From Mutation to Symptoms: A Multi-Center Study on HNF1B-Related Nephropathy in Chinese Children

Background 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. Methods Using the Chinese Children Genetic Kidney Disease Database (2017–2024), we analyzed 26 pediatric HNF1B cases to characterize renal phenotypes and genotype correlations. Results 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 HNF1B gene, while the remaining carried HNF1B intragenic mutations, 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/1.73m², p  = 0.11). Three of five CKD 5 children underwent kidney transplantation before 15; one developed reversible tacrolimus-induced hyperglycemia. Conclusion These results demonstrated genotype-phenotype divergence: 17q12 deletion may promote developmental renal anomalies via haploinsufficiency, while HNF1B variants likely accelerate tubular dysfunction through dominant-negative transcriptional dysregulation. Prenatal counseling, genotype-specific monitoring, and renal monitoring for affected families are recommended.