Generate QR code
Open Access
Subscription Access
Molecular and clinical features of Alport syndrome
https://doi.org/10.25557/2073-7998.2025.07.40-43
Abstract
Alport Syndrome (AS) is a heterogeneous progressive disease characterized by nephritic syndrome, often sensorineural deafness, and less frequently ophthalmological symptoms. There are autosomal dominant, autosomal recessive, and X-linked AS. he prevalence of Alport syndrome averages 1:5,000-10,000 newborns. The disease is caused by pathogenic and likely pathogenic variants in genes encoding α3, α4, and α5 chains of type IV collagen (COL4A3, COL4A4, COL4A5). Pathological variants in these genes account for 20-30% of chronic kidney diseases and end-stage renal disease in adulthood among inherited nephropathies. There were examined 327 unrelated patients, for 130 of whom the diagnosis was confirmed. X-linked inheritance was identified in 47%, autosomal recessive in 6.9% of cases, and autosomal dominant in 39.2%, what differs from the distribution structure of AS forms in the world. Repeating variants matching the literature data have been identified in all three genes. There was no clear correlation between the more severe course and the type of mutation in any of the genes.
Supporting agencies: The research was carried out within the state assignment by the Ministry of Science and Higher Education of the Russian Federation for Research Centre for Medical Genetics.
About the Authors
V. A. Kadnikova
Research Centre for Medical Genetics
Russian Federation
Russian Federation
1, Moskvorechie st., Moscow, 115522
N. M. Galeeva
Research Centre for Medical Genetics
Russian Federation
Russian Federation
1, Moskvorechie st., Moscow, 115522
E. A. Shestopalova
Research Centre for Medical Genetics
Russian Federation
Russian Federation
1, Moskvorechie st., Moscow, 115522
L. A. Bessonova
Research Centre for Medical Genetics
Russian Federation
Russian Federation
1, Moskvorechie st., Moscow, 115522
O. P. Ryzhkova
Research Centre for Medical Genetics
Russian Federation
Russian Federation
1, Moskvorechie st., Moscow, 115522
A. V. Polyakov
Research Centre for Medical Genetics
Russian Federation
Russian Federation
1, Moskvorechie st., Moscow, 115522
References
1. Gubler M., Levy M., Broyer M., et al. Alport’s syndrome. A report of 58 cases and a review of the literature. Am J Med. 1981; 70(3):493-505.
2. Savige J., Rana K., Tonna S., et al. Thin basement membrane nephropathy. Kidney Int. 2003; 64(4):1169-1178.
3. Gibson J., Fieldhouse R., Chan M.M.Y., et al. Prevalence Estimates of Predicted Pathogenic COL4A3-COL4A5 Variants in a Population Sequencing Database and Their Implications for Alport Syndrome. J Am Soc Nephrol. 2021; 32(9):2273-2290.
4. Groopman E.E., Marasa M., Cameron-Christie S., et al. Diagnostic Utility of Exome Sequencing for Kidney Disease. N Engl J Med. 2019; 380(2):142-151.
5. Bleyer A.J., Westemeyer M., Xie J., et al. Genetic Etiologies for Chronic Kidney Disease Revealed through Next-Generation Renal Gene Panel. Am J Nephrol. 2022; 53(4):297-306.
6. Zhao X., Chen C., Wei Y., et al. Novel mutations of COL4A3, COL4A4, and COL4A5 genes in Chinese patients with Alport Syndrome using next generation sequence technique. Mol Genet Genomic Med. 2019; 7(6):e653.
7. Matthaiou A., Poulli T., Deltas C. Prevalence of clinical, pathological and molecular features of glomerular basement membrane nephropathy caused by COL4A3 or COL4A4 mutations: a systematic review. Clin Kidney J. 2020; 13(6):1025-1036.
