J Med Genet 41:68-74 doi:10.1136/jmg.2003.010868
  • Letters to JMG

TBX22 mutations are a frequent cause of cleft palate

  1. A C B Marçano1,3,
  2. K Doudney1,
  3. C Braybrook1,*,
  4. R Squires2,
  5. M A Patton2,
  6. M M Lees2,
  7. A Richieri-Costa3,
  8. A C Lidral4,
  9. J C Murray5,
  10. G E Moore1,
  11. P Stanier1
  1. 1Institute of Reproductive and Developmental Biology, Imperial College London, Du Cane Road, London W12 ONN, UK
  2. 2Medical Genetics Unit, St George’s Hospital Medical School, Tooting, London SW17 0RE, UK
  3. 3Hospital de Reabilitação de Anomalias Craniofaciais, Universidade de São Paulo, Bauru, São Paulo, Brazil
  4. 4Department of Orthodontics, University of Iowa, IA, USA
  5. 5Department of Pediatrics, University of Iowa, IA, USA
  1. Correspondence to:
 Dr P Stanier
 4th Floor, Institute of Reproductive and Developmental Biology, Imperial College London, Du Cane Road, London, W12 ONN, UK;
  • Accepted 26 August 2003
  • Revised 2 June 2003

Cleft lip and/or cleft palate is among the most frequent birth defect seen in humans, with a reported prevalence of 1 in 700 births worldwide.1 Development of the secondary palate is a complex coordinated sequence of events, beginning with the appearance of palatal shelves from the first branchial arch derived maxillary prominences during the sixth week of embryogenesis. This involves mesenchymal–epithelial interactions, cell differentiation, migration, and transformation, with the interactive role of soluble growth factors, extracellular matrix molecules and their receptors, and programmed cell death.2,3 A disruption anywhere in the required sequence may result in a failure of the palate to close.

A genetic involvement in clefts was first recognised by Fogh-Anderson,4 with the majority of cases thought to display a multifactorial mode of inheritance.5 Analysis of recurrence risk patterns of cleft lip with or without cleft palate (CL/P) indicates that there are likely to be few major loci interacting epistatically with an oligogenic background.6,7 As a consequence, there have been numerous studies to identify genetic determinants, either studying individual candidate genes and loci,8,9 or screening at the whole genome level.10–12 These efforts have been encouraged by the many candidates revealed by mouse mutants that exhibit a cleft as at least part of their phenotype.13 Nevertheless, the results of many of these studies have not been informative, with only a few candidate genes or loci being strongly implicated in human CL/P or CP only.12 As a consequence, the mechanisms of interaction, which probably include both genes and the environment, remain poorly understood. Recently, however, significant progress has been made with the identification of gene mutations in several forms of CL/P and CP. These include the cell adhesion molecule PVRL114 and the transcription factors MSX1, IRF6 …