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The IRF6 p.274V polymorphism is not a risk factor for isolated cleft lip

2005; Elsevier BV; Volume: 7; Issue: 3 Linguagem: Inglês

10.1097/01.gim.0000157128.95526.79

1530-0366

Robert Hering, Kathrin Grundmann,

dental development and anomalies

To the Editor: Cleft lip (CL) with or without cleft palate (CP) is one of the most common birth defects in humans, with a prevalence of 1 in 700 worldwide.1.Bender P.L. Genetics of cleft lip and palate.1:STN:280:DC%2BD3cvjvVajtg%3D%3D10.1053/jpdn.2000.8148J Pediatr Nurs. 2000; 15: 242-249Google Scholar The majority of clefts are thought to display a multifactorial mode of inheritance.2.Fraser FC. The genetics of cleft lip and palate: yet another look. Pratt RM, Christiansen KL, eds. Current Research Trends in Prenatal Craniofacial Development. Elsevier: New York, 1980; 357–366.Google Scholar Recently, significant progress has been made with the identification of gene mutations in several forms of CL/P and CP, including the cell adhesion molecule PVRL13.Sozen M.A. Suzuki K. Tolarova M.M. Bustos T. Fernandez Iglesias J.E. Spritz R.A. Mutation of PVRL1 is associated with sporadic, non-syndromic cleft lip/palate in northern Venezuela.1:CAS:528:DC%2BD3MXnsFKgtb8%3D10.1038/ng740Nat Genet. 2001; 29: 141-142Google Scholar and the transcription factors MSX1,4.Jezewski P.A. Vieira A.R. Nishimura C. Ludwig B. Johnson M. O'Brien S.E. Complete sequencing shows a role for MSX1 in non-syndromic cleft lip and palate.1:CAS:528:DC%2BD3sXlvV2ksbg%3D10.1136/jmg.40.6.399J Med Genet. 2003; 40: 399-407Google Scholar,5.van den Boogaard M.J. Dorland M. Beemer F.A. van Amstel H.K. MSX1 mutation is associated with orofacial clefting and tooth agenesis in humans.1:CAS:528:DC%2BD3cXisVCjsLk%3D10.1038/74155Nat Genet. 2000; 24: 342-343Google Scholar TBX22,6.Braybrook C. Doudney K. Marcano A.C. Arnason A. Bjornsson A. Patton M.A. The T-box transcription factor gene TBX22 is mutated in X-linked cleft palate and ankyloglossia.1:CAS:528:DC%2BD3MXnsFKgurg%3D10.1038/ng730Nat Genet. 2001; 29: 179-183Google Scholar and IRF6,7.Kondo S. Schutte B.C. Richardson R.J. Bjork B.C. Knight A.S. Watanabe Y. Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes.1:CAS:528:DC%2BD38XotlaisLY%3D10.1038/ng985Nat Genet. 2002; 32: 285-289Google Scholar respectively. Originally, mutations in the IRF6 gene7.Kondo S. Schutte B.C. Richardson R.J. Bjork B.C. Knight A.S. Watanabe Y. Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes.1:CAS:528:DC%2BD38XotlaisLY%3D10.1038/ng985Nat Genet. 2002; 32: 285-289Google Scholar have been found to be associated with Van der Woude syndrome, a rare monogenic and syndromic form of cleft lip and palate associated with lip pits. However, Zucchero and coworkers8.Zucchero T.M. Cooper M.E. Maher B.S. Daack-Hirsch S. Nepomuceno B. Ribeiro L. Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate.1:CAS:528:DC%2BD2cXntVeitLc%3D10.1056/NEJMoa032909N Engl J Med. 2004; 351: 769-780Google Scholar recently suggested that a frequent polymorphism in the IRF6 gene might influence the development of nonsyndromic cleft lip. The authors state that the common p.274V polymorphism in the IRF6 gene triples the risk of recurrence of isolated cleft lips in families with one affected child.8.Zucchero T.M. Cooper M.E. Maher B.S. Daack-Hirsch S. Nepomuceno B. Ribeiro L. Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate.1:CAS:528:DC%2BD2cXntVeitLc%3D10.1056/NEJMoa032909N Engl J Med. 2004; 351: 769-780Google Scholar Because this fact would be an important consideration in genetic counseling, we investigated this polymorphism in a healthy German population. In general, one can safely assume that a subpopulation with a 3-fold increased risk must not exceed one third of the entire population. The authors defined the risk population as couples who might have a child homozygous for the p.274V polymorphism.8.Zucchero T.M. Cooper M.E. Maher B.S. Daack-Hirsch S. Nepomuceno B. Ribeiro L. Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate.1:CAS:528:DC%2BD2cXntVeitLc%3D10.1056/NEJMoa032909N Engl J Med. 2004; 351: 769-780Google Scholar Accordingly, the frequency of the risk allele should not exceed 35% in order to explain a 3-fold risk, among parents with an affected child as well as in the entire population. In Asians, which were predominantly investigated, the p.274V allele frequency has been estimated to be 66%.7.Kondo S. Schutte B.C. Richardson R.J. Bjork B.C. Knight A.S. Watanabe Y. Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes.1:CAS:528:DC%2BD38XotlaisLY%3D10.1038/ng985Nat Genet. 2002; 32: 285-289Google Scholar,8.Zucchero T.M. Cooper M.E. Maher B.S. Daack-Hirsch S. Nepomuceno B. Ribeiro L. Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate.1:CAS:528:DC%2BD2cXntVeitLc%3D10.1056/NEJMoa032909N Engl J Med. 2004; 351: 769-780Google Scholar Congruously, 78% of Asian couples are expected to belong to the so called “risk population.” Based on these data, a 3-fold risk is not allegeable. Zucchero and coworkers8.Zucchero T.M. Cooper M.E. Maher B.S. Daack-Hirsch S. Nepomuceno B. Ribeiro L. Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate.1:CAS:528:DC%2BD2cXntVeitLc%3D10.1056/NEJMoa032909N Engl J Med. 2004; 351: 769-780Google Scholar describe p.274V allele frequencies of 100% in 102 Europeans and 156 Africans, and of 97.5% in 200 Pakistani, respectively. We therefore investigated 193 German control individuals, all of whom displayed the p.274V variant. Of these, 192 subjects were homozygous, and one subject was heterozygous for the p.274V variant (allele frequency 97.7%). These results indicate that nearly all individuals of Caucasian, African, and Pakistani descent are carriers of the “risk allele.” We therefore argue that p.274V is not suitable for specifying the risk of recurrence of isolated cleft lip. Thus the p.274V polymorphism is irrelevant for genetic counseling.