LETTER TO JMG Linkage and linkage disequilibrium searched for between non-syndromic cleft palate and four candidate loci

Cleft palate (CP) is one of the most common congenital malformations. It can occur as part of a recognisable syndrome, associated with other malformations or, most commonly, be non-syndromic (CPO) (MIM 119540). The birth prevalence of CPO varies between and among populations but it is seen world wide. The highest incidence has been found in Finland, 1.01 per 1000 livebirths. Within Finland, there are regional differences in birth prevalence; the Oulu region (in northern central Finland) and central western Finland are over-represented, with up to twice the incidence compared to the average. Differences are even more striking when analysing the birth places of the grandparents of probands. The gene defects or susceptibility genes for clefts remain largely unknown and the basic mechanism causing the failure of the secondary palate to close is still poorly understood. Extrinsic factors like advanced paternal age, maternal smoking, and overall intake of medicines during the first trimester have been suggested to increase the risk of CPO. Although some pedigrees have shown autosomal dominant and X linked recessive inheritance, the risk of recurrence for relatives in large series of cases differs greatly from expected values calculated on the basis of a simple Mendelian mode of inheritance. Targeted mutations in mice have shown that malfunction of very different types of genes can lead to cleft palate, msx1 and tgfb3 among them. In humans, defects in genes encoding collagens, a fibroblast growth factor receptor, a sulphate transporter, 9 a nucleolar protein, and a thyroid transcription factor have appeared to be associated with syndromes where cleft palate can be involved. For non-syndromic cleft palate, neither mutations nor linkage to a specific chromosomal region has yet been established. However, linkage disequilibrium was suggested in two studies between MSX1 and non-syndromic CP. 13 In the Danish population, no association between CPO and MSX1 was found but an association between the risk for CP and variation at the TGFB3 locus was detected. A mutation in MSX1 leading to a preterm stop codon was found to cosegregate with cleft lip with or without cleft palate (CL/P) in a large pedigree. An MSX1 missense mutation has been shown to cause selective tooth agenesis. No mutations were found in coding regions of MSX1 and TGFB3 in patients with CPO in Iowa. Two genome scans for cleft lip with or without cleft palate (CL/P) have been published. 18 A genome wide scan has not been performed in families with CPO. Nine percent of patients with deletion in 22q11 manifest cleft palate. Patients also have other signs like velopharyngeal insufficiency, hypocalcaemia, thymic hypoplasia, cardiac problems, renal anomalies, and abnormal facies (CATCH 22 syndrome). The size of the commonly deleted region is 3 Mb, but so far the smallest deletion found has been 20 kb. The deletion of 20 kb removed exons 1 to 3 of the UFDL1 gene and the patient had typical features of 22q11 deletion. In a study of this chromosomal region, no 22q11 hemizygosity was detected in patients with isolated cleft palate. Cleft palate has also been described in patients having other chromosomal deletions, but always with other symptoms or signs. Recently, Brewer et al reported two patients with cleft palate and balanced translocations in 2q32 between the loci D2S311 and D2S116, within a region of approximately 2.5 Mb. They also analysed data on cleft palate patients with chromosomal deletions from the Human Cytogenetics Database (HCDB). Regions 2q32, 4p13-p16, and 4q31-q35 were significantly associated with cleft palate.