A cohort of UW researchers from the School of Dentistry and Institute for Stem Cell and Regenerative Medicine (ISCRM) assisted in the discovery of the genetic variant that helps explain the country of Finland’s high frequency and geographic distribution of cleft palate.
Cleft lip and cleft palate are some of the most common birth defects in people, affecting roughly one in every 700 babies. Across the world, cleft lip – when the upper lip is split – is more common than cleft palate – when the roof of the mouth (palate) is split – except in Finland, where cases of cleft palate are so common they flip the ratio of cleft lip to cleft palate.
The likely culprit is a DNA variant near the IRF6 gene. Previous studies had shown that DNA variation in IRF6 causes and contributes risk for both cleft lip and cleft palate. However, in this new study, researchers found the effect of this DNA variant only increases risk for cleft palate.
The UW School of Dentistry and ISCRM assisted geneticists Dr. Brian Schutte at Michigan State University, Dr. Fedik Rahimov at FinnGen, AbbVie Inc., and Dr. David Rice at the University of Helsinki, along with other key collaborators. They tie this IRF6 variant, which is found only in Finland and Estonia, to Finland’s high frequency of cleft palate. The team also connects this IRF6 variant to Finland’s pronounced geographic distribution of cleft palate cases, which become more frequent from the southwest to the northeast. This regional distribution of cleft palate has not been observed anywhere else in the world.
“Orofacial clefts, which is cleft lip, cleft palate, or a combination of the two, are among the most common congenital birth anomalies,” said Dr. Robert Cornell of the UW Department of Oral Health Sciences. “They are caused, most commonly, by a combination of genetic and environmental factors. This work clarifies the unusual prevalence of cleft palate over cleft lip in Finland and Estonia, which is the opposite of the trend in the rest of the world.”
The team of UW researchers, which included the teams of Drs. Cornell, Hannele Ruohola-Baker and Julie Mathieu (both from the ISCRM) identified which of the tested variants directly impacted the risk of cleft palate and determined how it did so. In their discovery, they found the causal variant disrupted the binding of a regulatory protein resulting in lower-than-normal expression of a gene that is essential for palate fusion.
In next steps, Dr. Schutte will work with the Michigan Department of Health and Human Services to genotype blood samples from Michigan’s BioTrust. These samples will come from babies born with cleft palates from Ontonagon, Houghton, Schoolcraft, Marquette and Chippewa counties, where a significant number of Michiganders with Finnish ancestry live. This research will help determine if environmental or other factors may be at play. Such findings would have clinical, risk and public health ramifications.
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Release written by E. LaClear of the Michigan State University College of Osteopathic Medicine, with additions by J. Swain of the UW School of Dentistry.
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