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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Related publications
- Vikkula M, Mariman EC, Lui VC, Zhidkova NI, Tiller GE, Goldring MB, van Beersum SE, de Waal Malefijt MC, van den Hoogen FH, Ropers HH, et al. Autosomal dominant and recessive osteochondrodysplasias associated with the COL11A2 locus. Cell 1995; 80(3):431-7.
- Ghassibé M, Revencu N, Bayet B, Gillerot Y, Vanwijck R, Verellen-Dumoulin C, Vikkula M. Six families with van der Woude and/or popliteal pterygium syndrome: all with a mutation in the IRF6 gene. J. Med. Genet. 2004; 41(2):e15.
- Ghassibé M, Bayet B, Revencu N, Verellen-Dumoulin C, Gillerot Y, Vanwijck R, Vikkula M. Interferon regulatory factor-6: a gene predisposing to isolated cleft lip with or without cleft palate in the Belgian population. Eur. J. Hum. Genet. 2005; 13(11):1239-42.
- Desmyter L, Ghassibe M, Revencu N, Boute O, Lees M, François G, Verellen-Dumoulin C, Sznajer Y, Moncla A, Benateau H, Claes K, Devriendt K, Mathieu M,Van Maldergem L, Addor MC, Drouin-Garraud V, Mortier G, Bouma M, Dieux-Coeslier A, Genevieve D, Goldenberg A, Gozu A, Makrythanasis P, McEntagart U,Sanchez A, Vilain C, Vermeer S, Connell F, Verheij J, Manouvrier S, Pierquin G, Odent S, Holder-Espinasse M, Vincent-Delorme C, Gillerot Y, Vanwijck R, Bayet B, Vikkula M. IRF6 Screening of Syndromic and a priori Non-Syndromic Cleft Lip and Palate Patients: Identification of a New Type of Minor VWS Sign. Mol. Syndromol. 2010; 1(2):67-74.
- Ghassibe-Sabbagh M, Desmyter L, Langenberg T, Claes F, Boute O, Bayet B, Pellerin P, Hermans K, Backx L, Mansilla MA, Imoehl S, Nowak S, Ludwig KU,Baluardo C, Ferrian M, Mossey PA, Noethen M, Dewerchin M, François G, Revencu N, Vanwijck R, Hecht J, Mangold E, Murray J, Rubini M, Vermeesch JR,Poirel HA, Carmeliet P, Vikkula M. FAF1, a gene that is disrupted in cleft palate and has conserved function in zebrafish. Am. J. Hum. Genet. 2011; 88(2):150-61.
- Jaureguiberry G, De la Dure-Molla M, Parry D, Quentric M, Himmerkus N, Koike T, Poulter J, Klootwijk E, Robinette SL, Howie AJ, Patel V, Figueres ML,Stanescu HC, Issler N, Nicholson JK, Bockenhauer D, Laing C, Walsh SB, McCredie DA, Povey S, Asselin A, Picard A, Coulomb A, Medlar AJ, Bailleul-Forestier I, Verloes A, Le Caignec C, Roussey G, Guiol J, Isidor B, Logan C, Shore R, Johnson C, Inglehearn C, Al-Bahlani S, Schmittbuhl M, Clauss F, Huckert M, Laugel V, Ginglinger E, Pajarola S, Spartà G, Bartholdi D, Rauch A, Addor MC, Yamaguti PM, Safatle HP, Acevedo AC, Martelli-Júnior H, dos Santos Netos PE, Coletta RD, Gruessel S, Sandmann C, Ruehmann D, Langman CB, Scheinman SJ, Ozdemir-Ozenen D, Hart TC, Hart PS, Neugebauer U, Schlatter E, Houillier P, Gahl WA, Vikkula M, Bloch-Zupan A, Bleich M, Kitagawa H, Unwin RJ, Mighell A, Berdal A, Kleta R., Nephrocalcinosis (enamel renal syndrome) caused by autosomal recessive FAM20A mutations. Nephron Physiol. 2012; 122(1-2):1-6.
- de la Dure-Molla M1, Quentric M, Yamaguti PM, Acevedo AC, Mighell AJ, Vikkula M, Huckert M, Berdal A, Bloch-Zupan A. Pathognomonic oral profile of Enamel Renal Syndrome (ERS) caused by recessive FAM20A mutations. Orphanet. J. Rare Dis. 2014; 9:84.
