition in Sudden Infant Death Syndrome. Journal of the American College of Cardiology. 2018 Mar 20;71(11):1217-1227. https://doi.org/10.1016/j.jacc.2018.01.030
Tester, David J. ; Wong, Leonie C.H. ; Chanana, Pritha ; Jaye, Amie ; Evans, Jared M. ; FitzPatrick, David R. ; Evans, Margaret J. ; Fleming, Peter ; Jeffrey, Iona ; Cohen, Marta C. ; Tfelt-Hansen, Jacob ; Simpson, Michael A. ; Behr, Elijah R. ; Ackerman, Michael John. / Cardiac Genetic Predisposition in Sudden Infant Death Syndrome. In: Journal of the American College of Cardiology. 2018 ; Vol. 71, No. 11. pp. 1217-1227.
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abstract = "Background: Sudden infant death syndrome (SIDS) is a leading cause of postneonatal mortality. Genetic heart diseases (GHDs) underlie some cases of SIDS. Objectives: This study aimed to determine the spectrum and prevalence of GHD-associated mutations as a potential monogenic basis for SIDS. Methods: A cohort of 419 unrelated SIDS cases (257 male; average age 2.7 ± 1.9 months) underwent whole exome sequencing and a targeted analysis of 90 GHD-susceptibility genes. The yield of “potentially informative,” ultra-rare variants (minor allele frequency <0.00005) in GHD-associated genes was assessed. Results: Overall, 53 of 419 (12.6{\%}) SIDS cases had ≥1 “potentially informative,” GHD-associated variant. The yield was 14.9{\%} (21 of 141) for mixed-European ancestry cases and 11.5{\%} (32 of 278) for European ancestry SIDS cases. Infants older than 4 months were more likely to host a “potentially informative” GHD-associated variant. There was significant overrepresentation of ultra-rare nonsynonymous variants in European SIDS cases (18 of 278 [6.5{\%}]) versus European control subjects (30 of 973 [3.1{\%}]; p = 0.013) when combining all 4 major cardiac channelopathy genes (KCNQ1, KCNH2, SCN5A, and RYR2). According to the American College of Medical Genetics guidelines, only 18 of 419 (4.3{\%}) SIDS cases hosted a “pathogenic” or “likely pathogenic” variant. Conclusions: Less than 15{\%} of more than 400 SIDS cases had a “potentially informative” variant in a GHD-susceptibility gene, predominantly in the 4- to 12-month age group. Only 4.3{\%} of cases possessed immediately clinically actionable variants. Consistent with previous studies, ultra-rare, nonsynonymous variants within the major cardiac channelopathy-associated genes were overrepresented in SIDS cases in infants of European ethnicity. These findings have major implications for the investigation of SIDS cases and families.",
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