Genetic differences discovered in kids with premature skull closure

November 19, 2012

UNIVERSITY PARK, Pa. -- An international team of researchers from 23 institutions across three continents has identified two genetic factors that are strongly associated with the most common form of non-syndromic craniosynostosis -- premature closure of the bony plates of the skull. The team of geneticists, pediatricians, surgeons and epidemiologists includes Joan Richtsmeier, professor of anthropology at Penn State, and Yann Heuzé, a post-doc in the Richtsmeier lab.

During fetal and early childhood development, 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.

If the bones fuse too early -- the condition called craniosynostosis -- a child will develop an abnormally shaped head. Left untreated the disorder can cause learning disabilities and other complications due to brain compression, such as neurologic and visual problems. Typically, craniosynostosis requires extensive neurosurgical correction.

About 20 percent of craniosynostosis cases previously have been linked to a number of different genetic syndromes, the researchers note, but the vast majority of cases (not associated with a syndrome involving other birth defects) arise without any known family history or cause. The most common form of non-syndromic craniosynostosis -- affecting about 1 in 5,000 newborns -- involves the sagittal suture, the main seam that runs down the center of the top of the skull. These cases were the subject of the investigation.

Although the condition has long been thought to be partially determined by genes, since it is three times more common in boys than in girls, and identical twins are much more likely to both be affected than non-identical twins, the exact basis was unclear.

To help determine the cause, the researchers conducted the first genome-wide association study for the disorder, which involves scanning the entire genome of a group of people with craniosynostosis and comparing it to a control group of people without it. The study searched for single nucleotide polymorphisms (SNPs) that are associated with craniosynostosis. SNPs are DNA sequence variations in which a single nucleotide differs from the usual one at that position. There are some 3 billion nucleotides, the basic building blocks of DNA, in the human genome.

The study first evaluated the DNA, which was extracted from whole blood or oral samples, of 201 cases and both of their parents, who did not have the condition. After reviewing the morphological and ethnic details of each case, the researchers restricted their final analysis to a group of 130 non-Hispanic white case-parent trios. This approach reduced the genetic variability inherent to individuals from different ethnicities and the potential of mixing of patients with other diseases. Their results identified very strong associations to SNPs in two areas of the genome, coding for bone morphogenetic protein 2 (BMP2) and Bardet-Biedl syndrome 9 protein (BBS9). Both proteins are known to play a role in skeletal development.

Richtsmeier studies the processes of growth and development that translate genetic information into tissues of specific shapes and sizes, using computed tomography scans of patients with craniofacial diseases and animal models for those same conditions. Heuzé analyzed the computed tomography data of cases in this genetic analysis, both qualitatively to establish the degree of suture closure and quantitatively to estimate the magnitude of dysmorphology, to guarantee that the individuals whose genes were analyzed in the study showed physical traits of the disease and were not mixing the sample with outlier cases.

The findings were replicated in another population of 172 cases of children with the condition and 548 unrelated controls. The extensive international collaboration came about because of the desire to include as many cases as possible worldwide to strengthen the findings.

"Our results provide strong evidence that non-syndromic sagittal craniosynostosis has a major genetic component and identifies where the problem is likely to originate," said Simeon Boyadjiev, a researcher affiliated with the University of California Davis MIND Institute. "The genetic changes we discovered could provide important clues for explaining how craniosynostosis occurs. This will be a critical first step in determining how it might be prevented."

He added that the genetic differences do not fully explain the development of the condition and that other genes and environmental factors are also likely important. Further research is planned.

The researchers published their study online in the journal Nature Genetics.

Richtsmeier and Heuzé's involvement in the study was funded by grants from the National Institute of Dental and Craniofacial Research (National Institutes of Health) and the American Recovery and Reinvestment Act.

(Media Contacts)

Last Updated January 31, 2013