A genome-wide scan of non-syndromic cleft palate only (CPO) in Finnish multiplex families.

O ral 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), 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. It has been suggested that, in humans, ,50% of cases of cleft palate are non-syndromic. The etiology and pathogenesis of non-syndromic cleft palate—and also of all other clefts—are poorly understood. Extrinsic factors, such as maternal smoking with a particular allele in TGFa locus, maternal alcohol consumption, 9 maternal intake of drugs during the first trimester, and advanced paternal age, have been shown to increase the risk of cleft palate only (CPO) in some studies, but conflicting results have also been published. Sparse intake of folic acid during the first trimester has been suggested to increase the risk for cleft palate. 12 The increased recurrence risk for siblings and the even higher risk for monozygotic twins suggest a genetic impact on cleft formation. 13 14 Some families have shown a dominant mode of inheritance, but oligogenic models with reduced penetrance and influence of extrinsic factors have also been proposed. 17 The risk of recurrence is ,2% if one child already has a CPO, ,6% if one parent has it, and,15% if one child and one parent have it. At the moment, nonsyndromic cleft palate is considered to be a multifactorial disease with a strong genetic background combined with extrinsic factors. 19–21 The incidence of non-syndromic CPO is 1/1000 live births in Finland, and this is one of the highest rates among white people. High incidences are seen in regions near Oulu and in central Finland. These regional differences become even more striking when the birthplaces of grandparents of probands are analysed; the Oulu region is heavily overrepresented. Usually, the incidence of cleft lip and palate (CL/P) is higher than the incidence of CPO, but in Finland the ratio is the opposite. Several association and linkage studies on CPO have been carried out. An association between TGFa2 and CPO has been found in three studies. 6 24 Later, Lidral et al found no association between CPO and TGBa, TGFb2, TGFb3, or MSX1. An association between the risk of CPO and variation at the TGFb3 locus was found in a Danish population. Evidence of linkage disequilibrium between CPO and MSX1 has been suggested. Recently, Hecht et al found evidence for a CPO locus on chromosome 4 near MSX1. MSX1 is of special interest because a mutation leading to a preterm stop codon was found to cosegregate with CL/P in a large pedigree. Linkage between CPO and VWS region 1q32–q41 has been excluded. Deletions in 4p16–14 and 4q31–35 were found to be highly significantly associated with cleft palate. Duplications in bands 3p24–23, 3p26, 3q23–25, 7q22–32, 8q21, 10p15–11, 14q11–21, 16p12– 13, and 22q12–13 were also found to be significantly associated with cleft palate. Two patients with cytogenetic rearrangements involving the same region of chromosome 2q32 were reported to have CPO with mild facial dysmorphia and learning disabilities. A genome-wide scan has not previously been performed in families with CPO, although several genome scans for CL/P have been published. Here, we present the results of the first genome-wide scan in Finnish multiplex families with non-syndromic CPO.