Nonsyndromic orofacial clefting (nsOFC) is a common, complex congenital disorder. The most frequent forms are nonsyndromic cleft lip with or without cleft palate (nsCL/P) and nonsyndromic cleft palate only (nsCPO). Although they are generally considered distinct entities, a recent study has implicated a region around the FOXE1 gene in both nsCL/P and nsCPO. To investigate this hypothesis, we analyzed the 2 most strongly associated markers (rs3758249 and rs4460498) in 2 independent samples of differing ethnicities: Central European (949 nsCL/P cases, 155 nsCPO cases, 1163 controls) and Mayan Mesoamerican (156 nsCL/P cases, 10 nsCPO cases, 338 controls). While highly significant associations for both single-nucleotide polymorphisms were obtained in nsCL/P (rs4460498: pEurope = 6.50 × 10-06, pMayan =.0151; rs3758249: pEurope = 2.41 × 10-05, pMayan =.0299), no association was found in nsCPO (p >.05). Genotyping of rs4460498 in 472 independent European trios revealed significant associations for nsCL/P (p =.016) and nsCPO (p =.043). A meta-analysis of all data revealed a genomewide significant result for nsCL/P (p = 1.31 × 10-08), which became more significant when nsCPO cases were added (pnsOFC = 1.56 × 10-09). These results strongly support the FOXE1 locus as a risk factor for nsOFC. With the data of the initial study, there is now considerable evidence that this locus is the first conclusive risk factor shared between nsCL/P and nsCPO.

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Keywords association study, case-control, cleft lip, cleft palate, genetic model, single-nucleotide polymorphism
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Journal Journal of Dental Research
Ludwig, K.U, Böhmer, M.R, Rubini, M, Mossey, P.A, Herms, S, Nowak, S, … Mangold, E. (2014). Strong association of variants around FOXE1 and orofacial clefting. Journal of Dental Research, 93(4), 376–381. doi:10.1177/0022034514523987