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- CL/P, cleft lip and palate
- CPO, cleft palate only
- NPL, non-parametric linkage
- VWS, van der Woude syndrome
Oral clefts are the most common congenital malformations worldwide. Cleft palate can be non-syndromic (MIM 119540) or it can appear as a part of a syndrome or recurrence pattern. Non-syndromic cleft palate and non-syndromic cleft lip with or without cleft palate (CL/P) are considered to be separate entities, on the basis of different embryonic timing and epidemiology. However, in some syndromes, both of these cleft types segregate in the same pedigree, suggesting that they might share a common genetic background. Oral clefts manifest in over 300 different syndromes, and in some of these syndromes the gene defect is already known (Online Mendelian Inheritance in Man database 2004, http://www.ncbi.nlm.nih.gov/Omim/). Identified mutations in cleft syndromes have shown that functionally and structurally very distinct types of genes have an effect on palatogenesis. Recently, a mutation in interferon regulatory factor 6 (IFR6) was found to cause van der Woude syndrome (VWS) (MIM 119300),1 which is one of the most common cleft syndromes.
Mutations in very different type of genes can lead to cleft palate in mice. These genes encode growth factors, receptors, transcription regulators, and enzymes for signalling molecule synthesis. Cleft palate, in addition to other congenital malformations, is found in ∼70 knock out mice strains (The Transgenic/Targeted Mutation Database, http://tbase.jax.org/). Other anomalies occur frequently, and therefore no exact model for non-syndromic cleft palate exists. Usually the penetrance is not complete, but Msx-1 knock outs result in 100% cleft palate.2
It has been suggested that, in humans, ∼50% of cases of cleft palate are non-syndromic.3 The etiology and pathogenesis of non-syndromic cleft palate—and also of all other clefts—are poorly understood. Extrinsic factors, such as maternal smoking4 with a particular allele in TGFα locus,5–7 maternal alcohol consumption,8,9 maternal intake of drugs during the first trimester,10 and …
This study was supported by the Sigrid Juselius Foundation, the Academy of Finland, and the Helsinki University Hospital Research Funds.
Conflict of interest: none declared.