| Title |
Presentation of patients with congenital anomalies of the kidney and urinary tract and PAX2 loss-of-function variants and implications for clinical management |
| Authors |
Greipel, Leonie ; Martens, Helge ; Werfel, Lina ; Gjerstad, Ann Christin ; Auber, Bernd ; Geffers, Robert ; Bräsen, Jan H ; Jankauskienė, Augustina ; Bjerre, Anna ; Kanzelmeyer, Nele ; Haffner, Dieter ; Weber, Ruthild G |
| DOI |
10.1016/j.ekir.2025.08.037 |
| Full Text |
|
| Is Part of |
Kidney international reports.. New York : Elsevier Inc.. 2025, vol. 10, iss. 11, p. 4041-4054.. ISSN 2468-0249 |
| Keywords [eng] |
albuminuria ; antiproteinuric measures ; dominant-negative effect ; kidney hypo-/dysplasia ; living related donor evaluation ; PAX2 |
| Abstract [eng] |
Introduction: 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. Methods: 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. Results: 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. Conclusion: 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. |
| Published |
New York : Elsevier Inc |
| Type |
Journal article |
| Language |
English |
| Publication date |
2025 |
| CC license |
|
