Study Uncovers Potential Genetic Determinants of Unexplained Child Deaths
A recent study published in Genetics in Medicine has revealed that various genetic determinants may cause a predisposition to Sudden Unexpected Death in Pediatrics (SUPD), a definition which encompasses commonly referenced syndromes such as Sudden Infant Death Syndrome (SIDS) and Sudden Unexpected Infant Death (SUID).
The researchers analyzed data from both proband (first affected individual)-only cases and proband-parent trios referred to Robert’s Program on SUDP, a clinical service at Boston Children's Hospital (BCH) for families who have experienced the unexpected and sudden death of a child. The study concluded that genetic variants contributed to SUPD in 11% of the 352 cases.
“One of the questions the study leaves us with is what the mechanisms of death actually are. These kids do not appear diseased. They didn’t look like they had seizure disorders or heart problems. We have to find clever ways to model them,” said Dr. Richard Goldstein, M.D., coauthor of the study, director of Robert’s Program and associate professor of pediatrics at Harvard Medical School, in an interview with Biospace.
Retrieving patient information was a foundational part of the research process. SUPD is a “rare medical event that’s devastating for family members,” added Dr. Hyunyong Koh, M.D., Ph.D., a coauthor of the study and post-doctoral fellow at BCH with a background in rare pediatric disorders, during the interview.
The DNA samples allowed the geneticists to focus on both previously known and new variants. “First, we can investigate variants in genes known to cause SIDS or SUDC. We can also identify newly generated variants in a child that the parents didn’t carry, or de novo variants. This can be established in our trio approach. We can see how genetic inheritance works in a family.”
The researchers’ trio-based approach, phenotyping and analyzing exome data from not only the child, but both parents, offered many new angles of discovery on SUDP.
“When we look at the parents, one of them may have had that gene and had an unaffected life. That’s been an Achilles heel of the first wave of genetics research. Our move into trios was absolutely essential,” Goldstein added. Relying on families involved with Robert’s Program in the past ten years, the study looked at both genotype and phenotype. “The dirty secret of good genetics is that genotype is less important than phenotype. The most important things come from consideration of both the family and the child that is affected.”
Dr. Alireza Haghighi, M.D., founding director of the Harvard Brigham International Center for Genetic Disease and coauthor of the study, further elaborated on the trio-approach during the interview, noting that advanced technologies in genetics have allowed wider applications for data and information from singular patients. Concerning rare diseases, however, the data sets have more limitations.
“In rare diseases, the concept of precision versus scale becomes very important. When you talk about common disorders, we talk about larger-scale datasets. Ten years ago, there were tens of thousands. Now, there are millions. We don’t have that luxury in rare diseases. Precision becomes very important. Phenotyping becomes very important,” he explained.
When genes are examined in relation to larger family groups, genetic studies can compare offspring to their parents, shedding new light on variants. “This trio-approach that Robert’s Program is taking to analyze SIDS is innovative. It’s very successful and helps to identify and interpret variants. If you identify a variant that is inherited from one parent and hypothesize that the variant causes that condition, but then you identify the same variant in the parent, you would think that it’s unlikely that that variant caused the condition,” Haghighi noted.
Goldstein outlined three primary points of interest regarding the research, first addressing the basic question surrounding SIDS and SUPD.
“Are these normal kids that will be fine if you just sleep them the right way, or is there something different about them? Part of what we look at is the burden analysis,” he said. “Genetically, are these kids the same as normal kids? The answer is no. They have more de novo mutations. They have more mutations in genes found in diseases related to sudden death. We think that this is important evidence about the intrinsic vulnerabilities of this population.”
The second point of interest referenced major hypotheses regarding studies of intrinsic vulnerabilities. “On a genetic level, are the kinds of vulnerabilities in epilepsy-related death, cardiac-related death, immune problems, brain issues and metabolic issues different in our population versus the controls? The answer is yes! They are different. They carry more mutations.” The study found “an excess of variants” in the 352 probands when compared with 1,433 controls.
Thirdly, Goldstein highlighted a particular area of interest for the research team. “Is the approach we have of assembling family information, using enhanced autopsies and phenotyping worthwhile?” The doctor explained that the research group’s method contrasts with the traditional route through the forensics system, which is unable to utilize deep levels of evaluation. “The children go into the forensics system because the state is looking for signs of maltreatment. You find that in a low percentage, but there’s much to be gained from our approach,” he said.
