FOXE1 association with both isolated cleft lip with or without cleft palate, and isolated cleft palate

Lina M. Moreno, Maria Adela Mansilla, Steve A. Bullard, Margaret E. Cooper, Tamara D. Busch, Junichiro Machida, Marla K. Johnson, David Brauer, Katherine Krahn, Sandy Daack-Hirsch, Jamie L'Heureux, Consuelo Valencia-Ramirez, Dora Rivera, Ana Maria López, Manuel A. Moreno, Anne Hing, Edward J. Lammer, Marilyn Jones, Kaare Christensen, Rolv T. LieAstanand Jugessur, Allen J. Wilcox, Peter Chines, Elizabeth Pugh, Kim Doheny, Mauricio Arcos-Burgos, Mary L. Marazita, Jeffrey C. Murray, Andrew C. Lidral

Research output: Contribution to journalArticlepeer-review

123 Scopus citations


Nonsyndromic orofacial clefts are a common complex birth defect caused by genetic and environmental factors and/or their interactions. A previous genome-wide linkage scan discovered a novel locus for cleft lip with or without cleft palate (CL/P) at 9q22-q33. To identify the etiologic gene, we undertook an iterative and complementary fine mapping strategy using family-based CL/P samples from Colombia, USA and the Philippines. Candidate genes within 9q22-q33 were sequenced, revealing 32 new variants. Concurrently, 397 SNPs spanning the 9q22-q33 2-LOD-unit interval were tested for association. Significant SNP and haplotype association signals (P = 1.45E - 08) narrowed the interval to a 200 kb region containing: FOXE1, C9ORF156 and HEMGN. Association results were replicated in CL/P families of European descent and when all populations were combined the two most associated SNPs, rs3758249 (P = 5.01E - 13) and rs4460498 (P = 6.51E - 12), were located inside a 70 kb high linkage disequilibrium block containing FOXE1. Association signals for Caucasians and Asians clustered 5′ and 3′ of FOXE1, respectively. Isolated cleft palate (CP) was also associated, indicating that FOXE1 plays a role in two phenotypes thought to be genetically distinct. Foxe1 expression was found in the epithelium undergoing fusion between the medial nasal and maxillary processes. Mutation screens of FOXE1 identified two family-specific missense mutations at highly conserved amino acids. These data indicate that FOXE1 is a major gene for CL/P and provides new insights for improved counseling and genetic interaction studies.

Original languageEnglish (US)
Pages (from-to)4879-4896
Number of pages18
JournalHuman molecular genetics
Issue number24
StatePublished - 2009
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by the National Institutes of Health [RO1-DE014667-8, KO2-AEO15291, a March of Dimes Basil O’Connor award # FY 98-0718 and Research Grant #6-FY01-616, a Cleft Palate Foundation Grant and an American Association of Orthodontics Foundation Faculty Development Award to A.C.L., DE-08559 to J.C.M., DE-11948 to K.C., P50-DE-16215 to M.L.M. and J.C.M., R01-DE016148 to M.L.M., R21-DE016930 to M.L.M., R01-DE09886 to M.L.M., R01-DE012472 to M.L.M. and Fogarty 1RO3-TW-007644 to J.C.M.]; and also by the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health. Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, Contract Number N01-HG-65403. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Dental and Craniofacial Research, or the National Institutes of Health.


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