Researchers report they now can predict whether some parents are more likely than others to have a second child with the "isolated" form of cleft lip and palate, one of the world's most common birth defects, according to results of a study published this week in the "New England Journal of Medicine". The research was supported in part by the National Institute of Dental and Craniofacial Research and the National Institute of Environmental Health Sciences, part of the National Institutes of Health (NIH).

The authors say their latest gene test applies to about 12 per cent of isolated cleft lip and palate, or babies born with clefts only and no other birth defects. Last year, the authors and their colleagues reported that mutations in another gene account for about 2 per cent of all cases of isolated clefts, meaning researchers in the field now can collectively screen for about 15 per cent of isolated cleft lip and palate, an impossibility just a few years ago.
Isolated clefts account for 70 per cent of all cleft lip and palate, NIH said in a release.

In the latest paper, the scientists report a so-called "haplotype" gene test, one of the first of its kind in medicine. A haplotype is the sum of several recurring variations in the usual DNA sequence of a species that are spaced out, like signposts, along a gene or chromosome. In this case, they found that distinct combinations of sequence variations in and around the gene IRF6 correlated with an increased chance that a child would be born with a cleft. IRF6, which encodes a gene-activating protein called a transcription factor, plays a role during development in orchestrating the normal formation of the lips, palate, skin, and genitalia.

"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 or 20 per cent," said Jeffrey Murray, a scientist at the University of Iowa and the 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," he added.

According to Murray, roughly one in every 600 babies in the United States is born with the isolated, also called "non- syndromic," cleft lip and palate. Though the condition is usually correctable with several surgeries, families undergo tremendous emotional and economic hardship during the process, and children often require many other services, including complex dental care and speech therapy.

The challenge has been how to move the field forward. Isolated clefts arise during fetal development from a dynamic and still poorly understood interplay of genes, diet, and environmental factors, and current research tools cannot adequately cut through the complexity.

One productive inroad has been to isolate genes linked to "syndromic" cleft lip and palate, hoping some might also play a role in causing the isolated condition. Syndromic cleft lip and palate refers to babies born with clefts that are accompanied with other birth defects. There are over 150 of these syndromes, and, collectively, they account for about 30 percent of all cleft lip and palate.

Two years ago, Murray and colleagues Brian Schutte and Shinji Kondo hit the jackpot when they found the IRF6 gene plays a role in causing Van der Woude syndrome (VWS), the most common of the syndromic conditions. The discovery marked a potentially important lead because, about 15 per cent of people with VWS have malformations that are clinically indistinguishable from isolated cleft lip and palate, suggesting the gene might be involved in both types of clefting.

While studying the structure of IRF6, the group noticed a sequence variation that they thought might play a role in causing isolated clefts. Such variations, called single nucleotide polymorphisms, or SNPs, occur about every 1,000 bases in our DNA and are generally considered to be harmless.

What interested them about this specific SNP is it caused an amino acid change, substituting an isoleucine for the normal valine, precisely where the IRF6 protein attaches to other substrates. They reasoned the isoleucine insertion might somehow hamstring the protein's normal biological activities during tissue and organ development. Fueling their suspicions was the fact that the normal valine is tightly conserved from fish to humans, meaning if the valine was trivial, species along the evolutionary ladder might have altered it with greater frequency.

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.