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Genotype of PAX2-related disorders

Genotype of PAX2-related disorders correlates with kidney and ocular manifestations


PAX2-related disorders encompass renal coloboma syndrome (RCS) and hereditary focal segmental glomerulosclerosis (FSGS) type 7. We retrospectively analyzed 27 Korean patients with PAX2 pathogenic variants detected between 2004 and 2022 and conducted a literature review of 328 cases, including 301 previously reported. In our cohort, 19 had RCS, 4 had FSGS, and 4 had isolated congenital anomalies of the kidneys and urinary tract.

Patients were classified by variant type into predicted loss of function (pLoF) and non-pLoF variant groups, and by variant location into paired domain and other sites group. pLoF variants were predominantly associated with RCS, observed in 82% of patients in both our data (18 of 22, P = 0.017) and the literature (140 of 171, P < 0.001). Kidney failure developed in 52% of Korean patients at a median age of 14.5 years, with no difference in kidney survival between variant types.

However, the literature review indicated faster progression to kidney failure in patients with pLoF variants (11.0 vs. 24.0 years; pLoF, n = 138 vs. non-pLoF, n = 71; P = 0.002), with no significant difference by variant location. Ocular manifestations were more common, had earlier onset, and were more severe in the pLoF variants group in our cohort (P = 0.038). The literature confirmed a higher prevalence of ocular involvement in patients with pLoF variants (pLoF, n = 175 vs. non-pLoF, n = 88; P < 0.001) and in those with paired domain variants (P = 0.01). pLoF variants in PAX2 were associated with worse kidney and ocular outcomes.

These findings support genotype-phenotype correlations, contributing to tailored management in patients with PAX2-related disorders.In conclusion, the clinical phenotypes of PAX2 pathogenic variants, including RCS, FSGS, and isolated CAKUT, were highly variable. A clear genotype-phenotype correlation was observed in both kidney and ocular manifestations. The pLoF variants were predominantly associated with RCS and exhibited a worse kidney prognosis compared to the non-pLoF variants in literature reviews, although this was not significant in our study.

The kidney survival did not differ by variant location. The pLoF variants were also associated with more common occurrence, earlier onset, and severe ocular involvement, which was not confined to the optic disc. The ocular involvement was more common in paired domain variants than in other sites. These insights demonstrate the significant implications of the genotype-based analysis approach in facilitating targeted and expedited patient care.

PAX2 gene, renal coloboma syndrome, CAKUT, optic nerve hypoplasia, transcription factor, autosomal dominant, gene mutation, developmental disorder, nephropathy, optic disc anomaly, missense mutation, nonsense mutation, frameshift mutation, kidney malformation, syndromic disorder, congenital defect, genotype-phenotype correlation, molecular diagnosis, hereditary nephropathy, eye development

#PAX2, #RenalColobomaSyndrome, #CAKUT, #GeneticDisorder, #KidneyDisease, #OpticNerveHypoplasia, #GeneMutation, #AutosomalDominant, #CongenitalAnomalies, #MolecularGenetics, #HereditaryDisorders, #MissenseMutation, #FrameshiftMutation, #PediatricNephrology, #EyeDevelopment, #SyndromicDisorder, #PAX2Mutation, #Nephropathy, #GeneticCounseling, #RareDisease

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