title: Tissue-specific mosaicism for a lethal osteogenesis imperfecta COL1A1 mutation causes mild OI/EDS overlap syndrome.
abstract: Type I collagen is the predominant protein of connective tissues such as skin and bone. Mutations in the type I collagen genes (COL1A1 and COL1A2) mainly cause osteogenesis imperfecta (OI). We describe a patient with clinical signs of Ehlers-Danlos syndrome (EDS), including fragile skin, easy bruising, recurrent luxations, and fractures resembling mild OI. Biochemical collagen analysis of the patients' dermal fibroblasts showed faint overmodification of the type I collagen bands, a finding specific for structural defects in type I collagen. Bidirectional Sanger sequencing detected an in-frame deletion in exon 44 of COL1A1 (c.3150_3158del), resulting in the deletion of three amino acids (p.Ala1053_Gly1055del) in the collagen triple helix. This COL1A1 mutation was hitherto identified in four probands with lethal OI, and never in EDS patients. As the peaks on the electropherogram corresponding to the mutant allele were decreased in intensity, we performed next generation sequencing of COL1A1 to study mosaicism in skin and blood. While approximately 9% of the reads originating from fibroblast gDNA harbored the COL1A1 deletion, the deletion was not detected in gDNA from blood. Most likely, the mild clinical symptoms observed in our patient can be explained by the mosaic state of the mutation.
authors.affiliation: Center for Medical Genetics Ghent, Ghent University Hospital, Ghent, Belgium.
authors.forename: Sofie
authors.identifier: http://orcid.org/0000-0003-4240-2772
authors.initials: S
authors.lastname: Symoens
authors.affiliation: Center for Medical Genetics Ghent, Ghent University Hospital, Ghent, Belgium.
authors.forename: Wouter
authors.initials: W
authors.lastname: Steyaert
authors.affiliation: Center for Medical Genetics Ghent, Ghent University Hospital, Ghent, Belgium.
authors.forename: Lynn
authors.initials: L
authors.lastname: Demuynck
authors.affiliation: Center for Medical Genetics Ghent, Ghent University Hospital, Ghent, Belgium.
authors.forename: Anne
authors.initials: A
authors.lastname: De Paepe
authors.affiliation: Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Karin E M
authors.initials: KE
authors.lastname: Diderich
authors.affiliation: Center for Medical Genetics Ghent, Ghent University Hospital, Ghent, Belgium.
authors.forename: Fransiska
authors.initials: F
authors.lastname: Malfait
authors.affiliation: Center for Medical Genetics Ghent, Ghent University Hospital, Ghent, Belgium.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coucke
mesh_terms: D001483:Base Sequence; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology; D024042:Collagen Type I / Q000235:genetics*; D000090602:Collagen Type I, alpha 1 Chain; D004535:Ehlers-Danlos Syndrome / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D005091:Exons; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000378:metabolism; D009030:Mosaicism; D009154:Mutation; D009928:Organ Specificity; D010013:Osteogenesis Imperfecta / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D012867:Skin / Q000378:metabolism / Q000473:pathology; D055815:Young Adult
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain
keywords: Ehlers-Danlos syndrome; mosaicism; next generation sequencing; osteogenesis imperfecta