Cleft lip and Palate

Involved group members: Miikka Vikkula, Nicole Revencu

Cleft lip and palate (CLP) is a congenital anomaly of complex etiology. Predisposition is governed by numerous genetic loci, in combination with environmental factors. Clefts have an incidence of 1/700 births.

We showed that IRF6 is the major causative gene of van der Woude syndrome (VWS) in our Belgian cohort (Ghassibé et al, 2005). This study led to several collaborations that allowed us to carry out a genotype-phenotype correlation on hundreds of patients from different ethnic backgrounds. Results showed that IRF6 is mutated in 69% of VWS patients and 97% of Popliteal Pterygium Syndrome (PPS) patients. Interestingly, mutation-distribution is non-random: 80% are localized in IRF6 exons 3, 4, 7 and 9 for VWS, and 72% in exon 4 for PPS patients (de Lima et al, 2009). These findings are of great importance for clinical diagnosis, mutational screens and genetic counseling. We also demonstrated that IRF6 predisposes to non-syndromic clefts in Europe and that it is mutated in familial clefts with minor lip anomalies (Desmyter et al, 2010). In parallel, we identified a new gene, FAF1, responsible for cleft palate only and Pierre Robin sequence (Ghassibé-Sabbagh et al, 2011). This gene is associated with clefts across populations. Zebrafish studies confirmed its role during embryonic development and jaw formation. We have begun to use Next Generation Sequencing (NGS) in an effort to uncover additional genes that play a role in non-syndromic orofacial clefts.



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