An international research team that includes a University of Iowa investigator and representatives from 23 other institutions has successfully identified two areas of the human genome associated with a childhood disorder that leads to a premature closure of the bony plates of the skull. The study is published online in the journal Nature Genetics.

Paul Romitti

"We identified two genetic factors that are strongly associated with the most common form of premature closure of the skull,” says Paul Romitti, associate professor of epidemiology in the UI College of Public Health and director of the Iowa Registry for Congenital and Inherited Disorders. “These results represent many years of hard work by a multidisciplinary team of investigators dedicated to understanding the genetic causes of diseases in children.”

“The identification of these genetics factors will be a critical first step in determining how craniosynostosis might be prevented," says Simeon Boyadjiev, principal investigator for the study and leader of the International Craniosynostosis Consortium.

Craniosynostosis is a relatively common birth defect estimated to affect one in every 2,500 births. The skull is made of separate bony plates that allow for growth of the head. The borders between the plates do not normally fuse completely until a child is about two years old, leaving temporary "soft spots" at the intersection of the seams. Craniosynostosis can occur if the bones fuse too early, leading to possible complications such as intracranial pressure, seizures, and developmental delay.

Although this condition has long been thought to be partially determined by genes, the exact basis was unclear. To help determine the cause, the investigators conducted the first genome-wide association study for the disorder, which involved scanning the entire genome of a group of people with craniosynostosis and comparing it to a control group. The researchers identified differences in two areas of the genome that are known to play a role in skeletal development.

Romitti then led a study to replicate the findings in a separate group of children. The combined results provide strong evidence that nonsyndromic sagittal craniosynostosis has a major genetic component.

The researchers note that the genetic differences do not fully explain the development of the condition and that other genes and environmental factors are also likely important. Boyadijiev and Romitti plan to extend the research to find the exact disease-causing genetic variants, to identify contributing environmental factors, and to study other types of craniosynostosis in various ethnic groups.

“The identification of two biologically plausible candidate genes affecting susceptibility to nonsyndromic saggital craniosynostosis provides promising leads in the search for understanding of how these conditions develop,” says Emily Harris, chief of the translational genomics research branch at the National Institute of Dental and Craniofacial Research, one of several groups to fund the research, along with U.S. Centers for Disease Prevention, the Robert Wood Johnson Foundation, and others.