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

Abstract

PurposeTo gain insights into potential genetic factors contributing to the infants vulnerability to Sudden Unexpected Infant Death (SUID). MethodsWhole Genome Sequencing (WGS) was performed on 145 infants that succumbed to SUID, and 576 healthy adults. Variants were filtered by gnomAD allele frequencies and predictions of functional consequences. ResultsVariants of interest were identified in 86 genes, 63.4% of our cohort. Seventy-one of these have been previously associated with SIDS/SUID/SUDP. Forty-three can be characterized as cardiac genes and are related to cardiomyopathies, arrhythmias, and other conditions. Variants in 22 genes were associated with neurologic functions. Variants were also found in 13 genes reported to be pathogenic for various systemic disorders. Variants in eight genes are implicated in the response to hypoxia and the regulation of reactive oxygen species (ROS) and have not been previously described in SIDS/SUID/SUDP. Seventy-two infants met the triple risk hypothesis criteria (Figure 1). O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=121 SRC="FIGDIR/small/23295207v2_fig1.gif" ALT="Figure 1"> View larger version (17K): org.highwire.dtl.DTLVardef@1569ae6org.highwire.dtl.DTLVardef@d376d4org.highwire.dtl.DTLVardef@11e62faorg.highwire.dtl.DTLVardef@1f42f90_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 1.C_FLOATNO Triple-risk Venn Diagram illustrating the risk factors found among our cohort. Seventy-two infants met the triple risk hypothesis criteria. There were 115 infants determined to be vulnerable. Eighty-nine infants experienced an exogenous stressor at or near the time of death and all 145 infants died during the critical development period, <1 year of age. C_FIG 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 have important mechanistic implications for the pathophysiology of SUID.