A study led by New York University suggests genetic variants implicated in medical conditions such as abnormal heart rhythms and seizures could be at least partly responsible for a significant percentage of sudden unexplained deaths in children between the age of 1 and 18 years.
The researchers found that genetic variants linked to cardiac and seizure disorders were tenfold greater in children who died than in the general population, suggesting a potential causative link.
Approximately 400 children older than 1 year of age die suddenly from unexplained causes (SUDC) in the U.S. each year. Although unexplained deaths in infants younger than 1 year, SIDS, is more common, researchers believe the two conditions may share a lot of factors. Despite this, there is 20 times more research investment put into investigating SIDS than SUDC.
For this reason, the SUDC Registry and Research Collaborative was set up as a nonprofit organization in 2014. It the only organization worldwide whose purpose is to promote awareness, advocate for research, and support those affected by SUDC, and was co-founded by study authors Laura Gould, who lost her daughter to SUDC in 1997, and neurologist Orrin Devinsky, from NYU Langone Health, as well as other affected parents and clinicians.
One of the purposes of the organization is to register children who die from SUDC and their parents and to carry out further examinations and assessments to try and understand why they may have died. These can include neuroimaging and neuropathological evaluations, as well as genetic sampling and exome sequencing of both the child and parents.
The current study, published in the Proceedings of the National Academy of Sciences, included 124 parent-child trios from the registry. Detailed phenotyping, as well as exome sequencing of each of the parents and deceased child was carried out. Although the group included children who died between the age of 1 and 18 years, many SUDC children (including most in this group) die between the age of 1 and 4 years.
Following analysis of the genomes of children who died, the researchers found significantly more mutations that change the way genes are expressed in genes linked to cardiac and seizure disorders than in the general population. For example, several children had mutations in the genes RYR2 and CACNA1C, both of which are known to be linked to cardiac arrhythmia.
“We focused on 137 genes linked by past studies to cardiac arrhythmias, epilepsy, and related conditions, because seizures and sudden cardiac death are known to be more prevalent in SUDC,” said Devinsky, director of NYU Langone’s Comprehensive Epilepsy Center, in a press statement.
“Among the children that died, we found a tenfold greater frequency of genetic changes in these genes than in the general population.”
Further analysis, showed 11 (9%) of the children who died had genetic mutations thought to be pathogenic that likely contributed to their deaths.
While most of the genetic variants seen in the children’s DNA were ‘de novo’ and not seen in their parents DNA, a small number parents were carriers of mutations that seem to have been passed on. Generally the risk of an inherited mutation causing SUDC seems to be small, however.
“Many of these pathogenic de novo mutations altered a protein network regulating calcium-related excitability at submembrane junctions in cardiomyocytes and neurons,” explain the authors.
Calcium signals play an important role in maintaining normal heart rhythms and keeping nerve cells healthy. When these are abnormal, heart problems and seizures can result and can even lead to death in some circumstances.
“Our study is the largest of its kind to date, the first to prove that there are definite genetic causes of SUDC, and the first to fill in any portion of the risk picture,” says co-lead study author Richard Tsien, chair of the Department of Neuroscience and Physiology and director of the Neuroscience Institute at NYU Langone.
“Along with providing comfort to parents, new findings about genetic changes involved will accumulate with time, reveal the mechanisms responsible, and serve as the basis for new treatment approaches.”
