A consortium of scientists supported by the National Institutes of Health reported today that it has identified two human genes that, when inherited in a slightly altered form, may play a role in causing cleft lip and/or palate (roof of the mouth), one of the world's most common congenital malformations. The finding, published online by the journal Nature Genetics, is unique in the study of congenital malformations because of how the discoveries were made. They come from the largest genome-wide association, or GWA, study to date on cleft lip and/or palate.
GWA studies allow researchers to survey the DNA of people with a shared condition to measure hundreds of thousands of different points across the genome that can be indicative of a nearby gene alteration. By working as a consortium and through the consent of more than 1,900 affected families from eight countries, the authors were able to detect variations close to genes called MAFB and ABCA4. The variations suggest that altered forms of these genes may be related to clefting. Had the researchers worked alone with their limited numbers of DNA samples, they likely would have lacked the needed statistical power to identify genes that are less frequently altered or have modest effects on the risk of developing a cleft.
As is standard for GWA studies, the discoveries were independently replicated by studying 1,965 more affected families from 12 countries, or a total of 8,115 people. Researchers later obtained additional DNA from participants born with a cleft, sequenced portions of the MAFB and ABCA4 genes, and identified protein-altering changes in some of these samples. Interestingly, they also found in studies with mice that MAFB is expressed early in the development of the head and face, including during the fusion of the roof of the mouth, an indication the Mafb protein is needed for the normal development of the palate. The scientists also confirmed in the GWA study the role of two previously reported genetic findings. "We confirmed that the previously identified gene IRF6 and a suspected segment of chromosome eight seem to be frequently altered in people born with clefts," said Terri Beaty, Ph. D., lead author on the study and a scientist at the Johns Hopkins University Bloomberg School of Public Health in Baltimore. "This finding pulls together past work, while the potential new genes help to move the science forward."
About 70 percent of babies born with a cleft lip/or palate have the isolated form, meaning they have no other associated birth defects. Among whites, isolated clefts occur in an estimated 1 in every 1,000 live births. The frequency seems to be even higher in some Asian countries, such as China and the Philippines, but lower among people of African descent. Though 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.
Families and physicians have long hoped for ways to prevent the problem before a baby is born, but solutions have been difficult to find. Isolated clefts arise early during fetal development from disruptions in the dynamic but still poorly understood interplay of genes, diet, and environment. The current study is part of the now four-year-old GENE enVironment Association studies consortium. The consortium was formed through the NIH-wide Genes, Environment, and Health Initiative, which supports studies to further scientific understanding of the interactions between genes and environment.
The cleft lip and/or palate GWA study was supported by the NIH's National Institute of Dental and Craniofacial Research, which also funded many of the research groups that contributed the samples used in the replication studies. The families in the GWA study were from the United States, Norway, Korea, Singapore, Taiwan, Denmark, the Philippines, and China. Approximately 50 percent of participants were Asian, 45 percent white, and about 5 percent African or other ancestry. The majority of the GWA genotyping was performed at the Center for Inherited Disease Research at Johns Hopkins University. The families in the replication study were from China, the Philippines, India, United States, Denmark, Hungary, Spain, Turkey, Ireland, Argentina, Colombia, and Guatemala. Replication genotyping primarily was done in the labs of Drs. Beaty, Murray, and Marazita. Investigators at NIH's National Institute of Child Health and Human Development and National Human Genome Research Institute contributed to this effort. "The study's multi-national nature was instrumental to its success," said Dr. Mary L. Marazita, Ph.D., a scientist at the University of Pittsburgh and an author on the study. "Drs. Beaty, Murray, and I had long-standing international collaborations that allowed us to assemble the very large sample sizes necessary for these genetic studies, which would not have been possible in any one country."
The National Institute of Dental and Craniofacial Research (NIDCR) is the Nation's leading funder of research on oral, dental, and craniofacial health. The National Institutes of Health (NIH) -- The Nation's Medical Research Agency -- includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit
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