impact factor, citescore
logo
In press
In Press
Recent issue
Recent issue
Recent Supplement
Recent supplement
archives
Archives
articles free
Free to view
Search
Search
 

Full Papers

 

Atypical variants in COL1A1 and COL3A1 associated with classical and vascular Ehlers-Danlos syndrome overlap phenotypes: expanding the clinical phenotype based on additional case reports

1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22

 

  1. Centre for Medical Genetics, Department of Biomolecular Medicine, Faculty of Medicine and Health Sciences, Ghent University and Ghent University Hospital, Belgium.
  2. Division of Medical Genetics, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy.
  3. Division of Medical Genetics, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy.
  4. Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Italy.
  5. Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Italy.
  6. Ehlers-Danlos Syndrome National Diagnostic Service London, North West Thames Regional Genetics Service, London North West Healthcare University NHS Trust, Harrow, Middlesex, UK.
  7. National Ehlers Danlos Syndrome Diagnostic Service, Northwick Park and St. Mark’s Hospitals, Harrow, UK.
  8. Clinique de Génétique, CHU Lille, France and Utrecht University, University Medical Center Utrecht, Department of Genetics, Utrecht, The Netherlands.
  9. Neurosurgery, Dalhousie University, Halifax, Nova Scotia, Canada.
  10. Maritime Medical Genetics Service, IWK Health Centre, Halifax, Nova Scotia, Canada.
  11. Maritime Medical Genetics Service, IWK Health Centre, Halifax, Nova Scotia, Canada.
  12. Département de Génétique, Centre National de Référence pour les Maladies Vasculaires Rares, Centre de Référence Européen VASCERN MSA, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
  13. Département de Génétique, Centre National de Référence pour les Maladies Vasculaires Rares, Centre de Référence Européen VASCERN MSA, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
  14. Département de Génétique, Centre National de Référence pour les Maladies Vasculaires Rares, Centre de Référence Européen VASCERN MSA, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
  15. Medical Genetics Unit, Experimental Medicine Department, Sapienza University, San Camillo-Forlanini Hospital, Rome, Italy.
  16. Medical Genetics Unit, Experimental Medicine Department, Sapienza University, San Camillo-Forlanini Hospital, Rome, Italy.
  17. Medical Genetics Unit, Experimental Medicine Department, Sapienza University, San Camillo-Forlanini Hospital, Rome, Italy.
  18. Deutsche Ehlers-Danlos Initiative e.V., Fürth, Germany.
  19. Bindweefsel.be, Koersel, Belgium.
  20. Centre for Medical Genetics, Department of Biomolecular Medicine, Faculty of Medicine and Health Sciences, Ghent University and Ghent University Hospital, Belgium.
  21. Centre for Medical Genetics, Department of Biomolecular Medicine, Faculty of Medicine and Health Sciences, Ghent University and Ghent University Hospital, Belgium.
  22. Centre for Medical Genetics, Department of Biomolecular Medicine, Faculty of Medicine and Health Sciences, Ghent University and Ghent University Hospital, Belgium. fransiska.malfait@ugent.be

CER15380
2022 Vol.40, N°5 ,Suppl.134
PI 0046, PF 0062
Full Papers

Free to view
(click on article PDF icon to read the article)

PMID: 35587586 [PubMed]

Received: 29/11/2021
Accepted : 20/04/2022
In Press: 18/05/2022
Published: 18/05/2022

Abstract

The vast majority of reported (likely) pathogenic missense variants in the genes coding for the fibrillar collagens leads to the substitution of one of the obligatory glycine residues in the Gly-Xaa-Yaa repeat sequence of the triple helical domain. Their phenotypic consequences and deleterious effects have been well-documented. However, with increasing access to molecular diagnostic testing based on next-generation sequencing techniques, such as sequencing of multi-gene panels and whole-exome sequencing, non-glycine substitutions are more frequently identified in individuals suspected to have a heritable collagen disorder, but their pathogenic effect is often difficult to predict. Some specific non-glycine substitutions in the proα1(I)- (p.(Arg312Cys)) and proα1(III)- (glutamic acid to lysine at different positions) collagen chain have been identified in a number of individuals presenting a phenotype showing features of both classical and vascular Ehlers-Danlos syndrome. The number of reported individuals with these defects is currently very low, and several of these non-glycine substitutions had initially been categorised as variants of unknown significance (VUS), complicating early diagnosis, accurate counselling, management guidelines, and correct classification. This collaborative study reports on the phenotype of 22 and 7 individuals harbouring these rare variants in COL1A1 and COL3A1, respectively, expanding our knowledge on clinical presentation, phenotypic variability, and natural history, and informing on the risk for potentially life-threatening events, such as vascular, gastro-intestinal, and pregnancy-related complications.

DOI: https://doi.org/10.55563/clinexprheumatol/kzkq6y

Rheumatology Article