Phenotypic and Genetic Analysis of Familial Congenital Aniridia Caused by a Run-on Mutation in the PAX6 Gene
Year: 2026
Type: preprint
Abstract: Background Congenital aniridia is a rare pan-ocular developmental disorder characterized by iris hypoplasia and foveal hypoplasia, frequently complicated by secondary corneal disease, glaucoma, and cataract. This study evaluates clinical phenotypes and identifies the causative mutation in a Chinese Han pedigree with congenital aniridia, aiming to explore genotype–phenotype correlations and inform genetic counseling and clinical management. Methods A three-generation non-consanguineous pedigree of seven members (three affected) was enrolled. Whole-genome sequencing was performed on the proband (II-2, a 31-year-old female) with Sanger sequencing used for validation across all family members. Comprehensive ophthalmic assessments included best-corrected visual acuity, slit-lamp biomicroscopy, and fundus imaging. Results Autosomal dominant inheritance was observed. All affected individuals showed variable iris defects, nystagmus, and foveal hypoplasia, with profound early-onset visual impairment. The proband developed progressive keratopathy post-puberty, with vision declining to hand motion; her two children (aged 7 and 3) maintained clear corneas but exihited typical iris and foveal abnormalities. A heterozygous mutation (c.1268 A > T, p.423Leu frameshift) in PAX6 exon 13 was identified in the proband. Sanger sequencing confirmed complete cosegregation of this mutation with the affected phenotype, while all four unaffected members carried the wild-type allele. Conclusion This rare PAX6 readthrough mutation cosegregates with pan-ocular developmental abnormalities in this pedigree, with notable age-dependent clinical progression. The mutation likely affect PAX6 transcriptional regulation via a C-terminally extended protein, consistent with haploinsufficiency, though the precise pathogenic mechanism requires further study. Our findings expand the PAX6 mutational spectrum and emphasize the necessity of lifelong systematic ophthalmic surveillance-particularly in pediatric patients- for timely complication management, as well as the critical role of genetic testing in confirming diagnosis and predicting prognosis.
Source: Research Square
Language: English
Subfield: Ophthalmology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7204991982