A new study found that changes in specific genes may contribute each year to the roughly 400 sudden unexplained deaths in children (SUDC) aged one year and older – and separately from sudden infant death syndrome (SIDS).
Children younger than one year old that die suddenly are officially diagnosed with SIDS, and older children with SUDC. But the conditions likely have many factors in common, say the study authors.
Although SIDS causes three times as many deaths as SUDC each year, it receives more than 20 times the research funding. Parents who lost an older child had few options to support their search for answers, and no research organization to join.
For this reason, study author Laura Gould, after losing her daughter, Maria, to SUDC at the age of 15 months in 1997, asked NYU Langone Health neurologist Orrin Devinsky, MD, to co-found the SUDC Registry and Research Collaborative (SUDCRRC). Since 2014, registry staff have worked with bereaved parents to enroll their families in the registry, which collects and analyzes genetic specimens from parents and their decedent child. Such molecular autopsies are not currently part of standard cause-of-death investigations conducted by most medical examiner and coroner’s offices.
Published online December 20 in the Proceedings of the National Academies of Sciences (PNAS), the new study is the first to identify genetic differences present in a large group of SUDC cases, most of which involved children who died between the ages of 1 and 4.
Led by researchers from NYU Langone Grossman School of Medicine, the study analyzed the DNA codes of 124 sets of parents, and of the child that each couple lost to SUDC. They found that 9 percent – or 11 of the 124 children – had DNA code changes (mutations) in genes that regulate calcium function. Calcium-based signals are important for brain cell and heart muscle function and when abnormal may cause arrhythmias (abnormal heart rhythms) or seizures, both of which increase risk of sudden death.
The researchers discovered that most DNA changes were new – arising randomly in the children of parents that did not have that genetic change (not inherited), says Gould. Thus, if SUDC occurs in one child, it is unlikely to occur again if the same couple has another child, providing some reassurance to families.
“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 senior study author Richard Tsien, Ph.D., chair of the Department of Neuroscience & Physiology, and director of the Neuroscience Institute, at NYU Langone Health. “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.”
First Hints
“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,” says study author Devinsky, director of NYU Langone’s Comprehensive Epilepsy Center. “Among the children that died, we found a ten-fold greater frequency of genetic changes in these genes than in the general population.”
Partly explaining these trends, the study’s statistical analysis found that the genetic changes present in the SUDC children occurred in clusters with similar functions, most controlling calcium channels in brain and heart muscle cells. Upon receiving the right signal, a cell opens such channels, enabling calcium ions to rush across membranes to create an electric current. In neurons this current triggers signals along nerve pathways, and in heart muscle cells, contractions as the heart beats.
Mutations found in the current study are known to slow calcium channel inactivation, prolong the current running through them, and potentially lead to abnormal heart rhythms that can cause the heart to stop, say the study authors. The two genes with de novo mutations in calcium processing found in more than one child in the study were RYR2 and CACNA1C, both of which are known to be linked to a cardiac arrhythmia. Other genes mutated in the SUDC group have been linked to seizures.
In addition, more than 91 percent of the children died while asleep or resting, including 50 percent of those with de novo mutations affecting genes involved with calcium physiology in the heart and brain (CACNA1C, RYR2, CALM1, and TNNI3). Moving forward, the team plans larger studies to look at the role of neurohumoral status (sleep vs. waking, rest vs. exercise), identify more mutations that may be harmful in SUDC, and determine if the calcium channel flaws cause more dire problems in brain cells or heart muscle.
Along with Gould, Devinsky and Tsien, study authors from NYU Grossman School of Medicine were Xiaohan Wang and Gariel Grant in the Neuroscience Institute, Rachel Rabin and John Pappas in the Department of Pediatrics, as well as Raquel Moya and Matthew Maurano from the Institute for Systems Genetics. Also study authors were Matthew Halvorsen and David Goldstein from the Institute for Genomic Medicine at Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center. Lead author Halvorsen continued work at the Department of Genetics, University of North Carolina. Study authors from the Mayo Clinic were Michael Ackerman and David Tester from the Windland Smith Rice Genetic Heart Rhythm Clinic and Windland Smith Rice Sudden Death Genomics Laboratory, as well as Peter Lin from the Department of Laboratory Medicine and Pathology.
This study was supported by funding NIH grants R01 DA040484 and R01 MH71739, funding from the SUDC Foundation, and Finding A Cure for Epilepsy and Seizures (FACES). None of the study authors participates in funding decisions for these organizations. Tsien reports participation in the Actelion Scientific Advisory Board, with no compensation during a three-year span. Devinsky reports an equity interest in Empatica. These relationships are being managed in keeping with the policies of NYU Langone.
