Background Cleft lip or palate (or the two in combination) isa common birth defect that results from a mixture of geneticand environmental factors. We searched for a specific geneticfactor contributing to this complex trait by examining largenumbers of affected patients and families and evaluating a specificcandidate gene.
Methods We identified the gene that encodes interferon regulatoryfactor 6 (IRF6) as a candidate gene on the basis of its involvementin an autosomal dominant form of cleft lip and palate, Van derWoude's syndrome. A single-nucleotide polymorphism in this generesults in either a valine or an isoleucine at amino acid position274 (V274I). We carried out transmission-disequilibrium testingfor V274I in 8003 individual subjects in 1968 families derivedfrom 10 populations with ancestry in Asia, Europe, and SouthAmerica, haplotype and linkage analyses, and case–controlanalyses, and determined the risk of cleft lip or palate thatis associated with genetic variation in IRF6.
Results Strong evidence of overtransmission of the valine (V)allele was found in the entire population data set (P<10–9);moreover, the results for some individual populations from SouthAmerica and Asia were highly significant. Variation at IRF6was responsible for 12 percent of the genetic contribution tocleft lip or palate and tripled the risk of recurrence in familiesthat had already had one affected child.
Conclusions DNA-sequence variants associated with IRF6 are majorcontributors to cleft lip, with or without cleft palate. Thecontribution of variants in single genes to cleft lip or palateis an important consideration in genetic counseling.
Source Information
From the University of Iowa, Iowa City (T.M.Z., S.D.-H., D.C., A.R.V., R.E.S., M.S., M.K.J., S.K., B.C.S., J.C.M.); School of Dental Medicine, University of Pittsburgh, Pittsburgh (M.E.C., B.S.M., T.H.G., M.L.M.); HOPE Foundation, Bacolod City, Philippines (B.N.); Hospital for Rehabilitation of Craniofacial Anomalies, University of Sao Paulo, Sao Paulo (L.R.); Institute of Public Health, University of Southern Denmark, Odense (K.C., J.C.M.); School of Dentistry, Aichi-Gakuin University, Nagoya, Japan (Y.S., J.M., N.N.); Nagasaki University School of Medicine, Nagasaki, Japan (K.-I.Y.); Estudio Colaborativo Latino Americano de Malformaciones Congénitas (ECLAMC), Federal University of Rio de Janeiro, Rio de Janeiro (I.M.O.); ECLAMC, Oswaldo Cruz Foundation, Rio de Janeiro, and Consejo de Investigationes Scientíficas y Técnicas, Buenos Aires (E.E.C.); College of Dentistry, University of Iowa, Iowa City (L.M., A.C.L.); Institute of Biology, University of Antioquia, Medellin, Colombia (M.A.-B.); University of British Columbia, Vancouver, Canada (L.L.F.); Zhabei Genetics Institute, Shanghai, China (Y.L.); and University of Toronto, Toronto (A.R.).
Address reprint requests to Dr. Murray at the University of Iowa, S. Grand Ave., 2182 ML, Iowa City, IA 52242, or at jeff-murray{at}uiowa.edu.
Pegelow, M., Peyrard-Janvid, M., Zucchelli, M., Fransson, I., Larson, O., Kere, J., Larsson, C., Karsten, A.
(2008). Familial non-syndromic cleft lip and palate--analysis of the IRF6 gene and clinical phenotypes. Eur J Orthod
30: 169-175
[Abstract][Full Text]
Lees, M.
(2008). Familial risks of oral clefts. BMJ
336: 399-399
[Full Text]
Vieira, A.R.
(2008). Unraveling Human Cleft Lip and Palate Research. J. Dent. Res.
87: 119-125
[Abstract][Full Text]
Romitti, P. A., Sun, L., Honein, M. A., Reefhuis, J., Correa, A., Rasmussen, S. A., the National Birth Defects Prevention Study,
(2007). Maternal Periconceptional Alcohol Consumption and Risk of Orofacial Clefts. Am J Epidemiol
166: 775-785
[Abstract][Full Text]
Chiquet, B. T., Lidral, A. C., Stal, S., Mulliken, J. B., Moreno, L. M., Arco-Burgos, M., Valencia-Ramirez, C., Blanton, S. H., Hecht, J. T.
(2007). CRISPLD2: a novel NSCLP candidate gene. Hum Mol Genet
16: 2241-2248
[Abstract][Full Text]
Cunningham, M. L.
(2007). Is Cleft Lip and Palate Ever Isolated?: Phenotype Is in the Eye of the Beholder. Arch Pediatr Adolesc Med
161: 811-812
[Full Text]
Riley, B. M., Mansilla, M. A., Ma, J., Daack-Hirsch, S., Maher, B. S., Raffensperger, L. M., Russo, E. T., Vieira, A. R., Dode, C., Mohammadi, M., Marazita, M. L., Murray, J. C.
(2007). Impaired FGF signaling contributes to cleft lip and palate. Proc. Natl. Acad. Sci. USA
104: 4512-4517
[Abstract][Full Text]
Thulstrup, A. M., Bonde, J. P.
(2006). Maternal occupational exposure and risk of specific birth defects. Occup Med (Lond)
56: 532-543
[Abstract][Full Text]
Park, J W, Cai, J, McIntosh, I, Jabs, E W, Fallin, M D, Ingersoll, R, Hetmanski, J B, Vekemans, M, Attie-Bitach, T, Lovett, M, Scott, A F, Beaty, T H
(2006). High throughput SNP and expression analyses of candidate genes for non-syndromic oral clefts. J. Med. Genet.
43: 598-608
[Abstract][Full Text]
Leoyklang, P, Siriwan, P, Shotelersuk, V
(2006). A mutation of the p63 gene in non-syndromic cleft lip.. J. Med. Genet.
43: e28-e28
[Abstract][Full Text]
Bailey, C. M., Khalkhali-Ellis, Z., Kondo, S., Margaryan, N. V., Seftor, R. E. B., Wheaton, W. W., Amir, S., Pins, M. R., Schutte, B. C., Hendrix, M. J. C.
(2005). Mammary Serine Protease Inhibitor (Maspin) Binds Directly to Interferon Regulatory Factor 6: IDENTIFICATION OF A NOVEL SERPIN PARTNERSHIP. J. Biol. Chem.
280: 34210-34217
[Abstract][Full Text]
Kang, P., Svoboda, K.K.H.
(2005). Epithelial-Mesenchymal Transformation during Craniofacial Development. J. Dent. Res.
84: 678-690
[Abstract][Full Text]
Ferguson, P J, Chen, S, Tayeh, M K, Ochoa, L, Leal, S M, Pelet, A, Munnich, A, Lyonnet, S, Majeed, H A, El-Shanti, H
(2005). Homozygous mutations in LPIN2 are responsible for the syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia (Majeed syndrome). J. Med. Genet.
42: 551-557
[Abstract][Full Text]
Srichomthong, C, Siriwan, P, Shotelersuk, V
(2005). 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-e46
[Abstract][Full Text]
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