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Clin Genet. 2016 Jul;90(1):28-34. doi: 10.1111/cge.12675. Epub 2015 Oct 1.

IRF6 mutation screening in non-syndromic orofacial clefting: analysis of 1521 families.

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Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
The Genome Institute, Washington University School of Medicine, St. Louis, MO, USA.
Department of Oral Maxillofacial Surgery, Peking University School of Stomatology, Beijing, China.
Department of Pediatrics, University of Texas Health Science Center at Houston, Houston, TX, USA.
Department of Health Management and Policy, College of Public Health, University of Iowa, Iowa City, IA, USA.
Department of Epidemiology, Institute of Public Health, University of Southern Denmark, Odense, Denmark.
Foundation for the Community Control of Hereditary Diseases, Budapest, Hungary.
Department of Surgery, Plastic and Reconstructive Surgery, University of Colorado School of Medicine, Denver, CO, USA.
Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI, USA.
Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.


Van der Woude syndrome (VWS) is an autosomal dominant malformation syndrome characterized by orofacial clefting (OFC) and lower lip pits. The clinical presentation of VWS is variable and can present as an isolated OFC, making it difficult to distinguish VWS cases from individuals with non-syndromic OFCs. About 70% of causal VWS mutations occur in IRF6, a gene that is also associated with non-syndromic OFCs. Screening for IRF6 mutations in apparently non-syndromic cases has been performed in several modestly sized cohorts with mixed results. In this study, we screened 1521 trios with presumed non-syndromic OFCs to determine the frequency of causal IRF6 mutations. We identified seven likely causal IRF6 mutations, although a posteriori review identified two misdiagnosed VWS families based on the presence of lip pits. We found no evidence for association between rare IRF6 polymorphisms and non-syndromic OFCs. We combined our results with other similar studies (totaling 2472 families) and conclude that causal IRF6 mutations are found in 0.24-0.44% of apparently non-syndromic OFC families. We suggest that clinical mutation screening for IRF6 be considered for certain family patterns such as families with mixed types of OFCs and/or autosomal dominant transmission.


interferon regulatory factor 6; mutation screening; non-syndromic oral clefts; syndromic cleft

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