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

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

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. (c) 2018 the American College of Cardiology Foundation. Published by Elsevier. All rights reserved.

Original language	English
Pages (from-to)	1217-1227
Number of pages	11
Journal	Journal of the American College of Cardiology
Volume	71
Issue number	11
Early online date	12 Mar 2018
DOIs	https://doi.org/10.1016/j.jacc.2018.01.030
Publication status	Published - 20 Mar 2018

Keywords / Materials (for Non-textual outputs)

genetic heart diseases
molecular autopsy
sudden infant death syndrome
whole exome sequencing
LONG-QT SYNDROME
SYNDROME SIDS
MUTATIONS
PREVALENCE
VARIANTS
CHANNELOPATHIES
PERSPECTIVE
MECHANISM
SPECTRUM
CHANNEL

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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

@article{decfdf4a1d0645ad9bbf0f74e56a4656,

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. (c) 2018 the American College of Cardiology Foundation. Published by Elsevier. All rights reserved.",

keywords = "genetic heart diseases, molecular autopsy, sudden infant death syndrome, whole exome sequencing, LONG-QT SYNDROME, SYNDROME SIDS, MUTATIONS, PREVALENCE, VARIANTS, CHANNELOPATHIES, PERSPECTIVE, MECHANISM, SPECTRUM, CHANNEL",

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",

publisher = "Elsevier Science",

number = "11",

}

TY - JOUR

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. (c) 2018 the American College of Cardiology Foundation. Published by Elsevier. All rights reserved.

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. (c) 2018 the American College of Cardiology Foundation. Published by Elsevier. All rights reserved.

KW - genetic heart diseases

KW - molecular autopsy

KW - sudden infant death syndrome

KW - whole exome sequencing

KW - LONG-QT SYNDROME

KW - SYNDROME SIDS

KW - MUTATIONS

KW - PREVALENCE

KW - VARIANTS

KW - CHANNELOPATHIES

KW - PERSPECTIVE

KW - MECHANISM

KW - SPECTRUM

KW - CHANNEL

U2 - 10.1016/j.jacc.2018.01.030

DO - 10.1016/j.jacc.2018.01.030

M3 - Article

SN - 0735-1097

VL - 71

SP - 1217

EP - 1227

JO - Journal of the American College of Cardiology

JF - Journal of the American College of Cardiology

IS - 11

ER -

Cardiac Genetic Predisposition in Sudden Infant Death Syndrome

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