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More than meets the eye: expanding and reviewing the clinical and mutational spectrum of brittle cornea syndrome
  • +13
  • Tibbe Dhooge,
  • Tim Van Damme,
  • Delfien Syx,
  • Laura Muiño Mosquera,
  • Sheela Nampoothiri,
  • Anil Radhakrishnan,
  • Pelin Simsek-Kiper,
  • Gülen Eda Utine,
  • Maryse Bonduelle,
  • Isabelle Migeotte,
  • Osama Essawi,
  • Serdar Ceylaner,
  • Adila Alkindi,
  • Brad Tinkle,
  • Sofie Symoens,
  • Fransiska Malfait
Tibbe Dhooge
Ghent University and Ghent University Hospital
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Tim Van Damme
Ghent University and Ghent University Hospital
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Delfien Syx
Ghent University and Ghent University Hospital
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Laura Muiño Mosquera
Ghent University and Ghent University Hospital
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Sheela Nampoothiri
Amrita Institute of Medical Sciences and Research Centre
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Anil Radhakrishnan
Amrita Institute of Medical Sciences and Research Centre
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Pelin Simsek-Kiper
Hacettepe University Faculty of Medicine
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Gülen Eda Utine
Hacettepe University
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Maryse Bonduelle
Universitair Ziekenhuis Brussel
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Isabelle Migeotte
Université Libre de Bruxelles
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Osama Essawi
Ghent University and Ghent University Hospital
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Serdar Ceylaner
Intergen Genetic Research Center
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Adila Alkindi
Sultan Qaboos University
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Brad Tinkle
Peyton Manning Children's Hospital
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Sofie Symoens
Ghent University and Ghent University Hospital
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Fransiska Malfait
Ghent University and Ghent University Hospital
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Abstract

Brittle cornea syndrome (BCS) is a rare autosomal recessive disorder characterized by corneal thinning and fragility, leading to corneal rupture, the main hallmark of this disorder. Non-ocular symptoms include hearing loss, but also signs of connective tissue fragility, placing it in the Ehlers-Danlos syndrome (EDS) spectrum. It is caused by biallelic pathogenic variants in ZNF469 or PRDM5, which presumably encode transcription factors for extracellular matrix components. We report the clinical and molecular features of nine novel BCS families, four of which harbor variants in ZNF469 and five in PRDM5. We also performed a genotype and phenotype-oriented literature overview of all (N=85) reported patients with ZNF469 (N=53) and PRDM5 (N=32) variants. Musculoskeletal findings may be the mean reason for referral, and often raise suspicion of another heritable connective tissue disorder such as kyphoscoliotic EDS, osteogenesis imperfecta or Marfan syndrome, especially when corneal rupture has not yet occurred. Our findings highlight the multisystemic nature of BCS and validate its inclusion in the EDS classification. Importantly, gene panels for heritable connective tissue disorders should include ZNF469 and PRDM5 to allow for timely diagnosis and appropriate preventive measures for this rare condition.

Peer review status:Published

06 Oct 2020Submitted to Human Mutation
08 Oct 2020Submission Checks Completed
08 Oct 2020Assigned to Editor
12 Oct 2020Reviewer(s) Assigned
13 Nov 2020Review(s) Completed, Editorial Evaluation Pending
23 Nov 2020Editorial Decision: Revise Minor
28 Nov 20201st Revision Received
30 Nov 2020Submission Checks Completed
30 Nov 2020Assigned to Editor
26 Jan 2021Reviewer(s) Assigned
01 Feb 2021Review(s) Completed, Editorial Evaluation Pending
16 Mar 2021Editorial Decision: Accept
19 Mar 2021Published in Human Mutation. 10.1002/humu.24199