An international team of pediatricians, surgeons, geneticists, and epidemiologists from 23 institutions across three continents have identified two areas of the human genome associated with the most common form of non-syndrome-related craniosynostosis ― premature closure of the bony plates of the skull.
"We have discovered two genetic factors that are strongly correlated with a common form of premature closure of the skull," said Simeon Boyadjiev, associate professor of pediatrics, principal investigator for the study and leader of the international collaboration.
"These findings may one day lead to prenatal diagnostic tests for this condition or early interventions to prevent the condition."
The study, "A genome-wide association study identifies susceptibility loci for non-syndromic sagittal craniosynostosis near BMP2 and within BBS9," is published online today in the journal, Nature Genetics.
During fetal 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 with a broad forehead. The disorder can lead to complications due to brain compression such as visual problems and learning disabilities. Depending on the severity, the condition may require extensive neurosurgical correction.
The most common form of 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. About 20 percent of cases of sagittal craniosynostosis have previously been linked to a number of different genetic disorders, but the vast majority of cases (not associated with a syndrome involving other birth defects) arise without any known family history or cause. These cases were the subject of the investigation.
Although the condition has long been thought to be partially determined by genes ― it is three times more common in boys than in girls, and identical twins are much more likely to both be affected than nonidentical 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 searches for single nucleotide polymorphisms (abbreviated as SNP and called "snips"), which are differences between the two populations in the base pairs ― the basic building blocks of DNA― of which there are some 3 billion in the human genome.
The study first evaluated the DNA ― extracted from whole blood or oral samples ― of 130 cases and both of their parents, who did not have the condition. Using related controls reduces the genetic variability inherent between different individuals. Their results identified 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.
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.
"No matter how we analyzed the data ― whether we included cases with other anomalies or mixed children of different ethnic groups together, these two genetic factors were significant," said Boyadjiev. "This provides strong evidence that non-syndrome-related sagittal craniosynostosis has a major genetic component and identifies where the problem is likely to originate."
Boyadjiev added that the genetic differences do not fully explain the development of the condition and that environmental factors are also likely important. He likened the condition to spina bifida: infants who develop this defect in their spine are known to have a genetic propensity, but vitamin supplementation with folic acid of pregnant women can prevent many cases. His laboratory is working to identify a marker in the blood of expectant mothers to identify risk during pregnancy and ideally find an intervention that can be administered during pregnancy to prevent the condition from developing.