From mutation to symptoms: a multi-center study on HNF1B-related nephropathy in Chinese children

Hepatocyte nuclear factor 1β (HNF1B) pathogenic variants constitute a major genetic contributor to congenital anomalies of the kidney and urinary tract (CAKUT), with patients simultaneously exhibiting distinct extrarenal features. Among these clinical manifestations, renal disease progression is crucial for long-term outcomes, needing comprehensive evaluation.

Using the Chinese Children Genetic Kidney Disease Database (2017-2024), we analyzed 26 pediatric HNF1B cases to characterize renal phenotypes and genotype correlations.

All patients exhibited abnormal renal phenotypes at diagnosis: renal cysts (50%) and multicystic dysplastic kidney (MCDK) (37.5%). Genetic analysis revealed 16 patients (61.5%) had a 17q12 deletion including the HNF1B gene, while the remaining carried HNF1B intragenic pathogenic variants, including a novel c.1390-1405dup. Comparing phenotypic trajectories, 17q12 deletion cases showed earlier renal phenotype onset (median age: 0 vs. 1 year 11 months, p = 0.121), while HNF1B variants showed faster renal function deterioration (latest eGFR: 85 vs. 45.6 mL/min/1.73 m², p = 0.11). Three of five CKD 5 children underwent kidney transplantation before 15; one developed reversible tacrolimus-induced hyperglycemia.

Our results suggest a potential trend wherein the 17q12 deletion may be associated with a higher prevalence of developmental renal anomalies, while HNF1B pathogenic variants might correlate with an increased risk of tubular dysfunction, indicating possible distinct genotype-phenotype correlations. Based on these observations, we recommend that affected families receive tailored clinical management, including prenatal counseling, genotype-specific monitoring, and regular renal function assessment.