Abstract: FR-PO0117
A Novel COL4A4 Missense Variant and a Nonsense Variant: Contrasting Presentations of Alport Syndrome
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
- Ruiz, Brian, Allegheny General Hospital, Pittsburgh, Pennsylvania, United States
- Turk, Michael Nabil, Allegheny General Hospital, Pittsburgh, Pennsylvania, United States
Introduction
Alport syndrome is a hereditary nephropathy and a recognized cause of progressive chronic kidney disease (CKD), classically associated with hematuria, proteinuria, sensorineural hearing loss, and ocular abnormalities. It is most commonly linked to mutations in COL4A5 encoding the
α5 chain of type IV collagen; however, the spectrum of disease related to type IV collagen mutations is broader and more heterogeneous than traditionally described. We present two cases of COL4A4-related Alport syndrome demonstrating discordant clinical severity and genotype–phenotype correlation.
Case Description
A 31-year-old female with T2DM, hypertension, and obesity presented with progressive proteinuria (500→2800 mg/g over two years) and lifelong microscopic hematuria, with preserved eGFR (>100 mL/min) and family history of hematuria. Kidney biopsy showed GBM thinning with segmental remodeling, focal lamellation, global glomerulosclerosis (8/22 glomeruli), and mild interstitial fibrosis. Genetic testing revealed a novel missense COL4A4 mutation (Gly→Asp, codon 1270, exon 40). She was treated with RAAS blockade (losartan) and antihypertensives. A 52-year-old female with hypertension and hyperlipidemia presented with progressive CKD (Cr 1.18→1.54 mg/dL), fatigue, hematuria, and proteinuria (ACR ~1019 mg/g). Autoimmune workup was negative. Genetic testing demonstrated a heterozygous nonsense COL4A4 mutation (exon 32), consistent with autosomal dominant Alport syndrome. Subsequent biopsy showed sclerosing glomerulopathy, abnormal GBM, tubular atrophy, and moderate interstitial fibrosis. She was started on losartan with planned audiology and ophthalmology evaluation.
Discussion
These cases highlight marked phenotypic variability in COL4A4-related Alport syndrome. A novel missense mutation was associated with preserved renal function despite longstanding hematuria, suggesting a milder disease course. In contrast, a truncating mutation correlated
with progressive CKD and advanced histopathologic changes. This variability underscores the importance of genetic testing for diagnosis, prognostication, and individualized management in Alport syndrome.