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DNA variant databases improve test accuracy and phenotype prediction in Alport syndrome

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Abstract

X-linked Alport syndrome is a form of progressive renal failure caused by pathogenic variants in the COL4A5 gene. More than 700 variants have been described and a further 400 are estimated to be known to individual laboratories but are unpublished. The major genetic testing laboratories for X-linked Alport syndrome worldwide have established a Web-based database for published and unpublished COL4A5 variants (https://grenada.lumc.nl/LOVD2/COL4A/home.php?select_db=COL4A5). This conforms with the recommendations of the Human Variome Project: it uses the Leiden Open Variation Database (LOVD) format, describes variants according to the human reference sequence with standardized nomenclature, indicates likely pathogenicity and associated clinical features, and credits the submitting laboratory. The database includes non-pathogenic and recurrent variants, and is linked to another COL4A5 mutation database and relevant bioinformatics sites. Access is free. Increasing the number of COL4A5 variants in the public domain helps patients, diagnostic laboratories, clinicians, and researchers. The database improves the accuracy and efficiency of genetic testing because its variants are already categorized for pathogenicity. The description of further COL4A5 variants and clinical associations will improve our ability to predict phenotype and our understanding of collagen IV biochemistry. The database for X-linked Alport syndrome represents a model for databases in other inherited renal diseases.

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Acknowledgments

We would like to thank the many patients and families with X-linked Alport syndrome whose mutations are published in the databases. We would also like to thank Dr. Dev Batish for helpful discussions.

Competing interests

The authors have no conflicts of interest to declare but DB, NZ, and HS are all employed by independent commercial or publicly listed laboratories that test for Alport syndrome.

Funding

We would also like to thank the US Alport Syndrome Foundation for providing establishment funding for the COL4A5 database, and the Australian Alport Foundation for providing funding to determine normal variants in non-Caucasian ethnicities.

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Authors and Affiliations

  1. Department of Medicine (Northern Health), The University of Melbourne, Epping, VIC, Australia

    Judy Savige & Hayat Dagher

  2. Nephrology Department, Fundacio Puigvert, Barcelona, Spain

    Elisabet Ars

  3. Human Variome Project, The University of Melbourne, Parkville, VIC, Australia

    Richard G. H. Cotton

  4. ARUP Laboratories, ARUP Institute of Clinical and Experimental Pathology, Salt Lake City, UT, USA

    David Crockett & Genevieve Pont-Kingdon

  5. Molecular Medicine Research Center and Laboratory of Molecular and Medical Genetics, Department of Biological Sciences, University of Cyprus, Nicosia, Cyprus

    Constantinos Deltas

  6. Pediatric Department, Peking University First Hospital, Beijing, China

    Jie Ding

  7. Department of Clinical Genetics, Guy’s and St Thomas’ NHS Trust Foundation, London, UK

    Frances Flinter

  8. GeneDx, Gaithersburg, MD, USA

    Nizar Smaoui

  9. Molecular Biology Laboratory, Fundacio Puigvert, Universitat Autonoma de Barcelona, Barcelona, Spain

    Roser Torra

  10. GSTS Pathology, Guy’s and St Thomas’ NHS Trust Foundation, London, UK

    Helen Storey

  11. The University of Melbourne (AH/NH), The Northern Hospital, Cooper, Epping, VIC, 3076, Australia

    Judy Savige

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  1. Judy Savige
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The International Alport Mutation Consortium

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Correspondence to Judy Savige.

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The International Alport Mutation Consortium., Savige, J., Ars, E. et al. DNA variant databases improve test accuracy and phenotype prediction in Alport syndrome. Pediatr Nephrol 29, 971–977 (2014). https://doi.org/10.1007/s00467-013-2486-8

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  • DOI: https://doi.org/10.1007/s00467-013-2486-8

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