Genotype-phenotype correlations and functional characterization of novel PAX2 variants in a 10-patient pediatric...

PAX2 is a key developmental gene, and its mutations are primarily associated with kidney and ocular anomalies, predominantly affecting children. This study aims to analyze the clinical manifestations and genetic characteristics of children with PAX2 mutations and to assess the functional impact of novel variants.

Clinical data were retrospectively reviewed in 10 children diagnosed with PAX2 mutations through whole-exome sequencing from a pediatric hereditary disease cohort database. AlphaFold 3 (AF3) was used for protein structural modeling. Novel variants were functionally assessed via HK-2 cell proliferation assays.

The median age at initial presentation was 4.2 years (IQR 0-6.5). All 10 patients presented with proteinuria or microscopic hematuria. Nine had kidney dysplasia, and five progressed to stage 5 chronic kidney disease. Five patients had PAX2-related ocular abnormalities. Hepatic dysfunction and spermatic cord hydrocele were reported as potential novel phenotypes. A total of nine distinct PAX2 mutations were identified, including five novel variants. AF3 modeling revealed significant conformational disruptions in the novel variants, with root mean square deviation (RMSD) values ranging from 1.1 to 43.6 Å. Functional assays demonstrated that four novel variants significantly impaired the proliferative capacity of HK-2 cells.

This study characterizes five novel PAX2 variants with confirmed structural (RMSD 1.1-43.6 Å) and functional (HK-2 proliferation impairment) impacts, expanding both the mutational and phenotypic spectra in Chinese children. The findings highlight the association between PAX2 mutations and early-onset kidney disease with potential extrarenal involvement. Early genetic diagnosis and timely kidney-protective interventions are essential to improve outcomes.