Abstract: TH-PO0610
Pathogenic NPHS2 Variants Predominantly Cause Adult-Onset FSGS in the United States While Childhood-Onset Disease Predominates in Europe and East Asia
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
- Saleem, Moin A., Bristol Royal Hospital for Children, Bristol, England, United Kingdom
- Ding, Wen Yi, Bristol Royal Hospital for Children, Bristol, England, United Kingdom
- Malone, Karen E., GeneScape, Leiden, Netherlands
- Clark, Dinah, Natera, Austin, Texas, United States
- Komers, Radko, Travere, San Diego, California, United States
- Harrison, Pille, Purespring Therapeutics Limited, London, England, United Kingdom
- Erlandsson, Fredrik, Purespring Therapeutics Limited, London, England, United Kingdom
Background
NPHS2 encodes podocin, a protein essential for the slit diaphragm. Biallelic pathogenic NPHS2 variants are traditionally thought to present as childhood steroid resistant nephrotic syndrome (SRNS) with focal segmental glomerulosclerosis (FSGS) histology. Recent data suggests up to 4% of adult FSGS may be caused by NPHS2 variants.
Methods
NPHS2 variant pathogenicity was classified by ACMG guidelines and cross-referenced with ClinVAR. Over 1.2 million genomes from diverse geographies were analysed to determine pathogenic variant frequencies. Published PodoNet data linking NPHS2 genotypes to age of renal failure was leveraged to estimate prevalence of paediatric versus adult disease. The modelling was confirmed in the DUPLEX and RenaSight™ cohorts.
Results
The R229Q variant, associated with late onset disease, is carried by 4.8% in the US population, but is absent in East Asia. In the US 77% of modelled pathogenic NPHS2 genotypes were R229Q compound heterozygotes, with half being R229Q/A284V. A284V is strongly associated with Hispanic/Latino ethnicity. Modelling suggested 2 of 3 US NPHS2 patients reach end stage kidney disease after 30 years of age.
67 NPHS2 patients were identified in the RenaSight™ cohort, with the most common genotype being R229Q/A284V (37%). 15 NPHS2 patients were identified in DUPLEX, with the most common genotype being R229Q/A284V (33%). Age and ethnicity distribution in RenaSight™ and DUPLEX confirmed the modelling findings for the US.
Conclusion
Modelling suggests NPHS2 driven disease is primarily a late onset / slow progression disease in the US, caused by high prevalence of R229Q in combination with specific variants causing disease with R229Q. The modelling was confirmed in the DUPLEX and RenaSight™ cohorts, where Hispanics/Latinos were over-represented and the majority of patients were adult at the time of genotyping, as predicted. The results suggest adult FSGS patients would benefit from NPHS2 genotyping in the US. In Europe more adults than expected were projected to exhibit NPHS2 nephropathy, while NPHS2 genotyping among adults is unnecessary in East Asia. Overall the prevalence of NPHS2 driven FSGS in adults is considerably higher than previously thought, especially in the US.
Funding
- Commercial Support – Purespring Therapeutics