Haploinsufficiency of PITX2 in Four Chinese Families With Axenfeld-Rieger Syndrome.

PRCIS: Axenfeld-Rieger syndrome (ARS) is a rare genetic disorder characterized by anterior segment dysgenesis and secondary glaucoma, often accompanied by systemic defects. This study investigated the clinical and genetic features in 4 Chinese families with ARS.

PURPOSE: To characterize the clinical phenotypes and identify the causative genetic mutations in 4 unrelated Chinese families with ARS.

METHODS

Affected individuals from 4 Han Chinese families underwent comprehensive clinical and ophthalmological examinations. Genetic analysis was performed using whole-exome sequencing (WES) and validated by copy number variation sequencing (CNV-seq) and qPCR.

RESULTS

All affected individuals exhibited anterior segment dysgenesis. Secondary glaucoma was present in 7 of them. Systemic manifestations, including dental and umbilical abnormalities, were observed in all affected individuals. Genetic analysis identified novel heterozygous PITX2 mutations in all 4 families: 3 distinct microdeletions (ranging from 206 bp-449.97 kb) and 1 nonsense mutation (p.Phe140*), all predicted to cause haploinsufficiency.

CONCLUSIONS

Four novel PITX2 mutations, including microdeletions, were identified in Chinese ARS families. The 206 bp genomic DNA deletion appeared to be an essential region (chr4: 111543411-111543616) for PITX2 function in ocular and systemic development, underscoring the necessity of full gene dosage.