Known pathogenic gene variants and new candidates detected in sudden unexpected infant death using whole genome sequencing

Abstract

The purpose of this study is to gain insights into potential genetic factors contributing to the infant's vulnerability to Sudden Unexpected Infant Death (SUID). Whole Genome Sequencing (WGS) was performed on 144 infants that succumbed to SUID, and 573 healthy adults. Variants were filtered by gnomAD allele frequencies and predictions of functional consequences. Variants of interest were identified in 88 genes, in 64.6% of our cohort. Seventy-three 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 and in two genes associated with immunological function. 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. Our 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.

Keywords: ROS; SIDS; SUDEP; SUID; WGS; arrhythmia; cardiomyopathy.

FIGURE 1

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 144 infants died during the critical development period, <1 year of age.

FIGURE 2

Flow chart. Tissue samples from 144 SUID affected infants were submitted for WGS. VCFs from 573 healthy adults were obtained from Let’s Get Checked (formerly Veritas) and both were joint called for variants. The results were subjected to both gene level and variant level analysis.

FIGURE 3

UMAP to visualize population structure across affected infants and healthy adults. Ancestry of clusters is labeled based on self-identified race as well as GrafPop results on the genotype data.

FIGURE 4

Gene-level Poisson test for rate of observation of variants in affected infants versus healthy adults. A total of 9717 variants filtered for allele frequency and evidence of pathogenicity were included for testing. Genes with significance at FDR < 0.05 are labeled.

FIGURE 5

Proportion of individuals with at least one potentially pathogenic variant in 16 genes of interest. Genes are shown here if they had a significantly higher rate of variants in affected as compared to healthy individuals, using 9717 variants filtered for allele frequency and evidence of pathogenicity. Ancestry was determined by clustering in UMAP. Individuals are split by affected/healthy and by ancestry group, with individuals of Asian ancestry not shown since only one case was of Asian ancestry. AFR, African ancestry; EUR, European ancestry. Error bars indicate 95% margin of error on proportions.

FIGURE 6

Visual representation of risk factors, cause of death and age at death for 144 infants in the study cohort. Colors on the top of each block indicate exogenous stressors, while colors on the bottom indicate vulnerabilities. Grey indicates no exogenous stressors and/or vulnerabilities. Cause of death is listed as stated by the medical examiner. “Genetic predisposition” indicates that the infant had at least one of the variants highlighted in our study.

FIGURE 7

ROS Pathway. Twenty variants in eight genes (AAGAB, ATM, BRCA1, CFTR, COL7A1, ITGB3, LAMB3, and SMAD3) that function in the ROS pathway were found in 20 infants who succumbed to SUID.

FIGURE 8

Median age at death by variant type in affected infants. Median age at death was 12.2 weeks (IQR = 8.4, 15.8) for all infants whose age at death was known (n = 143). Twenty-nine infants with a single cardiac gene variant died at a median age of 10.1 weeks (IQR = 8.9, 13.0), whereas the 14 infants that were found to have a single variant in a gene related to neurologic function died at a median age of 16.1 weeks (IQR = 11.1, 21.2). The 11 infants with a single variant in a ROS pathway gene died at a median age of 12.7 weeks (IQR = 9.5, 21.5). ANOVA was run in R and revealed that these differences were marginally significant (p = 0.053).