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 J. Ackerman

doi:10.1016/j.jacc.2018.01.030

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 J. Ackerman

^*Corresponding author af dette arbejde

30 Citationer (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.

Originalsprog	Engelsk
Tidsskrift	Journal of the American College of Cardiology
Vol/bind	71
Udgave nummer	11
Sider (fra-til)	1217-1227
Antal sider	11
ISSN	0735-1097
DOI	https://doi.org/10.1016/j.jacc.2018.01.030
Status	Udgivet - 20 mar. 2018

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10.1016/j.jacc.2018.01.030

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Tester, D. J., Wong, L. C. H., Chanana, P., Jaye, A., Evans, J. M., FitzPatrick, D. R., Evans, M. J., Fleming, P., Jeffrey, I., Cohen, M. C., Tfelt-Hansen, J., Simpson, M. A., Behr, E. 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

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title = "Cardiac Genetic Predisposition in Sudden Infant Death Syndrome",

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.",

keywords = "genetic heart diseases, molecular autopsy, sudden infant death syndrome, whole exome sequencing",

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

year = "2018",

month = mar,

day = "20",

doi = "10.1016/j.jacc.2018.01.030",

language = "English",

volume = "71",

pages = "1217--1227",

journal = "Journal of the American College of Cardiology",

issn = "0735-1097",

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T1 - Cardiac Genetic Predisposition in Sudden Infant Death Syndrome

AU - Tester, David J.

AU - Wong, Leonie C.H.

AU - Chanana, Pritha

AU - Jaye, Amie

AU - Evans, Jared M.

AU - FitzPatrick, David R.

AU - Evans, Margaret J.

AU - Fleming, Peter

AU - Jeffrey, Iona

AU - Cohen, Marta C.

AU - Tfelt-Hansen, Jacob

AU - Simpson, Michael A.

AU - Behr, Elijah R.

AU - Ackerman, Michael J.

PY - 2018/3/20

Y1 - 2018/3/20

N2 - 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.

AB - 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.

KW - genetic heart diseases

KW - molecular autopsy

KW - sudden infant death syndrome

KW - whole exome sequencing

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Cardiac Genetic Predisposition in Sudden Infant Death Syndrome

Abstract

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