[Clinical features and genetic analysis for PAX6-associated ocular diseases]

Objective: To analyze the genetic and clinical characteristics of patients with PAX6-associated ocular diseases (PAOD). Methods: This retrospective case series study recruited 40 PAOD patients from 26 families at Peking Union Medical College Hospital between January 2015 and March 2025. Medical history and ophthalmic examination results were collected, including visual acuity, color fundus photography, fundus autofluorescence, optical coherence tomography (OCT), and B-scan ultrasonography. Peripheral blood samples were obtained from patients and their family members for DNA extraction. The PAX6 pathogenic variants were detected using next-generation sequencing (NGS), multiplex ligation-dependent probe amplification (MLPA), and quantitative real-time quantitative PCR (qPCR), followed by segregation analysis in pedigrees. Results: A total of 40 patients from 26 unrelated families were identified, with an equal distribution of 20 males and 20 females. The age at first visit ranged from 0.5 to 59.0 years (median: 25.5 years). Best corrected visual acuity ranged from no light perception to 0.4 (median: 0.1). Among the cases, 23 patients were diagnosed with congenital aniridia, while 17 patients had non-aniridia phenotypes, including anterior segment dysgenesis, Peters anomaly, and foveal hypoplasia. Foveal hypoplasia was a common clinical manifestation (100%, 23/23) in PAOD patients, with other common manifestations including nystagmus (94.9%, 37/39), cataract (80.0%, 28/35), and glaucoma (59.3%, 16/27). Twenty-five PAX6 pathogenic variants were identified, among which 9 novel variants were reported in this study, including 3 missense mutations, 3 large chromosomal rearrangements, 1 frameshift mutation, 1 splicing variant, and 1 small deletion. Truncating mutations (68.7%) were the most common variant type in aniridia patients, whereas missense mutations (70.0%) predominated in other PAX6-associated ocular diseases, showing a significant difference (P<0.001). Conclusion: PAOD exhibits high phenotypic heterogeneity, with foveal hypoplasia as a common feature and congenital aniridia being the most prevalent phenotype. Nystagmus combined with multiple ocular structural abnormalities are key clinical features suggestive of PAOD. This study expands the clinical and genetic spectrum of PAOD and provides further insights into genotype-phenotype correlations.