Abstract: TH-PO0583
Novel Intronic Collagen4A5 Mutation Causing Familial Alport 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
- Koenigshausen, Eva, Heinrich-Heine-Universitat Dusseldorf, Düsseldorf, NRW, Germany
- Eisenberger, Tobias, MVZ Medizinische Genetik Mainz, Mainz, Germany
- Strueve, Marcel, MVZ Medizinische Genetik Mainz, Mainz, Germany
- Wiech, Thorsten, Universitatsklinikum Hamburg-Eppendorf, Hamburg, HH, Germany
- Rump, Lars C., Heinrich-Heine-Universitat Dusseldorf, Düsseldorf, NRW, Germany
- Bergmann, Carsten, MVZ Medizinische Genetik Mainz, Mainz, Germany
- Sellin, Lorenz, Heinrich-Heine-Universitat Dusseldorf, Düsseldorf, NRW, Germany
Background
Alport Syndrome is the most common genetic kidney disease and caused by mutations in Collagen 4A3, A4 and A5 (Col4A3, Col4A4 and Col4A5) genes. These genes encode for collagen IV alpha3, alpha4 and alpha5 chains which assemble to collagen IV alpha 3,4,5 heterotrimers. ColIV alpha 3,4,5 heterotrimers form the main network of the adult glomerular basement membrane. Col4A5 mutations cause the X-linked Alport Syndrome (XLAS). Typically, these mutations are located in Col4A5 exons, however, three intronic Col4A5 mutations have been previously described.
Methods
The index patient was evaluated for living kidney transplantation revealing a family history of hematuria, proteinuria and CKD. We investigated family members living in Germany for renal function and urine analysis. Three family members received indication-driven kidney biopsy. Whole genome sequencing (WGS) was performed in the index patient to screen for non-coding, deep-intronic variants. AI-driven bioinformatic prediction algorithms were applied to predict splicing effects of candidate variants. Finally, segregation analysis of the putative pathogenic variant was conducted within this large family.
Results
Study participants originated from a large two-generation, German-Turkish partially consanguine family. 14 family members in Germany were investigated. Clinical features ranged from hematuria, proteinuria and CKD5 or CKD5T. Renal histology showed a ColIV-associated nephropathy. Known mutations for ColIV-associated nephropathy were not found. WGS revealed an intronic mutation in Col4A5 located between exon 6 and 7. AI based prediction tools indicate a donor splice cite gain caused by the mutation resulting in a premature stop in all reading top three frames within the novel exon 6’. Due to convincing segregation analysis this novel variant could be classified as likely pathogenic. To address mutated Col4A5 function, RNA-seq analysis from index patients’ fibroblasts is planned.
Conclusion
Identification of this novel intronic Col4A5 mutation will help to identify a familial living kidney donor for the index patient and will help to identify the genetic cause of Col4-associated nephropathy in other unexplained cases.