Neeti Ghali1, Duncan Baker2, Angela F Brady3, Nigel Burrows4, Elena Cervi5, Deirdre Cilliers6, Michael Frank7, Dominique P Germain8, David J S Hulmes9, Marie-Line Jacquemont10, Peter Kannu11, Henrietta Lefroy6, Anne Legrand12, F Michael Pope13, Lisa Robertson14, Anthony Vandersteen15, Kate von Klemperer16, Renarta Warburton2, Margo Whiteford17, Fleur S van Dijk3. 1. Ehlers-Danlos Syndrome National Diagnostic Service London, North West Thames Regional Genetics Service, London North West Healthcare University NHS Trust, Harrow, Middlesex, UK. neeti.ghali@nhs.net. 2. Connective Tissue Disorders Service, Sheffield Diagnostic Genetics Service, Sheffield, UK. 3. Ehlers-Danlos Syndrome National Diagnostic Service London, North West Thames Regional Genetics Service, London North West Healthcare University NHS Trust, Harrow, Middlesex, UK. 4. Department of Dermatology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK. 5. Centre of Inherited Cardiovascular Diseases, Great Ormond Street Hospital NHS Foundation Trust, London, UK. 6. Oxford Centre for Genomic Medicine, Oxford University NHS Foundation Trust, Oxford, UK. 7. AP-HP Hopital Europeen Georges Pompidou, Departement de Genetique et Centre de Reference des Maladies Vasculaires Rares, Paris, France. 8. Division of Medical Genetics, University of Versailles, Paris-Saclay University, Montigny, France. 9. UMR5305, CNRS / Université Claude Bernard Lyon 1, Lyon, France. 10. Medical Genetics Unit, CHU La Réunion, Saint-Pierre, France. 11. Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada. 12. Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Centre de Référence des Maladies Vasculaires Rares, Paris, France. 13. Department of Dermatology, Chelsea & Westminster Hospital NHS Foundation Trust, London, UK. 14. Department of Clinical Genetics, Aberdeen Royal Infirmary, Scotland, UK. 15. Maritime Medical Genetics Service, IWK Health Centre, Halifax, NS, Canada. 16. Department of Cardiology, St Barthlomew's Hospital, London, UK. 17. Clinical Genetics West of Scotland Regional Genetics Service, Queen Elizabeth University Hospital Glasgow, Scotland, UK.
Abstract
PURPOSE: The Ehlers-Danlos syndromes (EDS) are a group of rare inherited connective tissue disorders. Vascular EDS (vEDS) is caused by pathogenic variants in COL3A1, most frequently glycine substitutions. We describe the phenotype of the largest series of vEDS patients with glutamic acid to lysine substitutions (Glu>Lys) in COL3A1, which were all previously considered to be variants of unknown significance. METHODS: Clinical and molecular data for seven families with three different Glu>Lys substitutions in COL3A1 were analyzed. RESULTS: These Glu>Lys variants were reclassified from variants of unknown significance to either pathogenic or likely pathogenic in accordance with American College of Medical Genetics and Genomics guidelines. All individuals with these atypical variants exhibited skin hyperextensibility as seen in individuals with classical EDS and classical-like EDS and evidence of tissue fragility as seen in individuals with vEDS. CONCLUSION: The clinical data demonstrate the overlap between the different EDS subtypes and underline the importance of next-generation sequencing gene panel analysis. The three different Glu>Lys variants point toward a new variant type in COL3A1 causative of vEDS, which has consistent clinical features. This is important knowledge for COL3A1 variant interpretation. Further follow-up data are required to establish the severity of tissue fragility complications compared with patients with other recognized molecular causes of vEDS.
PURPOSE: The Ehlers-Danlos syndromes (EDS) are a group of rare inherited connective tissue disorders. Vascular EDS (vEDS) is caused by pathogenic variants in COL3A1, most frequently glycine substitutions. We describe the phenotype of the largest series of vEDS patients with glutamic acid to lysine substitutions (Glu>Lys) in COL3A1, which were all previously considered to be variants of unknown significance. METHODS: Clinical and molecular data for seven families with three different Glu>Lys substitutions in COL3A1 were analyzed. RESULTS: These Glu>Lys variants were reclassified from variants of unknown significance to either pathogenic or likely pathogenic in accordance with American College of Medical Genetics and Genomics guidelines. All individuals with these atypical variants exhibited skin hyperextensibility as seen in individuals with classical EDS and classical-like EDS and evidence of tissue fragility as seen in individuals with vEDS. CONCLUSION: The clinical data demonstrate the overlap between the different EDS subtypes and underline the importance of next-generation sequencing gene panel analysis. The three different Glu>Lys variants point toward a new variant type in COL3A1 causative of vEDS, which has consistent clinical features. This is important knowledge for COL3A1 variant interpretation. Further follow-up data are required to establish the severity of tissue fragility complications compared with patients with other recognized molecular causes of vEDS.