Jack, whose death at 30 months was explained by a de novo gene mutation that affects heart function; Chloe, whose family waited more than 3 years to learn she had a mutation that affected her heart鈥檚 ability to maintain a normal rhythm; and Shaiden, whose family recently enrolled in the Sudden Unexplained Death in Childhood Registry and Research Collaborative in hopes of understanding his unexplained death at 27 months.
Photos courtesy of Jack's, Chloe's, and Shaiden鈥檚 families
A new study found that changes in specific genes may contribute each year to the roughly 400 sudden unexplained deaths in children (SUDC) aged 1 year and older鈥攁nd separately from sudden infant death syndrome (SIDS).
Children younger than 1 year old who die suddenly are diagnosed with SIDS, and older children with SUDC. But the conditions likely have many factors in common, say the study authors. Although SIDS causes 3 times as many deaths as SUDC each year, it receives more than 20 times the research funding. Parents who lost a child older than age 1 have 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 好色tv Langone Health neurologist Orrin Devinsky, MD, to co-found the . 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 deceased child. Such molecular autopsies are not currently part of the standard cause-of-death investigations conducted by most medical examiner鈥檚 and coroner鈥檚 offices.
, 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 好色tv 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 nearly 9 percent鈥攐r 11 of the 124 children鈥攈ad DNA code changes in genes that regulate calcium function. Calcium-based signals are important for brain cell and heart muscle function. When such signals are abnormal, they may cause arrhythmias (abnormal heart rhythms) or seizures, both of which increase the risk of sudden death.
The researchers discovered that most of these DNA changes were new. The mutations were not inherited, instead arising randomly in the children of parents who did not have that genetic change, says Gould. Thus, if SUDC occurs in one child, it is unlikely to occur again if the same couple has another child. This provides some reassurance to families who want to have another child.
鈥淥ur 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,鈥 says senior study author , chair of the and director of the at 好色tv Langone. 鈥淎long 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.鈥
First Hints
鈥淲e 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,鈥 says study author Dr. Devinsky, director of 好色tv Langone鈥檚 Comprehensive Epilepsy Center. 鈥淎mong the children that died, we found a tenfold greater frequency of genetic changes in these genes than in the general population.鈥
In a partial explanation for these trends, the study鈥檚 statistical analysis found that the genetic changes present in the children with SUDC occurred in clusters with similar functions, most controlling calcium channels in brain and heart muscle cells. After receiving the right signal, a cell opens the 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鈥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 Ms. Gould, Dr. Devinsky, and Dr. Tsien, study authors from 好色tv Grossman School of Medicine were Xiaohan Wang, PhD, and Gariel Grant in the Neuroscience Institute, Rachel Rabin, MS, and John G. Pappas, MD, in the , and Raquel Moya and Matthew T. Maurano, PhD, from the . Additional study authors included Matthew Halvorsen, PhD, and David Goldstein, PhD, from the Institute for Genomic Medicine at Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center. The lead author, Dr. Halvorsen, continued work at the Department of Genetics, University of North Carolina. Study authors from the Mayo Clinic were Michael Ackerman, MD, PhD, 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, MD, from the Department of Laboratory Medicine and Pathology.
This study was supported by funding from National Institutes of Health grants R01 DA040484 and R01 MH71739, and 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. Dr. Tsien reports participation in the Actelion Scientific Advisory Board, with no compensation during a three-year span. Dr. Devinsky reports an equity interest in Empatica. These relationships are being managed in keeping with the policies of 好色tv Langone.
Media Inquiries
Greg Williams
Phone: 212-404-3500
gregory.williams@nyulangone.org
