DOI: 10.1097/ijg.0000000000002748 ISSN: 1057-0829

Haploinsufficiency of PITX2 in Four Chinese Families with Axenfeld-Rieger Syndrome

Chumou Liu, Zhou Zhou, Li Xu, Guo Liu, Nanxin Liu, Li Hu, Junkai Tan, Zijie Chen, Mahri Hommodova, Ning Fan, Jiaoyue Hu, Xuyang Liu
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Précis:

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 four Chinese families with ARS.

Purpose:

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

Methods:

Affected individuals from four 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 seven of them. Systemic manifestations, including dental and umbilical abnormalities, were observed in all affected individuals. Genetic analysis identified novel heterozygous PITX2 mutations in all four families: three distinct microdeletions (ranging from 206 bp to 449.97 kb) and one nonsense mutation (p.Phe140*) , with 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.

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