Presentation of Patients With Congenital Anomalies of the Kidney and Urinary Tract and PAX2 Loss-of-Function Variants and Implications for Clinical Management.

PAX2 variants, particularly loss-of-function (LOF) variants, can cause congenital anomalies of the kidney and urinary tract (CAKUT), mostly associated with renal coloboma syndrome (RCS), and focal segmental glomerulosclerosis (FSGS) marked by proteinuria. Whole-exome sequencing (WES) was performed in 301 pediatric patients with CAKUT. Deep phenotyping was done in 7 carriers of a PAX2 LOF variant. The kidney phenotype was compared in pediatric patients with CAKUT and PAX2 LOF variants (n = 104), compiled from our cohort (n = 7) and 12 publications (n = 97), and in those with wildtype PAX2 from our cohort (n = 294). Genotype-phenotype correlations were explored. Heterozygous inherited or de novo PAX2 LOF variants were detected in 7 of 301 patients (2.3%), all presenting with bilateral (cystic) kidney hypoplasia/dysplasia/hypodysplasia (KHD). Full penetrance for a kidney phenotype, but variable expressivity was observed in our 10 carriers of a PAX2 LOF variant, including parents who were not necessarily affected by CAKUT but by albuminuria or FSGS. In 104 pediatric carriers of a PAX2 LOF variant with CAKUT, hallmark kidney manifestations were (cystic) KHD (97% vs. 59% in patients with CAKUT and wildtype PAX2, P < 0.0001) and albuminuria (significantly more severe than in patients with (cystic) KHD and wildtype PAX2, P < 0.0001), suggesting a proteinuric effect of PAX2 LOF variants. Severe kidney anomalies, that is, cystic KHD or agenesis, were significantly more frequent in patients carrying the NM_000278.5(PAX2):c.76dupG variant in exon 2 with a possible dominant-negative effect than in patients with nonsense or frameshift variants in exon 3 to 7. In patients with CAKUT and PAX2 LOF variants, close monitoring and antiproteinuric measures should be considered, and PAX2 variant testing is recommended in living related donors.