Researchers awarded $6.4 million grant to identify causes of neurodevelopmental disorders in children with CHDs

As advances in medicine are giving rise to growing numbers of children who are surviving severe heart defects, a phenomenon is emerging that is catching parents and healthcare providers off-guard. Over half of these children also have a seemingly unrelated disability: neurodevelopmental disorders. Some have severe cognitive and motor deficits that arise early. A greater proportion has social and behavioral difficulties that often don’t surface until they start having trouble in school. Inattention, hyperactivity, disruptive behaviors, and difficulty keeping up academically are among these symptoms and may create long term struggles if left unrecognized and untreated.

Two research groups at the University of Utah School of Medicine were awarded grants totaling $6.4 million from the National Heart, Lung, and Blood Institute (NHLBI) aimed in part at identifying causes of these disabilities so that health care providers can better predict who is at risk, and intervene early. The studies are part of the Bench to Bassinet initiative, which fosters collaborations between basic science and clinical researchers across the U.S. and Canada to improve outcomes for patients with CHD, the most common birth defect.

It’s estimated that up to 80 percent of developmental disability cases in patients with congenital heart defects (CHDs) remain unexplained. They cannot be traced to common risk factors, such as trauma or complications at birth. “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 principal investigator on one of the projects, Martin Tristani-Firouzi, M.D., a pediatric cardiologist and associate professor of pediatrics.

To get at the root of the problem, researchers are linking detailed accounts of patients’ behavioral and developmental challenges, to genetic data. The University Developmental Assessment Center, run by the Department of Pediatrics and launched on July 1, 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.

In parallel, the research team is searching for genetic mutations that affect both the brain and the heart. Reasoning that most of the straightforward genetic lesions have already been identified – one mutation causing a specific disorder – patient genomes will also undergo 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 USTAR 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.”

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 of 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 of U clinical effort led by Richard Willliams, M.D., professor of pediatrics, funded by NHLBI since 2001. Out of over 30 institutions, the U of 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 of 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 (USTAR) 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 (UPDB) 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 nation-wide effort is to develop long-term treatment plans for these children.”

University of Utah Health Sciences