Connecting the Genetic Dots in Sudden Unexpected Infant Death

July 24, 2024 – A new study from Dr. Nino Ramirez of Seattle Children’s Research Institute’s Norcliffe Foundation Center for Integrative Brain Research and colleagues, including researchers in Microsoft’s AI for Good Lab, is among the first to use whole genome sequencing to gain insights into potential genetic factors contributing to infants’ vulnerability to sudden unexpected infant death (SUID). The findings, which significantly expand the list of potential gene variants associated with SUID — including genes related to heart disease and neurological and metabolic disorders — were recently published in the American Journal of Medical Genetics Part A.

A leading cause of infant mortality, SUID encompasses three types of death in children under 1 year old: sudden infant death syndrome (SIDS); deaths from other ill-defined or unknown causes; and accidental suffocation or strangulation in bed. The Centers for Disease Control estimates SUID contributes to the deaths of about 3,400 infants in the U.S. annually.

Many risk factors have been identified for SIDS/SUID: race/ethnicity, prematurity, maternal smoking during pregnancy, lower birth weight, bed-sharing, prone (stomach) sleeping, recent infection, geography and environmental exposures such as air pollution. The recognition of prone sleeping as a major risk factor led to the adoption of safe sleep practices, which were associated with significant reductions in SUID rates in the 1990s and early 2000s. Despite increased educational efforts, SUID rates have remained steady since the early 2000s.

“Triple Risk” SUID Hypothesis

In this study, 72 infants met the criteria for a hypothesis known as “triple risk.” First proposed in the early 1970s, this concept suggests SUID occurs during a critical development period when a vulnerable infant is exposed to an extrinsic stressor; numerous gene variants may increase this vulnerability. While researchers believe a multitude of pathways may lead to SUID, separate risk factors for SUID have been consistently found worldwide: It occurs more often in males; peaks between the second month and 1 year of age; and is more common in infants whose mothers smoke and in babies who sleep on their stomachs.

For this study, whole genome sequencing was performed on 144 infants who had succumbed to SUID and on 573 healthy adults, with the goals of validating genes in which altered function have been previously implicated in SUID and identifying novel genes and pathways that tend to be disrupted in SUID to better understand the causes of these deaths. This complete, nontargeted approach to sequencing enabled an unbiased and thorough evaluation of the SUID genome.

Variants of interest were identified in 88 genes (64.6% of the cohort). Of these, 73 had been previously associated with SUID and/or sudden unexpected death in pediatrics (SUDP). Forty-three were characterized as cardiac genes related to cardiomyopathies, arrhythmias and other heart conditions. Variants in 22 genes were associated with neurologic functions. Variants were also found in 13 genes associated with various systemic disorders and in two genes associated with immunological function.

New Risky Gene Variants Identified

Variants in eight genes never before associated with SUID were implicated in the response to low blood oxygen levels (hypoxia) and the regulation of reactive oxygen species (a type of unstable molecule that contains oxygen and easily reacts with other molecules in a cell, which may cause cumulative damage to DNA, RNA and proteins, and cell death), offering new mechanistic understanding of its pathophysiology.

“Further deaths might be prevented through the early recognition of a child who is at higher risk for SUID,” said Ramirez, principal investigator and professor of neurological surgery at the University of Washington School of Medicine. “Thankfully, though, not every child who has these genetic variants will succumb to SUID. Nonetheless, identifying risk genes could potentially prevent deaths in older children, help in the diagnosis of a sudden death and bring closure for surviving family members, and help surviving parents weigh the risks of considering further children. Also, the knowledge of a genetic vulnerability, together with improved monitoring equipment, could increase the usefulness of devices that have so far failed to prevent deaths.

“Our research confirms and further expands the list of genetic variants associated with SUID,” Ramirez said. “Interestingly, many of these genes have previously been implicated in other causes of sudden death, including cardiac death or sudden death in epilepsy. Thus, we hypothesize that many children will survive the critical time period associated with SUID but they will carry this vulnerability into adult life, when they might face other stressors — for example, those known to be associated with sudden cardiac death. This highlights the importance of recognizing vulnerability early in life, which may not only help to prevent SUID, but sudden death in general.”

Ramirez said the findings underscore the complex genetic underpinnings of SUID, laying the groundwork for improved clinical practices and potentially lifesaving advancements in the management of infant health.

Collaborative Next Steps

As part of the Microsoft collaboration, Seattle Children’s researchers next plan to use machine learning and AI strategies to identify critical protein interactions, polygenic inheritance patterns (a single inherited trait controlled by two or more different genes) and gene modifiers that likely contribute to SUID, as traditional methods are insufficient given the large number of implicated genes.

After their work on this study, Ramirez said his team has sequenced 200 more individuals to search for similar genetic variants and plans to expand their collaborations to increase the number of infants sequenced. The researchers plan to include transcriptomics (gathering data on RNA) and metabolomics (metabolic profiling) studies in future work, acknowledging that whole genome sequencing alone doesn't provide a complete picture.

Additionally, the Ramirez team is working with medical examiners in Washington state to incorporate whole genome sequencing in autopsies, enhancing the understanding of SUID in forensic investigations.

In addition to Ramirez, Seattle Children’s contributing authors include: first author Angela (Michelle) Bard and Lely Quina of the Ramirez Lab; Dr. Lindsay Clark, Research Scientific Computing; Dr. Kimberly Aldinger, principal investigator of the Aldinger Lab; and former research institute scientists Drs. Andrew Timms, Tatiana Becker and Chelsea Pagan.

The study was funded by the Aaron Matthew SIDS Research Guild, Seattle Children's Research Institute and the National Institutes of Health.

— Colleen Steelquist