Abstract: TH-PO491
Unusual Glomerular Abnormalities in a Patient with Combined COL4A5-NPHS1 Variants
Session Information
- Genetic Kidney Diseases: Genotypes and Phenotypes in Cases
October 24, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1202 Genetic Diseases of the Kidneys: Non-Cystic
Authors
- Alwan, Abdelrahman, Atrium Health Wake Forest Baptist Medical Center, Winston-Salem, North Carolina, United States
- Vincent, Carol, Atrium Health Wake Forest Baptist Medical Center, Winston-Salem, North Carolina, United States
- Lyalin, Dmitry A., Virginia Commonwealth University, Richmond, Virginia, United States
- Mikhailov, Alexei V., Atrium Health Wake Forest Baptist Medical Center, Winston-Salem, North Carolina, United States
Introduction
Collagen IV a5 (gene COL4A5) isoform is an essential part of the glomerular basement membrane (GBM) lamina densa. Pathogenic variants in COL4A5 are associated with X-linked Alport syndrome. Nephrin (gene NPHS1) is a major component of the podocyte slit diaphragm; pathogenic NPHS1 variants are autosomal recessive and manifest as childhood proteinuria. We present the first case of a patient with combined pathogenic COL4A5-NPHS1 variants resulting in unique glomerular abnormalities
Case Description
A 5-year old female (proband) presented with recurrent gross hematuria and proteinuria 80 mg albumin/g creatinine. Renal function was normal; no hearing or ocular abnormalities were detected. Her sister (3 y.o.) exhibited similar symptoms; father was diagnosed with Alport syndrome. Panel-based DNA sequencing identified pathogenic heterozygous COL4A5 c.1633G>A (p.G545S) and NPHS1 c.2417C>A (p.A806N) variants in the proband, her father and sister. Whole exome sequencing did not identify additional pathogenic/likely pathogenic variants of renal significance. The kidney biopsy revealed immature glomeruli, 5% global glomerulosclerosis, and small foci of interstitial fibrosis and tubular atrophy. Electron microscopy showed the characteristic Alport-like GBM changes. Filamentous slit diaphragms were detected in 39.9% of filtration slits between non-effaced foot processes compared to 74.9% in control (acute tubulointerstitial nephritis). In some glomeruli several, or all, capillary segments were abnormal, displaying thin irregular GBMs with large gaps covered by podocytes forming tight junctions between each other and the underlying cells. Such capillaries never contained red blood cells, and were lined by cells lacking the endothelial morphology, displaying intraluminal cross-bridges with foci of aberrant GBM formation (Figure 1).
Discussion
Two previous reports of combined COL4A5-NPHS1 variants describe hematuria and moderate proteinuria detected at 2.5-6 years of age. A kidney biopsy done in one patient showed GBM gaps. In our patient, both pathogenic variants lead to a severe mosaic glomerular capillary malformation. We hypothesize that Alport-associated alterations in GBM positioning of extracellular matrix proteins and changes in nephrin-associated signaling combine to affect the developmental cues resulting in this striking phenotype.