By Julie Kiefer, manager, science communications, University of Utah Health Sciences Office of Public Affairs

Being born with a severe heart defect was practically a death sentence 30 years ago. But as advances in medicine have given rise to generations of survivors, it’s emerging that over half have behavioral problems and difficulty keeping up academically. Two groups from the University of Utah School of Medicine were awarded $6.4 million from the National Institutes of Health’s Bench to Bassinet initiative to identify causes of these disabilities, and ways to intervene.

It’s estimated that up to 80 percent of these neurodevelopmental disabilities cases remain unexplained. While it was first assumed that the symptoms were side effects of their heart condition, or were triggered by surgical trauma – some kids undergo three open-heart surgeries by the time they are 1 year old – a research team led by Martin Tristani-Firouzi, M.D., is coming to the conclusion that for many of these cases, genetics is the culprit.

“What the field is coming around to is that mutations that cause congenital heart disease sometimes also cause central nervous system disorders. We think it’s the combined genetic insult that results in patients having developmental delay,” says Tristani-Firouzi, a pediatric cardiologist and associate professor of pediatrics. The research team is uncovering genetic mutations that affect both the heart and the brain.

Reasoning that most of the straightforward genetic lesions have already been identified – one mutation causing a specific disorder – patient genomes are also undergoing a new type of analysis that measures the cumulative effect of numerous small changes in a patient’s DNA, termed “genomic load.” “It examines the overall health of patient genomes,” explains co-investigator Mark Yandell, Ph.D., co-director of the Utah Science Technology and Research Center for Genetic Discovery and professor of human genetics, who developed the technique. “Certain mutations may hit particularly hard depending on what else is going on in the background.”

In parallel, the researchers are linking detailed accounts of patients’ behavioral and developmental challenges to the genetic data. The University Developmental Assessment Center, run by the Department of Pediatrics, examines children with CHDs at strategic developmental periods in their lives: as newborns, toddlers, just before kindergarten, and at early adolescence. “Not only does that give us an opportunity to intervene early, but it also allows us to track the kids to see if genetics leads to certain developmental outcomes,” says Sarah Winter, M.D., associate professor of pediatrics and the center’s medical director.

Combining clinical information with genomics will eventually allow researchers to construct a road map for precision medicine in CHD patients. “When a child shows up in the clinics, we’d like to be able to predict her long-term outcomes based on genomic sequence, so that treatment can be tailored accordingly,” says co-investigator H. Joseph Yost, Ph.D., Vice Chairman for Basic Science Research in Pediatrics and professor of neurobiology and anatomy. As principal investigator on the second grant awarded to the U, a renewal of a project initiated in 2009, he is also leading research to discover the biology behind how mutations cause disease, in an effort to develop new treatments.

The two projects join a third U clinical effort led by Richard Willliams, M.D., professor of pediatrics, funded by the NIH program since 2001. Out of over 30 institutions, the U is one of only two to be represented in all three of Bench to Bassinet’s directives: basic science, genomics, and clinical research.

U’s strengths stem from investments in multidisciplinary programs, including those designed to push an understanding of the genetic basis of disease. 1.5 years ago, the state-funded Utah Science Technology and Research initiative launched the Center for Genetic Discovery, which has since built a robust pipeline for DNA sequence analysis and innovative tools for deciphering genetic signatures that impact health. In addition, the extensive genealogies combined with medical records represented in the Utah Population Database has proven to be a powerful resource for identifying inherited genetic mutations that cause disease.

What these groups learn from Utah families will be used to help interpret genomic data from 10,000 patients throughout the nation, represented within the Bench to Bassinet consortium.

“Our highly collaborative team of pediatric clinicians, human geneticists and laboratory scientists at the University of Utah is focused on finding the causes of these devastating diseases that arise before birth and that cause problems throughout life,” says Yost. “The goal of this nationwide effort is to develop long-term treatment plans for these children.”