COL1-related overlap disorder: A novel connective tissue disorder incorporating the osteogenesis imperfecta/Ehlers-Danlos syndrome overlap: Clinical Genetics

S. Morlino, L. Micale, M. Ritelli, M. Rohrbach, N. Zoppi, A. Vandersteen, S. Mackay, E. Agolini, D. Cocciadiferro, E. Sasaki, A. Madeo, A. Ferraris, W. Reardon, M. Di Rocco, A. Novelli, P. Grammatico, F. Malfait, T. Mazza, A. Hakim, C. GiuntaM. Colombi, M. Castori

Research output: Contribution to journalArticlepeer-review


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. © 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Original languageEnglish
Pages (from-to)396-406
Number of pages11
JournalClin. Genet.
Issue number3
Publication statusPublished - 2020


  • COL1A1
  • COL1A2
  • Ehlers-Danlos syndrome
  • joint hypermobility
  • osteogenesis imperfecta
  • collagen type 1
  • collagen type 2
  • glycine
  • procollagen n proteinase
  • COL1A2 protein, human
  • collagen type I, alpha 1 chain
  • adolescent
  • adult
  • arthralgia
  • Article
  • bone bowing
  • bone mass
  • child
  • clinical article
  • clinical feature
  • cohort analysis
  • controlled study
  • Ehlers Danlos syndrome
  • female
  • flatfoot
  • genotype phenotype correlation
  • high throughput sequencing
  • human
  • human cell
  • immunofluorescence
  • immunofluorescence microscopy
  • infant
  • joint dislocation
  • male
  • middle aged
  • mitral valve prolapse
  • muscle hypotonia
  • myopia
  • papule
  • phenotype
  • preschool child
  • priority journal
  • retrospective study
  • school child
  • short stature
  • spine fracture
  • young adult
  • classification
  • connective tissue
  • connective tissue disease
  • demography
  • genetic variation
  • genetics
  • heterozygote
  • ultrastructure
  • Adolescent
  • Adult
  • Child
  • Child, Preschool
  • Collagen Type I
  • Connective Tissue
  • Connective Tissue Diseases
  • Demography
  • Ehlers-Danlos Syndrome
  • Female
  • Genetic Variation
  • Heterozygote
  • Humans
  • Infant
  • Male
  • Middle Aged
  • Osteogenesis Imperfecta
  • Phenotype
  • Young Adult


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