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Linkage and linkage disequilibrium searched for between non-syndromic cleft palate and four candidate loci
  1. H Koillinen1,5,
  2. V Ollikainen2,3,
  3. J Rautio4,
  4. J Hukki4,
  5. J Kere1,2,6
  1. 1Department of Medical Genetics, University of Helsinki, Helsinki, Finland
  2. 2Finnish Genome Centre, University of Helsinki, Helsinki, Finland
  3. 3Department of Computer Science, University of Helsinki, Helsinki, Finland
  4. 4Cleft Centre, University Hospital of Helsinki, Helsinki, Finland
  5. 5Department of Child Neurology, University of Turku, Turku, Finland
  6. 6Department of Biosciences at Novum, Karolinska Institute, Stockholm, Sweden
  1. Correspondence to:
 Professor J Kere, Department of Biosciences at Novum, Karolinska Institute, 14157 Huddinge, Sweden;

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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.1 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.1 Differences are even more striking when analysing the birth places of the grandparents of probands.1

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.2 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.3–5 In humans, defects in genes encoding collagens,6 a fibroblast growth factor receptor,7 a sulphate transporter,8,9 a nucleolar protein,10 and a thyroid transcription factor11 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 …

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