[en] Van der Woude syndrome (VWS), caused by dominant IRF6 mutation, is the most common cleft syndrome. In 15% of the patients, lip pits are absent and the phenotype mimics isolated clefts. Therefore, we hypothesized that some of the families classified as having non-syndromic inherited cleft lip and palate could have an IRF6 mutation. We screened in total 170 patients with cleft lip with or without cleft palate (CL/P): 75 were syndromic and 95 were a priori part of multiplex non-syndromic families. A mutation was identified in 62.7 and 3.3% of the patients, respectively. In one of the 95 a priori non-syndromic families with an autosomal dominant inheritance (family B), new insights into the family history revealed the presence, at birth, of lower lip pits in two members and the diagnosis was revised as VWS. A novel lower lip sign was observed in one individual in this family. Interestingly, a similar lower lip sign was also observed in one individual from a 2nd family (family A). This consists of 2 nodules below the lower lip on the external side. In a 3rd multiplex family (family C), a de novo mutation was identified in an a priori non-syndromic CL/P patient. Re-examination after mutation screening revealed the presence of a tiny pit-looking lesion on the inner side of the lower lip leading to a revised diagnosis of VWS. On the basis of this data, we conclude that IRF6 should be screened when any doubt rises about the normality of the lower lip and also if a non-syndromic cleft lip patient (with or without cleft palate) has a family history suggestive of autosomal dominant inheritance.
Bailey CM, Abbott DE, Margaryan NV, Khalkhali- Ellis Z, Hendrix MJ: Interferon regulatory factor 6 promotes cell cycle arrest and is regulated by the proteasome in a cell cycle-dependent manner. Mol Cell Biol 28: 2235-2243 (2008).
Birnbaum S, Reutter H, Lauster C, Scheer M, Schmidt G, et al: Mutation screening in the IRF6-gene in patients with apparently nonsyndromic orofacial clefts and a positive family history suggestive of autosomal-dominant inheritance. Am J Med Genet A 146A:787-790 (2008).
Blanton SH, Cortez A, Stal S, Mulliken JB, Finnell RH, Hecht JT: Variation in IRF6 contributes to nonsyndromic cleft lip and palate. Am J Med Genet A 137A:259-262 (2005).
Brosch S, Baur M, Blin N, Reinert S, Pfister M: A novel IRF6 nonsense mutation (Y67X) in a German family with Van der Woude syndrome. Int J Mol Med 20: 85-89 (2007).
de Lima RL, Hoper SA, Ghassibe M, Cooper ME, Rorick NK, et al: Prevalence and nonrandom distribution of exonic mutations in interferon regulatory factor 6 in 307 families with Van der Woude syndrome and 37 families with popliteal pterygium syndrome. Genet Med 11: 241-247 (2009).
Du XY, Tang W, Tian WD, Li XY, Liu L, Zheng XH: Identification of three novel mutations of IRF6 in Chinese families with Van der Woude syndrome. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 23: 82-83 (2006).
Ghassibe 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 41:e15 (2004).
Ghassibe 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 13: 1239-1242 (2005).
Gorlin R, Cohen MJ, Hennekam R: Syndromes of the Head and Neck: Orofacial Clefting Syndromes: Common Syndromes, ed 4 (Oxford University Press, New York 2001).
Haines J, Korf B, Morton C, Seidman C, Seidman J, Smith D: Current protocols in human genetics. Forensic Genetics 4: 14.3.8 (2000).
Item CB, Turhani D, Thurnher D, Yerit K, Sinko K, et al: Van Der Woude syndrome: variable penetrance of a novel mutation (p.Arg 84Gly) of the IRF6 gene in a Turkish family. Int J Mol Med 15: 247-251 (2005).
Jehee FS, Burin BA, Rocha KM, Zechi-Ceide R, Bueno DF, et al: Novel mutations in IRF6 in nonsyndromic cleft lip with or without cleft palate: when should IRF6 mutational screening be done? Am J Med Genet A 149A:1319-1322 (2009).
Kayano S, Kure S, Suzuki Y, Kanno K, Aoki Y, et al: Novel IRF6 mutations in Japanese patients with Van der Woude syndrome: two missense mutations (R45Q and P396S) and a 17-kb deletion. J Hum Genet 48: 622-628 (2003).
Kim Y, Park JY, Lee TJ, Yoo HW: Identification of two novel mutations of IRF6 in Korean families affected with Van der Woude syndrome. Int J Mol Med 12: 465-468 (2003).
Kondo S, Schutte BC, Richardson RJ, Bjork BC, Knight AS, et al: Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes. Nat Genet 32: 285-289 (2002).
