Exome-Wide Rare Variant Analyses in Sudden Infant Death Syndrome

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

doi:10.1016/j.jpeds.2018.08.011

Exome-Wide Rare Variant Analyses in Sudden Infant Death Syndrome

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

^*Corresponding author af dette arbejde

6 Citationer (Scopus)

Abstract

Objective: To determine whether a monogenic basis explains sudden infant death syndrome (SIDS) using an exome-wide focus. Study design: A cohort of 427 unrelated cases of SIDS (257 male; average age = 2.7 ± 1.9 months) underwent whole-exome sequencing. Exome-wide rare variant analyses were carried out with 278 SIDS cases of European ancestry (173 male; average age = 2.7 ± 1.98 months) and 973 ethnic-matched controls based on 6 genetic models. Ingenuity Pathway Analysis also was performed. The cohort was collected in collaboration with coroners, medical examiners, and pathologists by St George's University of London, United Kingdom, and Mayo Clinic, Rochester, Minnesota. Whole-exome sequencing was performed at the Genomic Laboratory, Kings College London, United Kingdom, or Mayo Clinic's Medical Genome Facility, Rochester, Minnesota. Results: Although no exome-wide significant (P < 2.5 × 10⁻⁶) difference in burden of ultra-rare variants was detected for any gene, 405 genes had a greater prevalence (P < .05) of ultra-rare nonsynonymous variants among cases with 17 genes at P < .005. Some of these potentially overrepresented genes may represent biologically plausible novel candidate genes for a monogenic basis for a portion of patients with SIDS. The top canonical pathway identified was glucocorticoid biosynthesis (P = .01). Conclusions: The lack of exome-wide significant genetic associations indicates an extreme heterogeneity of etiologies underlying SIDS. Our approach to understanding the genetic mechanisms of SIDS has far reaching implications for the SIDS research community as a whole and may catalyze new evidence-based SIDS research across multiple disciplines. Perturbations in glucocorticoid biosynthesis may represent a novel SIDS-associated biological pathway for future SIDS investigative research.

Originalsprog	Engelsk
Tidsskrift	Journal of Pediatrics
Vol/bind	203
Sider (fra-til)	423-428.e11
ISSN	0022-3476
DOI	https://doi.org/10.1016/j.jpeds.2018.08.011
Status	Udgivet - dec. 2018

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@article{981332d6093b473b9f64cba145e27e06,

title = "Exome-Wide Rare Variant Analyses in Sudden Infant Death Syndrome",

abstract = "Objective: To determine whether a monogenic basis explains sudden infant death syndrome (SIDS) using an exome-wide focus. Study design: A cohort of 427 unrelated cases of SIDS (257 male; average age = 2.7 ± 1.9 months) underwent whole-exome sequencing. Exome-wide rare variant analyses were carried out with 278 SIDS cases of European ancestry (173 male; average age = 2.7 ± 1.98 months) and 973 ethnic-matched controls based on 6 genetic models. Ingenuity Pathway Analysis also was performed. The cohort was collected in collaboration with coroners, medical examiners, and pathologists by St George's University of London, United Kingdom, and Mayo Clinic, Rochester, Minnesota. Whole-exome sequencing was performed at the Genomic Laboratory, Kings College London, United Kingdom, or Mayo Clinic's Medical Genome Facility, Rochester, Minnesota. Results: Although no exome-wide significant (P < 2.5 × 10−6) difference in burden of ultra-rare variants was detected for any gene, 405 genes had a greater prevalence (P < .05) of ultra-rare nonsynonymous variants among cases with 17 genes at P < .005. Some of these potentially overrepresented genes may represent biologically plausible novel candidate genes for a monogenic basis for a portion of patients with SIDS. The top canonical pathway identified was glucocorticoid biosynthesis (P = .01). Conclusions: The lack of exome-wide significant genetic associations indicates an extreme heterogeneity of etiologies underlying SIDS. Our approach to understanding the genetic mechanisms of SIDS has far reaching implications for the SIDS research community as a whole and may catalyze new evidence-based SIDS research across multiple disciplines. Perturbations in glucocorticoid biosynthesis may represent a novel SIDS-associated biological pathway for future SIDS investigative research.",

keywords = "inherited cardiac conditions, molecular autopsy, sudden infant death syndrome, whole exome sequencing",

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

year = "2018",

month = dec,

doi = "10.1016/j.jpeds.2018.08.011",

language = "English",

volume = "203",

pages = "423--428.e11",

journal = "Journal of Pediatrics",

issn = "0022-3476",

publisher = "Mosby Inc.",

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TY - JOUR

T1 - Exome-Wide Rare Variant Analyses in Sudden Infant Death Syndrome

AU - Tester, David J.

