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Fransen E, Valgaeren H, Janssens K, et al. Resequencing of candidate genes for Keratoconus reveals a role for Ehlers-Danlos Syndrome genes. Eur J Hum Genet. 2021;29(12):1745-1755doi: 10.1038/s41431-021-00849-2.
Fransen, E., Valgaeren, H., Janssens, K., Sommen, M., De Ridder, R., Vandeweyer, G., Bisceglia, L., Soler, V., Hoischen, A., Mortier, G., Malecaze, F., Koppen, C., & Van Camp, G. (2021). Resequencing of candidate genes for Keratoconus reveals a role for Ehlers-Danlos Syndrome genes. European journal of human genetics : EJHG, 29(12), 1745-1755. https://doi.org/10.1038/s41431-021-00849-2
Fransen, Erik, et al. "Resequencing of candidate genes for Keratoconus reveals a role for Ehlers-Danlos Syndrome genes." European journal of human genetics : EJHG vol. 29,12 (2021): 1745-1755. doi: https://doi.org/10.1038/s41431-021-00849-2
Fransen E, Valgaeren H, Janssens K, Sommen M, De Ridder R, Vandeweyer G, Bisceglia L, Soler V, Hoischen A, Mortier G, Malecaze F, Koppen C, Van Camp G. Resequencing of candidate genes for Keratoconus reveals a role for Ehlers-Danlos Syndrome genes. Eur J Hum Genet. 2021 Dec;29(12):1745-1755. doi: 10.1038/s41431-021-00849-2. Epub 2021 Mar 19. PMID: 33737726; PMCID: PMC8633318.
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Eur J Hum Genet. 2021 Dec;29(12):1745-1755. doi: 10.1038/s41431-021-00849-2. Epub 2021 Mar 19.

Resequencing of candidate genes for Keratoconus reveals a role for Ehlers-Danlos Syndrome genes.

European journal of human genetics : EJHG

Erik Fransen, Hanne Valgaeren, Katleen Janssens, Manou Sommen, Raphael De Ridder, Geert Vandeweyer, Luigi Bisceglia, Vincent Soler, Alexander Hoischen, Geert Mortier, François Malecaze, Carina Koppen, Guy Van Camp

Affiliations

  1. Center of Medical Genetics, University of Antwerp & Antwerp University Hospital, Prins Boudewijnlaan 43, 2650, Edegem, Antwerp, Belgium.
  2. StatUa Center for Statistics, University of Antwerp, Antwerp, Belgium.
  3. Department of Ophthalmology, Antwerp University Hospital, Wilrijkstraat 10, 2650, Edegem, Antwerp, Belgium.
  4. IRCCS Casa Sollievo della Sofferenza, UOC Genetica Medica, San Giovanni Rotondo, Italy.
  5. Department of Ophthalmology, Pierre-Paul Riquet Hospital, Toulouse University Hospital, Toulouse, France.
  6. Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 10, 6525 GA, Nijmegen, the Netherlands.
  7. Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, 6500 HB, Nijmegen, the Netherlands.
  8. Department Ophthalmology, Visual optics and Visual rehabilitation, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium.
  9. Center of Medical Genetics, University of Antwerp & Antwerp University Hospital, Prins Boudewijnlaan 43, 2650, Edegem, Antwerp, Belgium. [email protected].

PMID: 33737726 PMCID: PMC8633318 DOI: 10.1038/s41431-021-00849-2

Abstract

The involvement of genetic factors in the pathogenesis of KC has long been recognized but the identification of variants affecting the underlying protein functions has been challenging. In this study, we selected 34 candidate genes for KC based on previous whole-exome sequencing (WES) and the literature, and resequenced them in 745 KC patients and 810 ethnically matched controls from Belgium, France and Italy. Data analysis was performed using the single variant association test as well as gene-based mutation burden and variance components tests. In our study, we detected enrichment of genetic variation across multiple gene-based tests for the genes COL2A1, COL5A1, TNXB, and ZNF469. The top hit in the single variant association test was obtained for a common variant in the COL12A1 gene. These associations were consistently found across independent subpopulations. Interestingly, COL5A1, TNXB, ZNF469 and COL12A1 are all known Ehlers-Danlos Syndrome (EDS) genes. Though the co-occurrence of KC and EDS has been reported previously, this study is the first to demonstrate a consistent role of genetic variants in EDS genes in the etiology of KC. In conclusion, our data show a shared genetic etiology between KC and EDS, and clearly confirm the currently disputed role of ZNF469 in disease susceptibility for KC.

© 2021. The Author(s), under exclusive licence to European Society of Human Genetics.

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