Phenotypic and genotypic analysis of pediatric nephronophthisis patients with different levels of proteinuria

While nephronophthisis (NPHP) classically manifests as mild tubular proteinuria, emerging evidence reports nephrotic-range proteinuria with edema. This study aims to explore the phenotypes and genotypes of pediatric NPHP patients with different levels of proteinuria. Twenty-one children with NPHP were recruited into this single-center cohort. They were divided into two groups according to proteinuria levels: group A (mild proteinuria, <i>n</i> = 12) and group B (moderate-to-heavy proteinuria, <i>n</i> = 9). The median age at symptom onset was 7.4 years (IQR 2.4–12.8). By the end of follow-up, 20 patients had progressed to ESRD at a median age of 9.8 years (IQR 5.8–12.9). Patients in group B exhibited significantly higher prevalence of family histories, hypertension, edema, and higher urine microalbumin-to-α1-microglobulin (MA/A1M) ratios. Genetic testing identified <i>NPHP1</i> mutations as the most prevalent (61.9%), followed by <i>TTC21B</i> variants (19.0%). However, <i>TTC21B</i> mutations were more commonly found in group B (3/4, 75.0%) with one homozygous mutation and two compound heterozygous mutations. Five novel mutations of NPHP genes were identified. Further literature review of patients with <i>TTC21B</i> gene mutations revealed that the P209L variant was almost present in all North African/European patients, while the C518R heterozygous mutation occurred in 72.7% of Asian patients. In conclusion, NPHP remains a diagnosis in patients presenting with moderate-to-heavy proteinuria, particularly when accompanied by characteristic features including positive family history, hypertension, and edema, with <i>TTC21B</i> emerging as the predominant pathogenic gene in this clinical subgroup.