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Lizhu Yang, Qi Zhou, Zixi Sun, Kaoru Fujinami, Huajin Li, Zhisheng Yuan, Kazuo Tsubota, Ruifang Sui; Phenotype and Genotype Features of PAX6-related Ocular Dysgenesis. Invest. Ophthalmol. Vis. Sci. 2017;58(8):577.
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© ARVO (1962-2015); The Authors (2016-present)
Paired box gene 6 (PAX6) is a master regulatory gene of eye development. PAX6 mutations can cause a series of ocular dysgenesis, including aniridia, Peter's anomaly, corneal anomaly, foveal hypoplasia, congenital cataract and so on. This study aims to identify the genetic defect for a cohort of ocular dysgenesis and to analyze the clinical features of PAX6-related developmental eye diseases.
Twenty patients from 8 aniridia pedigrees and 4 pedigrees with other developmental eye diseases were recruited and detailed ophthalmologic examinations were performed. Peripheral blood samples were taken to extract genomic DNA. (1) Sanger direct sequencing of PAX6 was performed in aniridia subjects. (2) Next-generation sequencing (NGS) was utilized in the samples with the other developmental eye diseases. (3) Multiplex ligation-dependent probe amplification (MLPA) of PAX6 was applied to detect large deletions/duplications in the samples negative for (1) and (2). Then co-segregation analysis was performed to further confirm the causative mutation.
There were 10 pedigrees with autosomal dominant inheritance and 2 sporadic cases. Eleven aniridia patients from 8 families were all bilaterally affected and had nystagmus, respectively combined with bilateral ptosis (3/11, 27.3%), cornea anomalies (3/11, 27.3%) and foveal hypoplasia (5/5, 100%). The phenotypes of the other 4 pedigrees include: 3 patients in 1 family had bilateral cornea opacity, developmental glaucoma and iris aplasia; 4 patients in 1 family had bilateral nystagmus, premature cataract and foveal hypoplasia; The other 2 patients had bilateral microcornea, iris hypoplasia and congenital cataract. PAX6 defects were found in all the 12 pedigrees including 9 heterozygous point mutations and 3 large chromosomal changes. 9 mutations include 2 nonsense mutations, 2 frameshift mutations, 2 splicing mutations and 3 missense mutations. Interestingly, all the 3 missense mutations were found in non-aniridia subjects. Totally, 6 novel point mutations and 3 novel large fragment changes were identified, which accounts for 75% of the total variants.
PAX6 plays an important role in developmental eye diseases. Twelve PAX6 pathogenic variants including 9 novel variants were determined in our study. Non-aniridia phenotypes are frequently associated with missense mutations, which elucidates the genotype-phenotype correlation in PAX6-related ocular dysgenesis.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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