The unexpected death of a child is tragic under any circumstance, but it becomes even more so when the reason behind it is unknown. When a traditional autopsy comes up empty, an interdisciplinary team from the University of Utah School of Medicine will dig deeper, searching for clues in the deceased’s genetic code.
As a pediatric cardiologist, Martin Tristani-Firouzi, M.D., is all too familiar with the fact that a malfunctioning heart is often to blame in cases of sudden unexpected death in the young. And when it comes to grave health conditions in children, the cause is typically thought to be genetic. With funding from the National Heart Lung and Blood Institute, he and computational biologist and co-lead investigator Mark Yandell, Ph.D., have created the Utah SDY (Sudden Death in the Young) Center, a team of physicians, geneticists, bioinformaticists, and genetic counselors. Using advanced bioinformatics technologies, they are scouring the genomes of young victims for glitches that may be responsible. These include defects already known to weaken the heart, and ones that have yet to be identified.
“We see this as an opportunity to help families, and to broaden our knowledge about genetic changes that lead to sudden death,” says Tristani-Firouzi. Previously unidentified candidates will be put to the test in the laboratory to determine whether they cause abnormalities in model systems. Does altering DNA in the same way cause a heart to beat irregularly, or cells to become malformed?
Reasoning that most of the straightforward genetic lesions have already been found – a single mutation causing a specific disorder – the center will also perform a new type of genomic analysis that measures the cumulative effect of numerous small changes, termed “genomic load”. “It examines the overall health of an individual’s genome,” explains Yandell, also co-director of the USTAR Center for Genetic Discovery, who developed the technique. Just as someone with a fragile immune system is more susceptible to getting the flu or pneumonia, someone with a weakened genome may be more vulnerable to changes that would otherwise be relatively harmless. “Certain mutations that typically have little to no effect may hit particularly hard if there is already a lot going on in the background,” Yandell says.
It’s not just the deceased’s DNA that has secrets to tell, the investigators postulate, but also their cells. Typically, liver or skin cells are sampled as part of an autopsy procedure. Using induced pluripotent stem (iPS) cell technology, the skin cells can be transformed into stem cells and then directed into forming heart cells. At this point they can be tested for mechanical or physiological defects that may have put the child at risk. Basic investigations like these could eventually lead to new diagnostics and approaches to treatment.
Just as important, the information could help identify living family who are also at risk for a familial disorder that threatens their health, or survival. “The real tragedy of sudden cardiac deaths is that they are largely preventable,” says Tristani-Firouzi. He adds that unlike twenty years ago, today many heart conditions can be mitigated with medicine or surgery. Once a plausible cause of death is found, family members can undergo genetic screening, or monitored for early signs of heart disease.
“Our goal is to turn stories of despair into stories of hope,” says Tristani-Firouzi.