A novel PITX2 mutation in non-syndromic orodental anomalies.

OBJECTIVE: To identify orodental characteristics and genetic aetiology of a family affected with non-syndromic orodental anomalies. SUBJECTS AND METHODS: Physical and oral features were characterised. DNA was collected from an affected Thai family. Whole-exome sequencing was employed to identify the pathogenic variants associated with inherited orodental anomalies. The presence of the identified mutation was confirmed by Sanger sequencing. RESULTS: We observed unique orodental manifestations including oligodontia, retained primary teeth, taurodont molars, peg-shaped maxillary central incisors, high attached frenum with nodule and midline diastema in the proband and her mother. Mutation analyses revealed a novel heterozygous frameshift deletion, c.573_574delCA, p.L193QfsX5, in exon 5 of PITX2A in affected family members. The amino acid alterations, localised in the transcriptional activation domain 2 in the C-terminus of PITX2, were evolutionarily conserved. Mutations in PITX2 have been associated with autosomal-dominant Axenfeld-Rieger syndrome and non-syndromic eye abnormalities, but never been found to cause isolated oral anomalies. CONCLUSIONS: This study for the first time demonstrates that the PITX2 mutation could lead to non-syndromic orodental anomalies in humans. We propose that the specific location in the C-terminal domain of PITX2 is exclusively necessary for tooth development.