By Allison Hydzik
An innovative federal initiative to accelerate research into pediatric diseases and conditions will fund a University of Pittsburgh-led effort to examine the entire genomes of nearly 1,300 people to learn more about the causes of cleft lip and palate, and look for treatments.
In its first round of funding under the Gabriella Miller Kids First Research Act, the National Institutes of Health (NIH), Office of the NIH Director, selected a proposal from Pitt’s School of Dental Medicine and Graduate School of Public Health to sequence the whole genomes of 430 children with clefts and their parents. According to the NIH, this is among the largest whole genome sequencing efforts to examine an oral condition that it has ever initiated.
“This sequencing will provide a wealth of data that will be made available to scientists everywhere, providing the basis for years of research into causes, prevention and treatment of cleft lip and palate,” said project director and principal investigator Mary L. Marazita, Ph.D., professor and vice chair of the University of Pittsburgh School of Dental Medicine Department of Oral Biology, and director of the Center for Craniofacial and Dental Genetics (CCDG). “We are thrilled that our project was among the first funded and excited for the crucial information this effort will reveal.”
Cleft lip and palate are among the most common birth defects, affecting about 1 in 700 babies. It occurs when a baby’s lip or mouth does not form properly during pregnancy, leaving a gap that can make it hard for the child to eat or speak. In about 70 to 80 percent of cases, the cause is believed to be due at least in part to genetics, but other factors, such as smoking during pregnancy, can also contribute to the chance of having a child with cleft lip or palate.
“In addition to looking at variations in genes that might lead us to treatments, we’re also looking for answers for parents who have a child with a cleft and want to know if any future children are at risk,” said principal investigator Eleanor Feingold, Ph.D., professor of human genetics and senior associate dean at Pitt Public Health. “This project will help us improve genetic counseling so we can tell parents if their family is predisposed to cleft lips and palates or if it’s a genetic aberration that is highly unlikely to happen again.”
Dr. Marazita has studied cleft lip and palate since the 1980s, building a database of almost 6,000 families with the condition. The research team will mine that database for appropriate “trios” – mother, father and child with cleft lip or palate – who will have their whole genomes sequenced to find the variations that caused the child’s cleft. This will allow researchers to determine if the child’s cleft was from a variant passed along by one of the parents or if it arose spontaneously.
Pitt will provide DNA samples for 430 trios to the McDonnell Genome Institute at Washington University in St. Louis for sequencing. In about three months, the information will come back to Pitt for analysis and will be shared through a centralized data repository.
“We’re expecting to get more than 200 terabytes of data back. It takes a village to do this kind of work, and we are eager to tackle it,” said Dr. Marazita. “About two dozen co-investigators and major collaborators at institutes nationwide, including the University of Iowa and Johns Hopkins University, are assisting us.”
The Gabriella Miller Kids First Research Act – named for a girl who died of brain cancer on Oct. 26, 2013, at the age of 10 after working to raise support for research into childhood illnesses – amends the U.S. tax code to allow the NIH to direct the funding of $12 million in pediatric research projects each year for the next 10 years.
Additional co-investigators from Pitt on this project include Elizabeth Leslie, Ph.D., Seth Weinberg, Ph.D., Alexandre Vieira, D.D.S., Ph.D., and Manika Govil, Ph.D., from the School of Dental Medicine, and John Shaffer, Ph.D., of Pitt School of Public Health.