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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
Abstract
A study of 269 children enrolled into a National Registry for children with persistent glomerular hematuria identified 131 individuals with genetically confirmed X-linked Alport Syndrome. A single variant c.1871G>A p.Gly624Asp (G624D) in COL4A5 was predominant and accounted for 39% of Xlinked Alport Syndrome in unrelated Polish families (44 of 113). To evaluate its origins, the genetic variation in a 2.79 Mb segment encompassing the COL4A5 locus on chromosome X was assessed. All G624D alleles were found on the same rare haplotype background, indicating a founder effect dating back to the 12-13th century. The phenotypic data of 131 children with X-linked Alport Syndrome and their 195 affected adult relatives revealed that the G624D variant was associated with a significantly milder clinical course in comparison to other pathogenic COL4A5 variants. Furthermore the clinical course of this genetically uniform cohort was milder than that observed in individuals with other COL4A5 missense mutations. In spite of the benign clinical manifestation throughout childhood and early adulthood, the G624D variant confers significant risk for both kidney failure and deafness in males, albeit 20-30 years later than that observed in individuals with other COL4A5 pathogenic variants (50% cumulative risk of starting dialysis at 54 years (95% confidence interval: 50-62) v. 26 years (95% confidence interval: 22-30)). Thus, males with G624D are candidates for existing and emerging therapies for Alport Syndrome.
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Authors (28)
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Aleksandra M. Żurowska
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Olga Bielska
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Patrycja Daca-Roszak
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Maciej Jankowski
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Maria Szczepańska
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Dagmara Roszkowska-Bjanid
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Elżbieta Kuźma-Mroczkowska
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Małgorzata Pańczyk-Tomaszewska
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Anna Moczulska
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Dorota Drożdż
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Despina Hadjipanagi
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Constantinos Deltas
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Danuta Ostalska-Nowicka
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Alina Rabiega
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Janina Taraszkiewicz
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Katarzyna Taranta-Janusz
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Anna Wieczorkiewicz-Plaza
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Katarzyna Jobs
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Judyta Mews
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Kinga Musiał
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Anna Jakubowska
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Hanna Nosek
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Anna E. Jander
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Constantina Koutsofti
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Dominka Kuleszo
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Ewa Ziętkiewicz
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Beata S. Lipska-Ziętkiewicz
Cite as
Full text
- Publication version
- Accepted or Published Version
- DOI:
- Digital Object Identifier (open in new tab) 10.1016/j.kint.2020.10.040
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Details
- Category:
- Articles
- Type:
- artykuły w czasopismach
- Published in:
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KIDNEY INTERNATIONAL
no. 99,
pages 1451 - 1458,
ISSN: 0085-2538 - Language:
- English
- Publication year:
- 2021
- Bibliographic description:
- Żurowska A. M., Bielska O., Daca-Roszak P., Jankowski M., Szczepańska M., Roszkowska-Bjanid D., Kuźma-Mroczkowska E., Pańczyk-Tomaszewska M., Moczulska A., Drożdż D., Hadjipanagi D., Deltas C., Ostalska-Nowicka D., Rabiega A., Taraszkiewicz J., Taranta-Janusz K., Wieczorkiewicz-Plaza A., Jobs K., Mews J., Musiał K., Jakubowska A., Nosek H., Jander A. E., Koutsofti C., Stanisławska-Sachadyn A., Kuleszo D., Ziętkiewicz E., Lipska-Ziętkiewicz B. S.: 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 INTERNATIONAL -Vol. 99,iss. 6 (2021), s.1451-1458
- DOI:
- Digital Object Identifier (open in new tab) 10.1016/j.kint.2020.10.040
- Verified by:
- Gdańsk University of Technology
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