# Variable Phenotypic Expression of PAX2 Variants in Two Lithuanian Families with Kidney Disease

## TL;DR

This study shows that PAX2 gene mutations can cause different kidney and eye problems in two Lithuanian families, highlighting the need for a multidisciplinary approach in diagnosis.

## Contribution

The study demonstrates variable phenotypic expression of PAX2 variants in unrelated families, emphasizing inconsistent genotype–phenotype correlations.

## Key findings

- Family A had chronic kidney disease and optic nerve dysplasia due to a PAX2 variant c.685C>T.
- Family B showed renal hypoplasia and focal segmental glomerulosclerosis with a PAX2 variant c.250G>A.
- The findings support that PAX2 variants can lead to diverse clinical manifestations within and across families.

## Abstract

Background and Objectives: Pathogenic variants in the PAX2 gene have been associated with a spectrum of eye and kidney disorders, ranging from papillorenal syndrome (known as renal coloboma syndrome) to isolated nephrosis without kidney morphological anomalies (focal segmental glomerulosclerosis), inherited in an autosomal dominant manner. However, due to the growing number of reports of pathogenic variants in the PAX2 gene, it is observed that genotype–phenotype correlation is not always consistent. We present patients from two unrelated families with PAX2 pathogenic variants c.685C>T and c.250G>A, highlighting the diverse phenotypic expression of PAX2-related disorders. Materials and Methods: We analyzed clinical and genetic data from two families who were tested for genomic abnormalities using targeted next-generation sequencing and Sanger sequencing for segregation analysis. Results: In Family A, a 27-year-old male presented with chronic kidney disease stage 3, proteinuria, and multicystic kidney dysplasia diagnosed at 11 years old. An ophthalmologic examination revealed bilateral optic nerve dysplasia. In Family B, a 6-year-old female and her 4-year-old sister were clinically diagnosed with renal hypoplasia, while their 36-year-old father presented with chronic kidney disease stage 3, focal segmental glomerulosclerosis, and optic disc pits. Genetic analysis identified a heterozygous PAX2 pathogenic variant c.685C>T, p.(Arg229*), in Family A and a heterozygous PAX2 pathogenic variant c.250G>A, p.(Gly84Ser) in Family B. Conclusions: The literature and our data further support that the same PAX2 variants may cause diverse kidney and ocular phenotypes among unrelated families and within the same family. Due to variable expressivity, a wide range of clinical manifestations of rare hereditary kidney diseases are still underdiagnosed, and a multidisciplinary approach is required to detect extrarenal signs of PAX2-related disorder.