The T-box transcription factor gene TBX22 is mutated in X-linked cleft palate and ankyloglossia

Formation of the secondary palate is a complex step during craniofacial dev elopment. Disturbance of the events affecting palatogenesis results in a fa ilure of the palate to close. As a consequence of deformity, an affected ch ild will have problems with feeding, speech, hearing, dentition and psychol ogical development. Cleft palate occurs frequently, affecting approximately 1 in 1,500 births; it is usually considered a sporadic occurrence(1) resul ting from an interaction between genetic and environmental factors(2). Alth ough several susceptibility loci have been implicated, attempts to link gen etic variation to functional effects have met with little success(3). Cleft palate with ankyloglossia (CPX; MIM 303400) is inherited as a semidominant X-linked disorder previously described in several large families of differ ent ethnic origins(4-11) and has been the subject of several studies that l ocalized the causative gene to Xq21 (refs. 10-13). Here we show that CPX is caused by mutations in the gene encoding the recently described T-box tran scription factor TBX22 (ref. 14). Members of the T-box gene family are know n to play essential roles in early vertebrate development, especially in me soderm specification(15). We demonstrate that TBX22 is a major gene determi nant crucial to human palatogenesis. The spectrum of nonsense, splice-site, frameshift and missense mutations we have identified in this study indicat es that the cleft phenotype results from a complete loss of TBX22 function.