Abstract: TH-PO0608
From Mild Proteinuria to Congenital Nephrotic Syndrome: Clinical Heterogeneity of NPHS1 Biallelic Variants in a Japanese Cohort
Session Information
- Monogenic Kidney Diseases: Glomerular
November 06, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Monogenic Kidney Diseases
Authors
- Yamamura, Tomohiko, Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
- Yamamoto, Asahi, Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
- Aoyama, Shuhei, Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
- Inoki, Yuta, Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
- Sakakibara, Nana, Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
- Nagano, China, Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
- Horinouchi, Tomoko, Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
- Ishimori, Shingo, Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
- Nozu, Kandai, Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
Background
The NPHS1 gene, which encodes nephrin, is a well-known causative gene of congenital nephrotic syndrome (CNS). Recently, NPHS1 variants have also been associated with childhood-onset steroid-resistant nephrotic syndrome (SRNS) and focal segmental glomerulosclerosis (FSGS). However, it remains under-recognized that NPHS1 biallelic variants can also be associated with milder phenotypes, such as asymptomatic proteinuria, and that these variants may show population-specific patterns and genotype–phenotype correlations.
Methods
A total of 920 unrelated Japanese patients with CNS, infantile nephrotic syndrome (INS), FSGS, or asymptomatic proteinuria were screened for mutations in podocyte-related genes, including NPHS1, using targeted exome sequencing. A retrospective review of clinical data was conducted for patients with pathogenic NPHS1 variants.
Results
We identified biallelic pathogenic NPHS1 variants in 38 cases, including 2 siblings, comprising 33 distinct variants. Clinically, 21 cases presented with CNS, 3 with INS, 4 with SRNS, 4 with nephrotic syndrome following proteinuria, and 4 with only asymptomatic mild to moderate proteinuria. Among cases without CNS/INS, the median age of onset of proteinuria was 3 years. Renal histology was available for 16 patients: 13 showed minor glomerular abnormalities, and one case each demonstrated FSGS, membranous nephropathy-like findings, and mesangial proliferation. Genetic analysis revealed that c.2464G>A (p.V822M) and c.2515del were recurrent variants in the Japanese cohort. All 6 patients with the V822M variant exhibited milder phenotypes, and none had CNS.
Conclusion
In this study, NPHS1 variants were identified not only in patients with CNS but also in those with SRNS and asymptomatic proteinuria. All non-CNS cases had at least one missense variant, and the presence of V822M was consistently associated with a milder phenotype, demonstrating a clear genotype–phenotype correlation. While common Finnish founder variants (Fin-major, Fin-minor) were not observed in our cohort, recurrent population-specific variants were identified in Japanese patients. These findings broaden the clinical spectrum of NPHS1-related disease and highlight the importance of NPHS1 screening even in milder phenotypes.