| Affiliation: | 1. Laboratory of Medical Genetics, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Rome, Italy;2. Division of Medical Genetics, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo (Foggia), Italy;3. Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy;4. Division of Metabolism and Children's Research Centre, University Children's Hospital, Zurich, Switzerland;5. Maritime Medical Genetics Service, Dalhousie University, Halifax, Canada;6. Laboratory of Medical Genetics, IRCCS Bambino Gesù Children Hospital, Rome, Italy;7. Department of Clinical Genetics, Children's Health Ireland (CHI) at Crumlin, Crumlin, Ireland;8. Unit of Rare Diseases, IRCCS Institute Gianna Gaslini, Genoa, Italy;9. Center for Medical Genetics, Ghent University, Ghent, Belgium;10. Unit of Bioinformatics, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo (Foggia), Italy;11. The Platinum Medical Center, The Wellington Hospital, London, UK;12. Connective Tissue Unit, Division of Metabolism and Children's Research Centre, University Children's Hospital, Zurich, Switzerland |
| Abstract: | The 2017 classification of Ehlers-Danlos syndromes (EDS) identifies three types associated with causative variants in COL1A1/COL1A2 and distinct from osteogenesis imperfecta (OI). Previously, patients have been described with variable features of both disorders, and causative variants in COL1A1/COL1A2; but this phenotype has not been included in the current classification. Here, we expand and re-define this OI/EDS overlap as a missing EDS type. Twenty-one individuals from 13 families were reported, in whom COL1A1/COL1A2 variants were found after a suspicion of EDS. None of them could be classified as affected by OI or by any of the three recognized EDS variants associated with COL1A1/COL1A2. This phenotype is dominated by EDS-related features. OI-related features were limited to mildly reduced bone mass, occasional fractures and short stature. Eight COL1A1/COL1A2 variants were novel and five recurrent with a predominance of glycine substitutions affecting residues within the procollagen N-proteinase cleavage site of α1(I) and α2(I) procollagens. Selected variants were investigated by biochemical, ultrastructural and immunofluorescence studies. The pattern of observed changes in the dermis and in vitro for selected variants was more typical of EDS rather than OI. Our findings indicate the existence of a wider recognizable spectrum associated with COL1A1/COL1A2. |
