WEDNESDAY, Aug. 18, 2004 (HealthDayNews) -- A variation in a single gene plays a significant role in the development of a cleft lip or cleft palate, says a major international study involving almost 2,000 families.
The discovery -- the first of its kind -- should improve genetic counseling for families at increased risk for these types of birth defects. It could also speed research into preventing cleft deformities before they start.
"Because we now know that this gene is involved in clefting, it gives us some insights into the other kinds of genes or environmental factors that we might want to look at," said lead researcher Dr. Jeffrey C. Murray, of the University of Iowa.
His team's findings appear in the Aug. 19 issue of the New England Journal of Medicine.
Oral-facial clefting -- usually of the lip, palate or both -- is among the most common congenital defect, occurring in as many as one in every 1,000 pregnancies. Expert surgeons can now repair these types of deformities in children fortunate enough to have ready access to modern medical care, allowing most of them to lead normal, healthy lives.
The search for the underlying cause of these types of defects has proven more difficult, however, since no one factor seems to predominate.
"We think it's actually a mixture of genetics and environmental factors," Murray said. Maternal-fetal exposure to specific toxins such as benzodiazepines, dioxins and tobacco smoke are thought to play a role, as are genes.
But which genes? Until now, no study has had the statistical power to come to any definite conclusion.
In their research, Murray and his colleagues joined hands with researchers around the world, collecting data on more than 8,000 cleft-affected individuals in Brazil, Denmark, Japan, the United States and elsewhere.
They found a single mutation in a gene encoding a immune-related chemical called interferon regulatory factor 6 (IRF6) "looks like it explains about 12 percent of the cases," Murray said. In families that already have at least one member affected by cleft lip/palate, passing on the mutation could triple the chances -- from 3 percent to 9 percent -- that a baby is born with the defect, he said.
In the near term, the finding may have implications for genetic counseling. Used together with ultrasound, gene testing could help spot those pregnancies at risk for cleft defects, helping parents make tough decisions early on.
Early detection can make all the difference, Murray said.
"I just saw a family in the clinic last week, they had had a child born with a cleft a couple days before, and it had come as a complete surprise to them," Murray said. "In the delivery room, the doctors weren't exactly sure what to do right away, the family was distressed."
"If parents can know about this before delivery, it really allows them to prepare for it both emotionally and in terms of medical care," he added. "They might choose to deliver at a hospital that's a little better prepared to deal with a baby with a cleft, for example."
In the longer term, the discovery of gene variants such as IRF6 could further research into the constellation of factors that work together to cause clefts.
Until now, untangling the role of genes and environment in cleft deformities has been impossible, since it's been hard to separate the two. Identification of specific genes "will allow us to distinguish groups of patients from one another in a more subtle and specific way as we search for other genes, as well as environmental factors," explained Aravinda Chakravati, director of the Institute of Genetic Medicine at Johns Hopkins University.
Chakravati, whose commentary on the study appears in the same issue of the journal, said the finding "peels away one more layer of ignorance" in understanding cleft palate. In years to come, he said, women may be routinely tested to assess their babies' risk for cleft lip, cleft palate and other birth defects.
"If she had genes A, B, C and D, and had been exposed to some toxin, then that particular pregnancy might be at much greater risk," he speculated.
A better understanding of the causes of cleft lip/palate might even lead to ways of preventing the deformity.
"When we know the genes, we know the [developmental] biochemistry that isn't quite right," Chakravati explained. "And if we know that the biochemistry isn't quite right, we can think of specific therapies to correct it."
More information
To learn more about cleft lip/palate, visit the March of Dimes.
