Clinical and Genetic Differences between Congenital and Infantile Nephrotic Syndrome

Background: More than half of the patients with congenital nephrotic syndrome (CNS) or infantile nephrotic syndrome (INS) are known to have a monogenic etiology. However, the difference in clinical course, disease-causing gene, and genotype-phenotype correlation between genetic CNS and INS remains unknown. Methods: Patients diagnosed with nephrotic syndrome within the first year of life and referred to our hospital for genetic analysis were enrolled.In patients with identified causative genes, characteristics and their renal outcome were compared between CNS and INS patients. Results: Among 74 patients enrolled, disease-causing genetic variants were detected in 52 patients. The median age at development of end-stage kidney disease (ESKD) in the CNS and INS groups was 13.2 and 20.0 months old, respectively (P = 0.13). Compared to the CNS patients with NPHS1 variants, the age at development of ESKD was significantly earlier in CNS patients with the other variants (1.0 vs. 31.0 months old; P < 0.001). In patients with pathogenic variants other than NPHS1, there was significant difference in the age at development of ESKD between CNS and INS patients (1.0 vs. 17.0 months old; P < 0.001). All INS patients with NPHS1 variants had no truncating variants. Patients with no truncating variant did not develop ESKD during follow-up, and the age at ESKD in patients with no truncating variant was significantly later than in those with biallelic or monoallelic truncating variants (- vs 31.0 months old; P = 0.025). In addition, among patients with WT1 pathogenic variants, those with severe variants, exon 8 or 9 missense variants in DNA-binding regions, developed ESKD significantly earlier than those without severe variant (1.5 vs. 15.0 months old; P = 0.0058). All of the CNS patients and 37.5% (3/8) of the INS patients had severe variants. Conclusion: Our findings suggest that whether CNS onset or INS onset could influence renal prognosis in patients with genetic nephrotic syndrome who are less than 1 year old. Moreover, among patients with pathogenic variant in the same gene, INS patients can be more likely to have a mild genotype and good renal prognosis.