Researchers Report New Gene Test For Isolated Cleft Lip And Palate

September 13, 2004

 Researchers have developed a new genetic test that can help predict whether parents who have one child with the "isolated" form of cleft lip or palate are likely to have a second child with the same birth defect. Isolated clefts account for 70 percent of all cleft lip and palate cases.

The National Institute of Environmental Health Sciences, the National Institute of Dental and Craniofacial Research, and the National Institute of General Medical Sciences provided funding for the study. All three agencies are components of the National Institutes of Health. The study results appear in the August 19 issue of the New England Journal of Medicine.

"This study shows that we've reached a point where it's possible to take blood samples from parents, test certain genes, and determine whether their risk for a second child with cleft lip or palate is, say, 1 percent or 20 percent," said Jeffrey Murray, M.D., a scientist at the University of Iowa and senior author on the study. "Now is the time to begin thinking about how best to apply these types of tests clinically and ensure that they truly benefit the families and their children."

Isolated clefts arise during fetal development from a dynamic interplay of genes, diet, and environmental factors, and current research tools are just beginning to cut through the complexity. Though the condition is usually correctable with several surgeries, families undergo tremendous emotional and economic hardship during the process. Children with this condition often require many other services, including complex dental care and speech therapy.

"These results show that a specific gene plays a crucial role in the development of isolated cleft lip and palate," said Dr. Kenneth Olden, director of NIEHS. "This discovery will provide parents with important information that will enable them to make informed decisions about future pregnancies."

According to Murray, babies born with the isolated form of cleft lip and palate do not have other birth defects often associated with this condition. Roughly one in every 600 babies in the United States is born with the isolated cleft lip and palate.

The authors say this latest gene test, when used with parents who already have one child with isolated cleft lip and palate, can predict this birth defect in subsequent children about 12 percent of the time. Utilizing this new gene test along with others that have already been developed, scientists now can collectively predict about 15 percent of isolated cleft lip and palate cases, impossible just a few years ago.

One of the first diagnostic tools of its kind, the gene test is based on distinct mutations in and around the gene IRF6, which encodes a specific protein that plays a vital role in the normal formation of the lips, palate, skin and genitalia during the early stages of development. The researchers found that mutations of the IRF6 gene are associated with an increased chance that a child would be born with a cleft lip or palate.

Two years ago, Murray and colleagues found that the IRF6 gene plays a role in Van der Woude Syndrome, a condition in which babies are born with clefts that are accompanied by other birth defects. There are more than 150 such syndromes, accounting for the remaining 30 percent of all cleft lip and palate.

Upon detailed analysis of the IRF6 gene, the researchers noticed a variation in the DNA sequence that they guessed may play a role in causing isolated clefts. The team reasoned the variation would somehow interfere with the normal biological activities of the IRF6 protein during tissue and organ development.

To test their hypothesis, the researchers focused their attention on a pool of 1,968 families, in Europe, South America, and Asia, with a history of isolated clefts. According to Murray, the rate of isolated clefts in some parts of the world, such as the Philippines, Brazil, and China, is even higher than in the United States. "We wanted to see whether the variation could be found across multiple ethnic and ancestral groups, or if it was confined to a single population."

When the researchers looked at the gene and nearby regions of the chromosome, they identified a total of 36 DNA variations, nine of which seemed to be associated with clefting. The individual variations were then assembled into a collective profile called a "haplotype." "What we found is that a particular haplotype is over-transmitted in some families with isolated clefts, suggesting a predictive association with the birth defect, and this was true in the populations that we analyzed from The Philippines, Denmark, and the United States."

Based on a detailed analysis of 1,316 families, the scientists estimated that the risk of parents with this haplotype having a second child with isolated cleft lip and palate is about 12 percent. As the researchers noted, their estimate is based on their analysis of the families and cannot be generalized to the broader public.

"For a complex trait like cleft lip and palate, this is a nice step forward because there may be dozens of genes that contribute to the condition," said Murray.