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

AbstractIntroduction 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, and focal segmental glomerulosclerosis (FSGS) marked by proteinuria. Methods Whole-exome sequencing was performed in 301 pediatric CAKUT patients. Deep phenotyping was done in seven PAX2 LOF variant carriers. The kidney phenotype was compared in pediatric CAKUT patients with PAX2 LOF variants (n=104), compiled from our data (n=7) and 12 publications (n=97), and in those with wildtype PAX2 from our cohort (n=294). Genotype-phenotype correlations were explored. Results Heterozygous inherited or de novo PAX2 LOF variants were detected in 7/301 (2. 3%) patients, all presenting with bilateral (cystic) kidney hypo-/dysplasia (KHD). Full penetrance for a kidney phenotype, but variable expressivity was observed in our ten PAX2 LOF variant carriers including parents, who were not necessarily affected by CAKUT but by albuminuria/FSGS. In 104 pediatric PAX2 LOF variant carriers with CAKUT, hallmark kidney manifestations were (cystic) KHD (97% versus 59% in CAKUT patients with wildtype PAX2, pPAX2, pPAX2 LOF variants. Severe kidney anomalies, i. e. cystic KHD or agenesis, were significantly more frequent in patients carrying the NM₀00278. 5 (PAX2): c. 76dupG variant in exon 2 with a potential dominant-negative effect than in patients with nonsense/frameshift variants in exon 3-7. Conclusion In CAKUT patients with PAX2 LOF variants close monitoring and antiproteinuric measures should be considered, and PAX2 variant testing is recommended in living related donors.