Cardiac Genetic Predisposition in Sudden Infant Death Syndrome
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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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 J.
I: Journal of the American College of Cardiology, Bind 71, Nr. 11, 20.03.2018, s. 1217-1227.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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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.
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
UR - http://www.scopus.com/inward/record.url?scp=85042852912&partnerID=8YFLogxK
U2 - 10.1016/j.jacc.2018.01.030
DO - 10.1016/j.jacc.2018.01.030
M3 - Journal article
C2 - 29544605
AN - SCOPUS:85042852912
VL - 71
SP - 1217
EP - 1227
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
SN - 0735-1097
IS - 11
ER -
ID: 203553305