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Haploinsufficiency of PITX2 in Four Chinese Families With Axenfeld-Rieger Syndrome
Chumou Liu1,2, Zhou Zhou2, Li Xu3
1NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, Xiangya School of Basic Medical Sciences, Central South University, Changsha.
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.
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