Geneticists find clues to sudden unexplained child deaths | Science

In 1997, Laura Gould put her 15-month-old daughter, Maria, down for a nap and returned to find her unresponsive. She had died suddenly, with no clues to explain the tragedy besides a fever the night before. When her daughter’s body was sent to the medical examiner’s office, “I thought they’d call me in an hour and tell me what happened … like on TV,” Gould says. Months later, neither that office nor independent pathologists had an explanation. “I hated ending it with ‘the autopsy was inconclusive, go on and live your life now,’” she says. “It just didn’t really feel like that was an option.”

Gould co-founded a nonprofit foundation to support grieving parents, raise research funds, and increase awareness of sudden unexplained death in childhood (SUDC), a term used for children older than 12 months. In the United States, roughly 400 deaths fall into this category each year—about one-quarter as many as are labeled sudden infant death syndrome (SIDS). Two recent genetic analyses, one funded in part by Gould’s SUDC Foundation, now suggest potential causes for at least a small fraction of cases: mutations in genes associated with epilepsy, heart arrhythmias, and neurodevelopmental disorders.

“Having this data is important,” says Marco Hefti, a neuropathologist at the University of Iowa Carver College of Medicine who was not involved in the new studies. SUDC is not a single disease, but “a grab bag of different things—and the more of those different things you can pull out, the better for everybody.” Neither study can say with certainty that a mutation is responsible for a child’s death. But the findings provide a basis for animal studies that could reveal how the genetic changes interfere with vital functions. They might also inform future child death investigations and potentially even screening programs to prevent deaths.

Research on SUDC has lagged that on the more common and better known SIDS. Yet, biologically, SIDS and SUDC “may be part of a spectrum,” says Ingrid Holm, a medical geneticist at Boston Children’s Hospital. In both, death often occurs during sleep, and researchers suspect contributors including undetected heart defects, metabolic disorders, and central nervous system abnormalities. The children who die are roughly 10 times more likely than the average child to have a history of febrile seizures—convulsions that come with fevers in young children, notes neurologist Orrin Devinsky of New York University (NYU) Langone Health.

Following a death, medical examiners routinely take blood or tissue samples and sometimes order genetic tests to look for dangerous known mutations. With SIDS, studies that sequenced entire exomes—the proteincoding regions of DNA—implicated certain rare genetic mutations. But until now, no whole-exome studies have looked at a large collection of SUDC cases to find genetic clues.

A registry of SUDC cases set up by Gould and Devinsky at the NYU Grossman School of Medicine in 2014 made such a study possible. Their team sequenced the exomes of 124 “trios,” each made up of parents and a child who died suddenly and without explanation between the ages of 11 months and 19 years. The researchers searched for mutations in genes previously associated with cardiac dysfunction or epilepsy. They found variants in eight genes that they think contributed to 11 of the deaths, they reported in the Proceedings of the National Academy of Sciences in December 2021.

In seven of those cases, the mutation was de novo, meaning neither parent carries it—a finding that bolsters the case that it contributed to death. Six of the variants affected genes involved in calcium signaling—the flow of ions across cellular channels, which regulates diverse processes, including heart contractions and neuron firing.

In a second study, Holm and colleagues explored 352 cases of death in either infants or children. They searched for mutations in 294 genes linked to neurologic conditions, cardiac dysfunction, and conditions that affect metabolism or multiple organ systems. In the 73 cases where DNA from both parents was available, they also looked across the exome for de novo variants. “Likely contributory variants” emerged for 37 of the deaths, including six of the 32 deaths in children older than 1 year, the team reported last month in Genetics in Medicine. Two of these variants were in genes already associated with rare neurodevelopmental disorders but not with sudden death, suggesting an unrecognized potential consequence of those disorders. Both studies identified mutations in SCN1A, a gene known to be involved in epilepsy.

The proportions of deaths with possible explanations in the new studies may seem small, Hefti says, but the approach applied broadly could provide new information to dozens of families in the United States alone. Learning that the potential cause of a child’s death is a de novo variant could reassure parents that they’re unlikely to have passed a dangerous mutation to their other children, he says.

In contrast, if a potential genetic cause is inherited, other family members could be tested and take preventive steps if they’re affected, notes Rachel Rabin, a genetic counselor at NYU Langone. For example, if parents or siblings carry a diseaselinked variation of SCN1A, a neurologist can run tests and may prescribe medication if seizures are identified, Rabin says.

Despite the potential value of genetic testing in child or infant death investigations, it’s not always done. “The factors are mostly money, of course,” says Michael Klintschar, a forensic pathologist at Hannover Medical School. Among U.S. medical examiners’ offices, “I would guess that the majority do not do [genetic testing] on every case,” says Kathryn Pinneri, director of Montgomery County Forensic Services in Conroe, Texas, and president of the National Association of Medical Examiners. But declining costs have made it more common in the past 5 years, she says.

The New York City medical examiner’s office investigates unexplained deaths among infants and children using its own panels of genetic tests. Geneticist Yingying Tang, who heads the in-house molecular genetics lab there, says the new study results make her “pretty confident with the cardiac and epilepsy panels I have.” Investigations of pediatric deaths in that office have revealed mutations in several of the genes identified in these studies, she says.

Some parents of children who died suddenly hope genetic analysis will make it possible to screen embryos for a dangerous genetic variant before another pregnancy, says Richard Goldstein, a palliative care pediatrician at Boston Children’s and coauthor of the new study. Developing and justifying such screening would require first firming up any causal link between a variant and sudden death. His team plans to delve into the mechanisms of some of the recently identified variants by inserting them into zebrafish to look for differences in behavior or life span.

In principle, some dangerous variants could be added to those routinely screened for in newborns, Devinsky says. “I think that’s where [the field] should probably go.” But in many cases the consequences of a mutation remain obscure, Klintschar notes. Linking a child’s death to a rare mutation in an arrhythmia-related gene doesn’t tell researchers the risk of cardiac arrest in a living baby with the same mutation. Giving all such children implants to correct irregular rhythms might cause more problems than it solves, he says.

Gould, whose daughter’s death remains unexplained, hopes the SUDC registry can help clarify the risk factors. It now includes 292 families, and her team continues to invite parents to participate. “If you want your child’s information to benefit research,” she says, “that opportunity can sometimes be comforting.”