8. Macheroux E.P., Braunisch M.C., Pucci Pegler S., et al. The Hypomorphic Variant p.(Gly624Asp) in COL4A5 as a Possible Cause for an Unexpected Severe Phenotype in a Family With X-Linked Alport Syndrome. Front Pediatr. 2019; 7:485.
9. Kashtan C.E. Familial hematurias: what we know and what we don’t. Pediatr Nephrol. 2005; 20(8):1027-1035.
10. Marinakis N.M., Svingou M., Veltra D., et al. Phenotype-driven variant filtration strategy in exome sequencing toward a high diagnostic yield and identification of 85 novel variants in 400 patients with rare Mendelian disorders. Am J Med Genet A. 2021; 185(8):2561-2571.
11. Zupan A., Matjasic A., Grubelnik G., Tasic V., Momirovska A. Mutations in Collagen Genes in the Context of an Isolated Population. Genes (Basel). 2020; 11(11):1377.
12. Zurowska A.M., Bielska O., Daca-Roszak P., et al. Mild X-linked Alport syndrome due to the COL4A5 G624D variant originating in the Middle Ages is predominant in Central/East Europe and causes kidney failure in midlife. Kidney Int. 2021; 99(6):1451-1458.
13. Pierides A., Voskarides K., Kkolou M., Hadjigavriel M., Deltas C. X-linked, COL4A5 hypomorphic Alport mutations such as G624D and P628L may only exhibit thin basement membrane nephropathy with microhematuria and late onset kidney failure. Hippokratia. 2013; 17(3):207-213.
14. Slajpah M., Gorinsek B., Berginc G., et al. Sixteen novel mutations identified in COL4A3, COL4A4, and COL4A5 genes in Slovenian families with Alport syndrome and benign familial hematuria. Kidney Int. 2007; 71(12):1287-1295.
15. Bekheirnia M.R., Reed B., Gregory M.C., et al. Genotype-phenotype correlation in X-linked Alport syndrome. J Am Soc Nephrol 2010, 21(5):876-883.
16. Kopadze S., Shoshiashvili I., Dumbadze A., Tkemaladze T., Kiladze I. Neuroendocrine pancreatic tumor in a patient with dual diagnosis of tuberous sclerosis complex and basement membrane disease: A case report and review of the literature. Radiol Case Rep. 2021; 16(11):3581-3588.
17. Doreille A., Lombardi Y., Dancer M., et al. Exome-First Strategy in Adult Patients With CKD: A Cohort Study. Kidney Int Rep. 2023; 8(3):596-605.
18. Groen In ‘t Woud S., Rood I.M., Steenbergen E., et al. Kidney Disease Associated With Mono-allelic COL4A3 and COL4A4 Variants: A Case Series of 17 Families. Kidney Med. 2023; 5(4):100607.
19. Jayasinghe K., Stark Z., Kerr PG., et al. Clinical impact of genomic testing in patients with suspected monogenic kidney disease. Genet Med. 2021; 23(1):183-191.
20. Li Y., Groopman E.E., D’Agati V., et al. Type IV Collagen Mutations in Familial IgA Nephropathy. Kidney Int Rep. 2020; 5(7):1075-1078.
21. Storey H., Savige J., Sivakumar V., Abbs S., Flinter F.A. COL4A3/ COL4A4 mutations and features in individuals with autosomal recessive Alport syndrome. J Am Soc Nephrol. 2013; 24(12):1945-1954.
22. Zhang Y., Ding J., Zhang H., et al. Effect of heterozygous pathogenic COL4A3 or COL4A4 variants on patients with X-linked Alport syndrome. Mol Genet Genomic Med. 2019; 7(5):e647.
Review
For citations:
Kadnikova V.A., Galeeva N.M., Shestopalova E.A., Bessonova L.A., Ryzhkova O.P., Polyakov A.V. Molecular and clinical features of Alport syndrome. Medical Genetics. 2025;24(7):40-43. (In Russ.) https://doi.org/10.25557/2073-7998.2025.07.40-43
Views:
4
Email this article 