Abstract: FR-PO0127
A Novel Case of Multigenerational COL4A3/A4 Glomerulopathy 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
- Shahreki, Elham, Geisinger Health, Danville, Pennsylvania, United States
- Urban, Gretchen M., Geisinger Health, Danville, Pennsylvania, United States
- Sanghi, Pooja, Geisinger Health, Danville, Pennsylvania, United States
Introduction
Pathogenic and likely pathogenic variants in COL4A3/COL4A4 and COL4A5 can cause a spectrum of glomerular disease( GD) ranging from thin basement membrane nephropathy to Autosomal Recessive Alport Syndrome ( ARAS) and X linked Alport syndrome( AS).Digenic inheritance has been associated with any combination of the three AS genes and may produce clinical outcomes similar to biallelic disease. We present a family illustrating a phenotypic spectrum of COL4A3/COL4A4 related GD and clinical implications of potential digenic inheritance.
Case Description
The proband is a 16-year-oldmale presenting with mild proteinuria and hematuria. He was found to carry a monoallelic pathogenic COL4A4variant. His father, compound heterozygous for 2 pathogenic variants (ARAS), progressed to ESKD and has undergone 2 kidney transplants (Tx). His father also has retinal atrophy in both eyes and sensorineural hearing loss. His mother has personal history of hematuria and is heterozygous for likely pathogenic variants in COL4A3 gene. Of note she is not a part of paternal genetic lineage. The father’s post Tx course remains stable. The proband’s creatinine is normal and has normal audiometry exam.
Discussion
This family( fig 1) emphasizes the phenotypic severity of biallelic COL4A4 disease, with progression to ESKD requiring repeat Tx. It also highlights the impact genetic testing can have on our understanding of disease progression for an individual as those with digenic disease ( COL4A3+COL4A4 in trans) who which would confer a worse prognosis than monoallelic disease alone. The presence of proteinuria in the proband, rather than isolated hematuria, is a recognized risk factor for disease progression in heterozygous carriers. Current guidelines recommend early RAS blockade, lifelong nephrology follow-up, and avoidance of kidney donation in all.
Acknowledgment
1-COL4A3/COL4A4 Mutations and Features in Individuals With Autosomal Recessive Alport Syndrome. Storey H, Savige J, Sivakumar V, Abbs S, Flinter FA. Journal of the American Society of Nephrology : JASN. 2013;24(12):1945-54. doi:10.1681/ASN.2012100985.
2- Features of Autosomal Recessive Alport Syndrome: A Systematic Review. Lee JM, Nozu K, Choi DE, et al. Journal of Clinical Medicine. 2019;8(2):E178. doi:10.3390/jcm8020178.