Calcium Regulation Genes Tied to Sudden Unexplained Death in Children

NEW YORK — Researchers have traced cases of sudden unexplained death in children to de novo genetic mutations affecting calcium ion regulation.

About 400 children over the age of 1 die suddenly each year in the US. In older individuals, sudden death can be explained in a quarter of cases by pathogenic cardiac gene variants, while sudden unexplained death in children, or SUDC, which largely affects children between 1 and 4 years old, has been less studied but is thought to be influenced by genes involved in both cardiac- and epilepsy-related pathways.

Using data from the SUDC Registry and Research Collaborative, researchers from New York University sequenced and analyzed the genomes of 124 parent-child trios in which the child died of SUDC. As they reported in the Proceedings of the National Academy of Sciences on Monday, the researchers homed in on de novo mutations enriched in genes previously associated with cardiac and seizure disorders. Most of these mutations affected a protein network involved in regulating calcium-related excitability in cardiomyocytes and neurons, which could lead to cardiac arrhythmias.

"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," co-senior author Richard Tsien from NYU Langone said in a statement. "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."

For their analysis, the researchers conducted whole-exome sequencing of 124 children who died suddenly at an average age of 34.2 months, as well as of their living parents. They identified 125 de novo mutations within the affected children, including 116 single-nucleotide variants and nine indels, and validated them by Sanger sequencing.

Compared to two sets of control trios, the SUDC cohort had no excess of nonsynonymous mutations but did have a higher burden of mutations in a set of 137 genes previously associated with cardiac or seizure disorders.

The researchers constructed a protein-protein interaction network of the SUDC-linked mutations. They largely fell into four clusters, one of which encompassed CACNA1C, CALM1, GNAO1, RYR2, SCN1A, and TNNI3, all of which are in the CardiacEpilepsy gene set. Another cluster, meanwhile, included genes involved in neural development, like FN1 and NTNG1, suggesting that other gene networks might also have a role in SUDC.

By widening their analysis to genes outside their CardiacEpilepsy gene set, such as ones tied to neurodevelopmental disorders, the researchers found evidence of overlap between SUDC and neurodevelopmental disorders like autism spectrum disorder and developmental delay.

Overall, they identified variants that likely contributed to death in 11 of their 124 cases, a yield of nearly 9 percent.

Many of these mutations affect genes involved in calcium ion signaling, the researchers noted, adding that such signaling is important in both heart and brain cells. For instance, two cases had variants in CACNA1C, which encodes a voltage-dependent L-type calcium channel pore-forming subunit. Another child had a variant in CALM1, encoding the calcium ion sensor calmodulin, which has previously been linked to cardiac arrhythmias. As six cases had those or similar mutations, there might be a role for calcium dysregulation in SUDC, the researchers wrote.

They also noted that most of the children in their cohort died while sleeping or otherwise resting, and that they plan to next examine how sleeping versus waking or resting versus exercise may affect SUDC risk.