University of Oulu

Gibson, J., Fieldhouse, R., Chan, M. M. Y., Sadeghi-Alavijeh, O., Burnett, L., Izzi, V., Persikov, A. V., Gale, D. P., Storey, H., Savige, J., & on behalf of the Genomics England Gibson, J., Fieldhouse, R., Chan, M., Sadeghi-Alavijeh, O., Burnett, L., Izzi, V., Persikov, A., Gale, D., Storey, H., & Savige, J. (2021). Prevalence estimates of predicted pathogenic COL4A3–COL4A5 variants in a population sequencing database and their implications for Alport syndrome. Journal of the American Society of Nephrology, 32(9), 2273–2290. https://doi.org/10.1681/ASN.2020071065

Prevalence estimates of predicted pathogenic COL4A3COL4A5 variants in a population sequencing database and their implications for Alport syndrome

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Author: Gibson, Joel1; Fieldhouse, Rachel2; Chan, Melanie M.Y.3,4;
Organizations: 1The University of Melbourne Department of Medicine, Melbourne Health and Northern Health, Royal Melbourne Hospital, Parkville, Victoria, Australia
2Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
3Department of Renal Medicine, University College London, London, United Kingdom
4Genomics England, Queen Mary University of London, London, United Kingdom
5Center for Cell-Matrix Research and Biocenter Oulu, University of Oulu, Oulu, Finland
6Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey
7Molecular Genetics, Viapath Laboratories, Guy’s Hospital, London, United Kingdom
Format: article
Version: accepted version
Access: open
Online Access: PDF Full Text (PDF, 0.9 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2022022320638
Language: English
Published: American Society of Nephrology, 2021
Publish Date: 2022-02-23
Description:

Abstract

Background: The reported prevalence of Alport syndrome varies from one in 5000 to one in 53,000 individuals. This study estimated the frequencies of predicted pathogenic COL4A3COL4A5 variants in sequencing databases of populations without known kidney disease.

Methods: Predicted pathogenic variants were identified using filtering steps based on the ACMG/AMP criteria, which considered collagen IV α3–α5 position 1 Gly to be critical domains. The population frequencies of predicted pathogenic COL4A3COL4A5 variants were then determined per mean number of sequenced alleles. Population frequencies for compound heterozygous and digenic combinations were calculated from the results for heterozygous variants.

Results: COL4A3COL4A5 variants resulting in position 1 Gly substitutions were confirmed to be associated with hematuria (for each, P<0.001). Predicted pathogenic COL4A5 variants were found in at least one in 2320 individuals. p.(Gly624Asp) represented nearly half (16 of 33, 48%) of the variants in Europeans. Most COL4A5 variants (54 of 59, 92%) had a biochemical feature that potentially mitigated the clinical effect. The predicted pathogenic heterozygous COL4A3 and COL4A4 variants affected one in 106 of the population, consistent with the finding of thin basement membrane nephropathy in normal donor kidney biopsy specimens. Predicted pathogenic compound heterozygous variants occurred in one in 88,866 individuals, and digenic variants in at least one in 44,793.

Conclusions: The population frequencies for Alport syndrome are suggested by the frequencies of predicted pathogenic COL4A3COL4A5 variants, but must be adjusted for the disease penetrance of individual variants and for the likelihood of already diagnosed disease and non-Gly substitutions. Disease penetrance may depend on other genetic and environmental factors.

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Series: Journal of the American Society of Nephrology
ISSN: 1046-6673
ISSN-E: 1533-3450
ISSN-L: 1046-6673
Volume: 32
Issue: 9
Pages: 2273 - 2290
DOI: 10.1681/ASN.2020071065
OADOI: https://oadoi.org/10.1681/ASN.2020071065
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
Subjects:
Copyright information: Copyright © 2021 by the American Society of Nephrology.