University of Iowa News Release
Aug. 19, 2004
photos: top, Theresa Zucchero, a study author and doctoral student in the UI Interdisciplinary Program in Genetics; bottom, Jeff Murray
Genetic Contributor To Cleft Lip and Palate Identified
Researchers from eight countries, led by a team at the University of Iowa, have identified a genetic variation that significantly increases the risk of a baby being born with cleft lip and palate, one of the most common birth defects in the world.
The finding helps explain 10 to 15 percent of all cases of the common form of cleft lip and palate and points scientists in new directions for improved prediction, prevention and treatment of the condition. The study results appear in the Aug. 19 issue of the New England Journal of Medicine.
"Cleft lip and palate is very complex, with genetic and environmental factors interacting together to cause these birth defects," said Jeff Murray, M.D., the study's principal investigator and professor of pediatrics in the UI Roy J. and Lucille A. Carver College of Medicine. "We hope this finding leads us to insights into other factors that might be involved, such as smoking or infection during pregnancy."
Understanding the interactive picture is key to helping patients in the future, particularly in terms of individualizing care. Currently, treatment can include surgery, speech therapy and dental care, yet outcomes vary.
"In future studies, if we make a correlation with a gene and the clinical outcome, then we might change the treatment approach, such as individualizing the timing of surgery or preventively providing nutritional supplements to mothers," said Murray, who also is a professor of pediatric dentistry and biological sciences.
In cleft lip and palate, the lip or both the lip and palate (roof of the mouth) fail to close. The facial defects occur in approximately one of every 1,000 babies, with some ethnic groups affected more than others.
The team analyzed genetic samples taken from 8,003 individuals in 1,968 families and found that a single change on a gene called Interferon Regulatory Factor 6 (IRF6) was responsible for 12 percent of the non-syndromic cleft lip and palate cases. The finding builds on a previous study from the labs of Brian Schutte, Ph.D., UI assistant professor of pediatrics, and Murray in which the teams discovered that an aberration on this same gene causes Van der Woude syndrome, a rare, syndromic form of cleft lip and palate.
Syndromic forms, of which there are about 400 different types, account for about 30 percent of cleft lip and palate cases. People with the syndromic forms have other physical problems, such as lip pits.
In the non-syndromic form of cleft lip and palate, the only birth defects occur in the lip or palate. About 70 percent of all people who are born with a cleft lip and palate have the non-syndromic form.
"We were interested in the relationships between common cleft lip and palate and the syndromic forms of the disease," said Theresa Zucchero, the study's lead author and a doctoral student in the UI Interdisciplinary Program in Genetics. "When the gene for Van der Woude was discovered, we decided to look at it in people with the common form of cleft lip and palate."
Zucchero generated the data to get the investigation started and then helped organize the DNA testing of thousands of study participants. "It was a huge collaborative effort among multiple labs in Asia, Europe and South America," she noted.
Murray said the gene is neither completely recessive nor dominant, and some people can have the gene defect but not have any facial defects. These complexities underscore that cleft lip and palate is caused by a genetic defect plus other "players" -- environmental factors and other genes.
In terms of prevention, Murray said it might be easier to manipulate environmental factors rather than initiating a genetic treatment. "For now we hold gene therapy in the background and look towards manipulating environmental factors," he said.
One of the next steps is to find the specific element that is changed in IRF6.
"Most likely, it is a single letter in the DNA sequence that is changed," Murray said. "There are thousands of letters that are potentially causing the problem so we need to search through them to find the one that is specific."
To find out which one it is, the team will go back to the DNA samples and do more sequencing, then statistical and functional analyses. Zucchero will also study how the effects of the gene lead to the different types of cleft lip and palate.
"I am interested in what changes occur at the molecular level that may be causing the birth defect," she said.
Zucchero first presented the IRF6 findings at the annual meeting of the American Society of Human Genetics that was held last fall in Los Angeles. Her paper was one of four -- out of a total of 2,700 -- that earned honors for "best paper" by a student or fellow.
In addition to Zucchero and Murray, a researcher on the team who made a major contribution to the paper was Mary Marazita, Ph.D., of the Center for Craniofacial and Dental Genetics in the University of Pittsburgh School of Dental Medicine.
The study was supported in part by grants from the National Institute for Dental and Craniofacial Research, the Canadian Institutes of Health, the Egmont Foundation, the March of Dimes Foundation and the National Institutes of Environmental Science.
For information on cleft lip and palate, visit the Virtual Hospital Web site http://www.vh.org/navigation/vh/topics/pediatric_patient_cleft_lip_and_palate.html
For information on the Van der Woude finding in 2002, see this UI news release: http://news-releases.uiowa.edu/2002/september/0903cleft-lip.html.
University of Iowa Health Care describes the partnership between the UI Roy J. and Lucille A. Carver College of Medicine and UI Hospitals and Clinics and the patient care, medical education and research programs and services they provide. Visit UI Health Care online at http://www.uihealthcare.com.
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Illustrative Image: http://www.nidr.nih.gov/news/digest/cleftPic.jpg
Caption: In cleft lip, there is a gap or split in the lip. The condition sometimes is accompanied by cleft palate, in which the roof of the mouth is not properly formed.
Credit: National Institute of Dental and Craniofacial Research.