Abstract: TH-PO0600
Contribution of COL4A3-5 Variants to Idiopathic Nephrotic Syndrome
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
- Martinelli, Elena, Columbia University, New York, New York, United States
- Schneider, Ronen, Boston Children's Hospital, Boston, Massachusetts, United States
- Ke, Juntao, Columbia University, New York, New York, United States
- Santoriello, Dominick, Columbia University, New York, New York, United States
- Kretzler, Matthias, University of Michigan, Ann Arbor, Michigan, United States
- Kiryluk, Krzysztof, Columbia University, New York, New York, United States
- Sampson, Matt G., Boston Children's Hospital, Boston, Massachusetts, United States
- Gbadegesin, Rasheed A., Duke University, Durham, North Carolina, United States
- Saleem, Moin A., University of Bristol Bristol Renal, Bristol, England, United Kingdom
- D'Agati, Vivette D., Columbia University, New York, New York, United States
- Pollak, Martin, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
- Hildebrandt, Friedhelm, Boston Children's Hospital, Boston, Massachusetts, United States
- Sanna-Cherchi, Simone, Columbia University, New York, New York, United States
Background
COL4A3, COL4A4 and COL4A5 encode type IV collagen molecules, key structural components of the glomerular basement membrane. While mutations in these genes typically cause Alport syndrome(AS), recent evidence links them to idiopathic nephrotic syndrome (INS), presenting as focal segmental glomerulosclerosis(FSGS) or minimal change disease(MCD). The genetic and molecular mechanisms underlying the pleiotropic role of COL4A3-5 variants on different kidney diseases is unresolved.
Methods
We analyzed exome/genome sequencing data from 5,260 individuals with INS, classified as FSGS, MCD, steroid-resistant NS(SRNS), or steroid-sensitive NS(SSNS) and 11,111 controls. We extracted COL4A3-4-5 variants and made variant annotation using ACMG criteria to define them as pathogenic/likely pathogenic(P/LP) or variants of unknown significance(VUS). We performed qualitative analyses to identify protein-truncating variants, glycine substitutions, and their localization in collagenous domains. Ancestry was assigned via principal component analysis, and statistical comparisons were made using Fisher’s exact test.
Results
Among individuals with INS(N=5,260), 3.9% carried P/LP COL4A3-5 variants, rising to 5.25% in the FSGS/SRNS group. VUS carriers accounted for 3.7%. In controls, 0.74% had P/LP variants, and 2.06% carried VUS. P/LP variants were significantly enriched in NS cases (OR 5.48,P=2.81×10-43) and particularly in FSGS/SRNS(OR 7.5,P=8.05×10-53). Individuals of genetic African ancestry had a 2.5-fold lower burden of P/LP variants than non-African cases(1.89%vs4.20%, OR 0.4,P=2.1×10-3), with no significant difference in controls. Missense variants accounted for 64% of cases, of which 89% involved glycine substitutions and 87.3% were in collagenous domains. Clinical and pathologic correlations are ongoing.
Conclusion
COL4A3-5 variants contribute to INS, with ancestry-related differences in genetic burden. The qualitative variant analysis underscores structural alterations that may contribute specifically to INS subgroups. Clinical and histological correlations, together with functional studies, are needed to delineate the mechanisms distinguishing AS from idiopathic NS with potential implications for genetic diagnosis and treatment strategies.
Funding
- NIDDK Support