Lacombe D, Pedespan JM, Fontan D, Chateil JF, Verloes A: Phenotypic variability in van der Woude syndrome. Genet Couns 6: 221-226 (1995).
Ng PC, Henikoff S: SIFT: Predicting amino acid changes that affect protein function. Nucleic Acids Res 31: 3812-3814 (2003).
Park JW, McIntosh I, Hetmanski JB, Jabs EW, Vander Kolk CA, et al: Association between IRF6 and nonsyndromic cleft lip with or without cleft palate in four populations. Genet Med 9: 219-227 (2007).
Peyrard-Janvid M, Pegelow M, Koillinen H, Larsson C, Fransson I, et al: Novel and de novo mutations of the IRF6 gene detected in patients with Van der Woude or popliteal pterygium syndrome. Eur J Hum Genet 13: 1261-1267 (2005).
Ramensky V, Bork P, Sunyaev S: Human nonsynonymous SNPs: server and survey. Nucleic Acids Res 30: 3894-3900 (2002).
Richardson RJ, Dixon J, Malhotra S, Hardman MJ, Knowles L, et al: Irf6 is a key determinant of the keratinocyte proliferation-differentiation switch. Nat Genet 38: 1329-1334 (2006).
Rizos M, Spyropoulos MN: Van der Woude syndrome: a review. Cardinal signs, epidemiology, associated features, differential diagnosis, expressivity, genetic counselling and treatment. Eur J Orthod 26: 17-24 (2004).
Sabel JL, d'Alencon C, O'Brien EK, Van Otterloo E, Lutz K, et al: Maternal Interferon Regulatory Factor 6 is required for the differentiation of primary superficial epithelia in Danio and Xenopus embryos. Dev Biol 325: 249-262 (2009).
Scapoli L, Palmieri A, Martinelli M, Pezzetti F, Carinci P, Tognon M, Carinci F: Strong evidence of linkage disequilibrium between polymorphisms at the IRF6 locus and nonsyndromic cleft lip with or without cleft palate, in an Italian population. Am J Hum Genet 76: 180-183 (2005).
Srichomthong C, Siriwan P, Shotelersuk V: Significant association between IRF6 820G → A and non-syndromic cleft lip with or without cleft palate in the Thai population. J Med Genet 42:e46 (2005).
Suazo J, Santos JL, Jara L, Blanco R: Linkage disequilibrium between IRF6 variants and nonsyndromic cleft lip/palate in the Chilean population. Am J Med Genet A 146A:2706-2708 (2008).
Sunyaev S, Ramensky V, Koch I, Lathe W 3rd, Kondrashov AS, Bork P: Prediction of deleterious human alleles. Hum Mol Genet 10: 591-597 (2001).
Thomas PD, Campbell MJ, Kejariwal A, Mi H, Karlak B, et al: PANTHER: a library of protein families and subfamilies indexed by function. Genome Res 13: 2129-2141 (2003).
Thomas PD, Kejariwal A: Coding single-nucleotide polymorphisms associated with complex vs. Mendelian disease: evolutionary evidence for differences in molecular effects. Proc Natl Acad Sci USA 101: 15398-15403 (2004).
Tolarova MM, Cervenka J: Classification and birth prevalence of orofacial clefts. Am J Med Genet 75: 126-137 (1998).
Van Der Woude A: Fistula labii inferioris congenita and its association with cleft lip and palate. Am J Hum Genet 6: 244-256 (1954).
Vieira AR, Cooper ME, Marazita ML, Orioli IM, Castilla EE: Interferon regulatory factor 6 (IRF6) is associated with oral-facial cleft in individuals that originate in South America. Am J Med Genet A 143A:2075-2078 (2007).
Vieira AR, Seymen F, Patir A, Menezes R: Evidence of linkage disequilibrium between polymorphisms at the IRF6 locus and isolate tooth agenesis, in a Turkish population. Arch Oral Biol 53: 780-784 (2008).
Wang X, Liu J, Zhang H, Xiao M, Li J, et al: Novel mutations in the IRF6 gene for Van der Woude syndrome. Hum Genet 113: 382-386 (2003).
Wang XF, Xiao MZ, Shi JN, Zhang HB, Hu LD, Kong XY: IRF6 gene mutation analysis in a van Der Woude syndrome family in Henan province. Shanghai Kou Qiang Yi Xue 14: 234-237 (2005).
Zucchero TM, Cooper ME, Maher BS, Daack- Hirsch S, Nepomuceno B, et al: Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate. N Engl J Med 351: 769-780 (2004).
