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, n = 12) and group B (moderate-to-heavy proteinuria, n = 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 NPHP1 mutations as the most prevalent (61.9%), followed by TTC21B variants (19.0%). However, TTC21B 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 TTC21B 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 TTC21B emerging as the predominant pathogenic gene in this clinical subgroup.