AU - Wong, Leonie C.H.

AU - Chanana, Pritha

AU - Gray, Belinda

AU - Jaye, Amie

AU - Evans, Jared M.

AU - Evans, Margaret

AU - Fleming, Peter

AU - Jeffrey, Iona

AU - Cohen, Marta

AU - Tfelt-Hansen, Jacob

AU - Simpson, Michael A.

AU - Behr, Elijah R.

AU - Ackerman, Michael J.

PY - 2018/12

Y1 - 2018/12

N2 - Objective: To determine whether a monogenic basis explains sudden infant death syndrome (SIDS) using an exome-wide focus. Study design: A cohort of 427 unrelated cases of SIDS (257 male; average age = 2.7 ± 1.9 months) underwent whole-exome sequencing. Exome-wide rare variant analyses were carried out with 278 SIDS cases of European ancestry (173 male; average age = 2.7 ± 1.98 months) and 973 ethnic-matched controls based on 6 genetic models. Ingenuity Pathway Analysis also was performed. The cohort was collected in collaboration with coroners, medical examiners, and pathologists by St George's University of London, United Kingdom, and Mayo Clinic, Rochester, Minnesota. Whole-exome sequencing was performed at the Genomic Laboratory, Kings College London, United Kingdom, or Mayo Clinic's Medical Genome Facility, Rochester, Minnesota. Results: Although no exome-wide significant (P < 2.5 × 10−6) difference in burden of ultra-rare variants was detected for any gene, 405 genes had a greater prevalence (P < .05) of ultra-rare nonsynonymous variants among cases with 17 genes at P < .005. Some of these potentially overrepresented genes may represent biologically plausible novel candidate genes for a monogenic basis for a portion of patients with SIDS. The top canonical pathway identified was glucocorticoid biosynthesis (P = .01). Conclusions: The lack of exome-wide significant genetic associations indicates an extreme heterogeneity of etiologies underlying SIDS. Our approach to understanding the genetic mechanisms of SIDS has far reaching implications for the SIDS research community as a whole and may catalyze new evidence-based SIDS research across multiple disciplines. Perturbations in glucocorticoid biosynthesis may represent a novel SIDS-associated biological pathway for future SIDS investigative research.

AB - Objective: To determine whether a monogenic basis explains sudden infant death syndrome (SIDS) using an exome-wide focus. Study design: A cohort of 427 unrelated cases of SIDS (257 male; average age = 2.7 ± 1.9 months) underwent whole-exome sequencing. Exome-wide rare variant analyses were carried out with 278 SIDS cases of European ancestry (173 male; average age = 2.7 ± 1.98 months) and 973 ethnic-matched controls based on 6 genetic models. Ingenuity Pathway Analysis also was performed. The cohort was collected in collaboration with coroners, medical examiners, and pathologists by St George's University of London, United Kingdom, and Mayo Clinic, Rochester, Minnesota. Whole-exome sequencing was performed at the Genomic Laboratory, Kings College London, United Kingdom, or Mayo Clinic's Medical Genome Facility, Rochester, Minnesota. Results: Although no exome-wide significant (P < 2.5 × 10−6) difference in burden of ultra-rare variants was detected for any gene, 405 genes had a greater prevalence (P < .05) of ultra-rare nonsynonymous variants among cases with 17 genes at P < .005. Some of these potentially overrepresented genes may represent biologically plausible novel candidate genes for a monogenic basis for a portion of patients with SIDS. The top canonical pathway identified was glucocorticoid biosynthesis (P = .01). Conclusions: The lack of exome-wide significant genetic associations indicates an extreme heterogeneity of etiologies underlying SIDS. Our approach to understanding the genetic mechanisms of SIDS has far reaching implications for the SIDS research community as a whole and may catalyze new evidence-based SIDS research across multiple disciplines. Perturbations in glucocorticoid biosynthesis may represent a novel SIDS-associated biological pathway for future SIDS investigative research.

KW - inherited cardiac conditions

KW - molecular autopsy

KW - sudden infant death syndrome

KW - whole exome sequencing

UR - http://www.scopus.com/inward/record.url?scp=85053932297&partnerID=8YFLogxK

U2 - 10.1016/j.jpeds.2018.08.011

DO - 10.1016/j.jpeds.2018.08.011

M3 - Journal article

C2 - 30268395

AN - SCOPUS:85053932297

SN - 0022-3476

VL - 203

SP - 423-428.e11

JO - Journal of Pediatrics

JF - Journal of Pediatrics

ER -

Exome-Wide Rare Variant Analyses in Sudden Infant Death Syndrome

Abstract

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