Novel PITX 2 gene mutations in patients with Axenfeld‐Rieger syndrome

Purpose Mutations in the bicoid‐like transcription factor PITX 2 gene often result in Axenfeld‐Rieger syndrome ( ARS ), an autosomal‐dominant inherited disorder. We report here the discovery and characterization of novel PITX 2 deletions in a small kindred with ARS . Methods Two familial patients (father and son) from a consanguineous family were examined in the present study. Patient DNA samples were screened for PITX 2 mutations by DNA sequencing and for copy number variation by SYBR Green quantitative polymerase chain reaction (PCR) analysis. Results We report a novel deletion involving the coding region of PITX 2 in both patients. The minimum size of the deletion is 1 421 914 bp that spans one upstream regulatory element ( CE 4), PITX 2 and a minimum of 13 neighbouring genes. The maximum size of the deletion is 3 789 983 bp. The proband (son) additionally possesses a novel 2‐bp deletion in a non‐coding exon of the remaining PITX 2 allele predicted to alter correct splicing. Conclusion Our findings implicate a novel deletion of the PITX 2 gene in the pathogenesis of ARS in the affected family. This ARS family presented with an atypical and extremely severe phenotype that resulted in four miscarriages and the death at 10 months of age of a sib of the proband. As the phenotypic manifestations in the proband are more severe than that of the father, we hypothesize that the deletion of the entire PITX 2 allele plus a novel 2‐bp deletion (observed in the proband) within the remaining PITX 2 allele together contributed to the atypical ARS presentation in this family. This is the first study reporting on bi‐allelic changes of PITX 2 potentially contributing to a more severe ARS phenotype.