Traditional advice regarding safe sleeping practices for infants that reduces the risk of SIDS includes placing babies to sleep on their back. The study found comparable numbers of children whose position at death was prone or supine, however. In response to this, Goldstein noted that the research hypotheses are separate from safe sleep recommendations and that parents should always ensure that their babies are sleeping in a safe position.
“Sleep position is potentially a provocative stressor. If there is more CO2 and less oxygen, that can be enough to set it off,” he explained. “We don’t want to undermine the messaging for safe sleep.”
“We need much more data,” Dr. Haghighi stated, noting that SIDS is potentially not just one condition, but an umbrella of various conditions. The effect size of the identified genetic contributors is unknown but large. “Genetics plays an important role here. Learning about the mechanism helps us understand the interaction between the genetic factors and the environment, the intrinsic vulnerabilities. Understanding the mechanism will help us to find the causes and the factors that contribute to this outcome. I think that having larger data sets, expanding collaborations across countries, continents, populations and ethnicities, will help us to have more statistical power and a better understanding of what’s going on.”
Koh added that “it’s helpful to comprehensively think about SIDS or SUDC as an outcome derived from many factors. There are many intrinsic and extrinsic vulnerabilities. It’s not monogenetic, which means that this phenomenon is not caused by a single mutation or a single deterministic factor. That may mean that the relationships between sleep position, environmental factors and genetic features together are what make the difference. There are many factors contributing to this outcome.”
Koh said the next steps for the research team will involve proving the functional validity of their results in zebrafish. “We believe that zebrafish may be an appropriate model for reconciling the variants, then seeing how they affect the longevity or developmental processes of the organisms. We have the human genetics findings in regards to SIDS and SUDC, but it’s still questionable how the findings are causing a SIDS-like phenomenon.”
Haghighi added that “in the past, limited technology meant limited methods. Now, we have CRISPR, which is much more accurate. We can use CRISPR to make models with multiple mutations at the same time. If there’s no change, we know they don’t do anything. This method is very important. Zebrafish are standard because they have most of the criteria for a good model. However, they are not very close to humans. Our first step is to start with the easiest, most visible, cheaper and faster model, then when we find a hypothesis that is more promising, we can test it in a much better model that is closer to humans. There is a balance between how close the model is to humans and how easy it is to do.”
For families, the main takeaway is to continue to follow advice, said Goldstein. Families should also be aware “that there are changes coming in our understanding of and in our approach to this problem. SIDS is the leading reason that babies die in the United States. We have not fully embraced SIDS as a clinical medical issue. With some luck, more studies, and more groups doing work like ours, that could change.”
Haghighi reinforced the importance of Robert’s Program in studying SUDP, naming academia as a springboard for medical innovation. “In health and disease, the first step starts from academia. We go and discover things. We learn about the mechanisms. We learn about the causes. When there is a critical mass of information, other sectors, like biotech and industry, take over and make diagnostics or therapeutics.”
When little is known about a disease, it’s difficult to take action, he explained. “SIDS has social, psychological and emotional implications. When the unknown is death, which is the most catastrophic event for a human, it causes a lot of different types of burdens. Families are torn apart because of one event. There’s no knowledge of what has happened. If we learn about the mechanisms and the factors, then the next step will be diagnostic approaches that will hopefully predict conditions. Then, we can strategize measures to prevent the event. Hopefully, we can identify or devise some methods, medications, or interventions that stop the mechanism and save lives.”
Koh added that “genes associated with epilepsy and cardiac diseases are frequently identified, even when the phenotype has not yet shown itself. Through this genetic work, we can establish evidence for these associations. Many of our results rely not only on academic findings but on the patients’ families as well as clinical accomplishments. This is a good example of precision medicine.”
A table included in the study outlines genetic variants that the researchers found especially important, including family histories of SIDS or SUDC, or family histories of febrile seizures.
According to Goldstein, “Parents worry about their other children or family members once SIDS or SUDC occurs. Providing this information to them allows them to take that information to their larger family, sometimes as reassurance and sometimes as an identified medical issue. There’s a really important dialogue that occurs between research and clinical care.”