Known pathogenic gene variants and new candidates detected in Sudden Unexpected Infant Death using Whole Genome Sequencing

Abstract

PurposeIn this study we performed WGS of children that succumbed to SUID during their first year of life to gain insights into potential genetic risk factors that could contribute to an infant’s vulnerability to this tragic outcome.MethodsWhole genome sequencing was performed on 145 SUID cases, and 576 healthy adult controls. Variants were filtered by gnomAD allele frequencies and predictions of functional consequences using computational tools.ResultsIn 63.4% of our cohort, we identified 156 variants of interest in 86 genes, including 128 rare/ultra-rare variants in 71 genes that were previously associated with SIDS/SUID/SUDP. Eighty-eight variants were found in 43 genes that can be characterized as cardiac genes, and have previously been associated with cardiomyopathies, Brugada and Long QT syndromes, among others. Twenty-nine variants were also found in 22 genes previously reported in SIDS/SUID/SUDP that are related to neurologic function. Nineteen variants were found in 13 genes that are reported to be pathogenic for various systemic disorders, 11 of which occurred in six genes that have been previously described in SIDS/SUID/SUDP and eight that have not. We also identified 20 variants in eight genes implicated in the response to hypoxia and the regulation of reactive oxygen species (ROS) not previously described in SIDS/SUID/SUDP.ConclusionOur study confirms and further expands the list of genetic variants associated with SUID. The abundance of genes associated with heart disease and the discovery of variants associated with the redox metabolism has important mechanistic implications for the pathophysiology of SUID.