Abstract: FR-PO0122
Two Unrelated Families Demonstrating Autosomal Dominant COL4-Related Nephropathy Across the Thin Basement Membrane-Alport Spectrum
Session Information
- Hereditary Glomerular and Tubulointerstitial Kidney Diseases
October 23, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1202 Genetic Diseases of the Kidneys: Non-Cystic (Complex and Non-Cystic Monogenic)
Authors
- Shaju, Ronald, The University of Texas Rio Grande Valley School of Medicine, Edinburg, Texas, United States
- Sepulveda, Alyssa, The University of Texas Rio Grande Valley School of Medicine, Edinburg, Texas, United States
- Gutierrez, Yolanda, The University of Texas Rio Grande Valley School of Medicine, Edinburg, Texas, United States
- Manllo-Sudario, Christopher Patrick, Science Academy of South Texas, Mercedes, Texas, United States
- Manllo-Sudario, Robert Alexander, The University of Texas at Austin, Austin, Texas, United States
- Manllo-Karim, Roberto, The University of Texas Rio Grande Valley School of Medicine, Edinburg, Texas, United States
Background
Thin basement membrane nephropathy (TBMN), historically considered benign familial hematuria, is now recognized as part of a broader COL4-related nephropathy spectrum. Heterozygous pathogenic variants in COL4A3 and COL4A4 can cause autosomal dominant (AD) disease with phenotypes ranging from isolated microscopic hematuria to proteinuria, chronic kidney disease (CKD), and Alport-spectrum pathology.
Methods
We reviewed nephrology records, renal biopsy findings, urine protein studies, renal function data, pedigree information, and renal genetic testing from two unrelated families evaluated for hereditary nephropathy. Clinical findings were correlated with COL4 variant segregation, renal outcomes, and histopathology.
Results
In family 1, the likely pathogenic heterozygous COL4A3 c.1372G>C (p.Gly458Arg) variant was identified across three generations and traced to the maternal grandmother, consistent with AD COL4A3-related nephropathy. Phenotypes range from persistent microscopic hematuria with preserved kidney function to proteinuria. A pediatric biopsy showed diffuse glomerular basement membrane thinning, focal lamina densa splitting, and segmental podocyte foot process effacement, consistent with Alport-spectrum disease. Alpha-5 collagen IV staining was preserved. Unaffected relatives tested negative for the familial variant, supporting segregation.
In family 2, an affected father with biopsy-confirmed TBMN had three daughters, two affected and one unaffected, supporting AD inheritance. Affected relatives carried a pathogenic heterozygous COL4A4 c.1441G>A (p.Gly481Ser) variant. Severity ranged from microscopic hematuria with preserved renal function to CKD stage 3 with renal atrophy and proteinuria. No hearing or ocular involvement was documented. Although additional renal variants were identified, the COL4A3/COL4A4 variants best aligned with the nephropathy phenotypes.
Conclusion
These families demonstrate marked phenotypic heterogeneity in AD COL4-related nephropathy, spanning isolated microscopic hematuria, TBMN, Alport-spectrum biopsy findings, and progressive CKD. The findings support the view that TBMN and AD Alport syndrome represent a unified COL4-related disease spectrum. Pedigree analysis, genetic testing, renal pathology, longitudinal monitoring, and extrarenal screening are essential for diagnosis, risk stratification, and cascade family evaluation.