Exome-Wide Rare Variant Analyses in Sudden Infant Death Syndrome

• Published in: The Journal of pediatrics Vol. 203; pp. 423 - 428.e11
• Main Authors: Tester, David J., Wong, Leonie C.H., Chanana, Pritha, Gray, Belinda, Jaye, Amie, Evans, Jared M., Evans, Margaret, Fleming, Peter, Jeffrey, Iona, Cohen, Marta, Tfelt-Hansen, Jacob, Simpson, Michael A., Behr, Elijah R., Ackerman, Michael J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-12-2018
• Subjects: Autopsy; Case-Control Studies; Child; Child, Preschool; Ethnicity; Exome; Female; Genetic Predisposition to Disease; Genetic Variation; Humans; Infant; inherited cardiac conditions; Male; Minnesota; molecular autopsy; Mutation; Sudden Infant Death - epidemiology; Sudden Infant Death - ethnology; Sudden Infant Death - genetics; sudden infant death syndrome; United Kingdom; whole exome sequencing; United Kingdom; Minnesota; CADD; M3-receptor; SIDS; WES; inherited cardiac conditions; sudden infant death syndrome; IPA; whole exome sequencing; molecular autopsy
• ISSN: 0022-3476; 1097-6833
• DOI: 10.1016/j.jpeds.2018.08.011

To determine whether a monogenic basis explains sudden infant death syndrome (SIDS) using an exome-wide focus.
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.
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).
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.