Initial Next-Generation Sequencing NGS Results of Alport Syndrome

Abstract

Objectives: We have no series report concerning genetic etiology of Alport Syndrome AS in our country. So, we aimed to investigate AS related pathogenic variants of COL4A3, COL4A4 and COL4A5 genes in index cases and their families who referred to our center.Patients and Methods: The study includes 32 subjects 17 index cases and their relatives who are investigated between years 2018-2019 by NGS targeting the coding regions of related genes. The test results and clinical findings of the cases are studied retrospectively.Results: By the presented study, 19 individuals identified to have COL4A3 and COL4A5 variations which could be important for the clinical management. In four cases, there are novel variants. In two cases, there are digenic variations. There is no clinically relevant variant in COL4A4 gene. The most frequent three mutations of COL4A5 gene reported in United States US are not determined in our study group.Conclusion: The diagnostic genetic tests of AS should be designed to include whole coding regions of COL4A3 and COL4A5 genes, not just for the frequently reported pathogenic variants. The cases without pathogenic variants by sequencing should be investigated for deletions/duplications of COL4A5 gene. Clinical findings of our cases with novel genetic variants are presented as a contribution to literature

Keywords

• Alport syndrome,Hereditary Nephritis,COL4A3,COL4A4,COL4A5

References

1. Kashtan CE. Alport Syndrome. GeneReviews®. University of Washington, Seattle; pp.1993–2019. Available at: http://www.ncbi. nlm.nih.gov/books/NBK1207/
2. Kashtan CE. Genetics, pathogenesis, and pathology of Alport syndrome (hereditary nephritis). Uptodate. 2018. Available at: https://www. uptodate.com/contents/genetics-pathogenesis-and-pathology-of- alport-syndrome-hereditary-nephritis?search=alport&source=sear ch_result&selectedTitle=2~40&usage_type=default&display_rank=2
3. Nozu K, Nakanishi K, Abe Y, et al. A review of clinical characteristics and genetic backgrounds in Alport Syndrome. Clin Exp Nephrol 2019;23:158–168. [CrossRef]
4. Yilmaz VT, Dinckan A, Yilmaz F, Suleymanlar G, Kocak H. Outcomes of Renal Transplantation in Patients With Alport Syndrome. Transplant Proc 2015;47:1377–1381. [CrossRef]
5. Kamiyoshi N, Nozu K, Fu XJ, et al. Genetic, Clinical, and Pathologic Backgrounds of Patients with Autosomal Dominant Alport Syndrome. Clin J Am Soc Nephrol 2016;11:1441–1449. [CrossRef]
6. Mencarelli MA, Heidet L, Storey H, et al. Evidence of digenic inheritance in Alport syndrome. J Med Genet 2015;52:163–174. [CrossRef]
7. Fallerini C, Baldassarri M, Trevisson E, et al. Alport syndrome: impact of digenic inheritance in patients management. Clin Genet 2017;92:34–44. [CrossRef]
8. Krol RP, Nozu K, Nakanishi K, et al. Somatic mosaicism for a mutation of the COL4A5 gene is a cause of mild phenotype male Alport syndrome. Nephrol Dial Transplant 2008;23:2525–2530. [CrossRef] https://doi.org/10.1093/ndt/gfn005

9. Adıyeke SK, Ture G, Mutlubaş F, et al. Increased Subfoveal Choroidal Thickness and Retinal Structure Changes on Optical Coherence Tomography in Pediatric Alport Syndrome Patients. J Ophthalmol 2019;2019:1–7. [CrossRef]
10. Antignac C, Heidet L. Mutations in Alport Syndrome associated with diffuse esophageal leiomyomatosis. Contrib Nephrol 1996;117:172– 82. [CrossRef]
11. Gross O, Kashtan CE, Rheault MN, et al. Advances and unmet needs in genetic, basic and clinical science in AS: report from the 2015 International Workshop on AS. Nephrol Dial Transplant 2017;32:916– 924. [CrossRef]
12. Savige J, Gregory M, Gross O, Kashtan C, Ding J, Flinter F. Expert guidelines for the management of AS and thin basement membrane nephropathy. J Am Soc Nephrol 2013;24:364–375. [CrossRef]
13. Uzak AS, Tokgoz B, Dundar M, Tekin M. A Novel COL4A3 Mutation Causes Autosomal-Recessive AS in a Large Turkish Family. Genet Test Mol Biomarkers 2013;17:260–4. [CrossRef]
14. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17:405–423. [CrossRef]
15. Hertz JM, Thomassen M, Storey H, Flinter F. Clinical utility gene card for: Alport syndrome - update 2014. Eur J Hum Genet 2015;23:1269. [CrossRef]