The findings, which appeared in the Dec. 15 issue of the journal Human Molecular Genetics, could improve genetic counseling and potentially lead to prevention or improved treatment of this type of birth defect.
Previous work by the UI team had identified a segment of the human genome called chromosome 9 as the location of an important genetic cause of cleft lip and palate. Through further analysis of DNA from affected families, the researchers have now identified a single gene on that chromosome as a root cause of these common birth defects that affect between one in 500 and one in 1,000 births worldwide. In Iowa, the occurrence is one in 650 births.
The gene, known as FOXE1, appears to contribute to cleft lip with or without cleft palate and to isolated cleft palate. Previously, these two forms of clefting were thought to arise from different genetic abnormalities.
“For us to find that this one gene actually is involved in both types of clefting is interesting because it suggests that this gene is involved very early in the development of both the lip and palate,” said Lina Moreno, Ph.D., assistant professor in the Department of Orthodontics at the UI College of Dentistry, who co-led the study with Adela Mansilla, Ph.D., a postdoctoral researcher in pediatrics at the UI Carver College of Medicine.
“In normal development, the lips form during the seventh week of pregnancy and then the palate forms by week 12. Our study suggests this gene is required for lip formation early on and then again, later, for palate formation,” Moreno added.
Although the UI study suggests that FOXE1 abnormalities contribute to cleft lip and cleft palate, the researchers have not yet found the exact mutation in the gene that causes clefting. Instead, they have identified a variation in the genetic code that acts as a marker for the mutation.
The variation appears to “travel” with the mutation that causes cleft lip and palate when the gene is inherited, and the study suggests that the presence of the variant contributes to approximately 20 percent of all clefts. The team found the variant in affected families from the United States, the Philippines, Columbia and Europe.
“The genetic finding was true across patient populations from around the world, which suggests it is a true finding and contributes risk for every population,” Moreno said. “Once we find the actual mutation within this gene that causes cleft lip and palate, we can better estimate people’s risk of having a cleft. So it has implications for genetic counseling.”
Genetic testing and counseling can help families prepare for the possibility that their child might be born with a cleft. For example, a family might choose to have their baby at a hospital capable of providing the multidisciplinary care needed to treat cleft lip or palate.
Although researchers do not yet know how FOXE1 abnormalities cause clefting, the gene might be part of a new pathway involved in lip and palate formation. In addition, FOXE1 is known to have role in formation of the thyroid gland, which might mean there is a connection between thyroid function and cleft lip and palate.
Understanding what the mutation does to the gene and which biological pathways are affected could potentially lead to new therapeutic approaches.
Moreno works with Andrew Lidral, D.D.S., Ph.D., UI professor of orthodontics, who was senior author of the study. Mansilla works in the lab of Jeff Murray, M.D., professor in the UI Carver College of Medicine, as well as colleges of dentistry, liberal arts and sciences, and public health.
The international research team also included scientists from University of Pittsburgh; University of Antioquia in Medellin, Columbia; University of Washington in Seattle; Children’s Hospital Oakland Research Institute in Oakland, Calif.; University of Southern Denmark; University of Bergen in Norway; Royal Children’s Hospital in Melbourne, Australia; the National Institutes of Health; and Johns Hopkins University.
“The study was funded in part by grants from the March of Dimes, the National Institutes of Health, the Cleft Palate Foundation and the American Association of Orthodontists Foundation.”
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