title: An overlapping phenotype of Osteogenesis imperfecta and Ehlers-Danlos syndrome due to a heterozygous mutation in COL1A1 and biallelic missense variants in TNXB identified by whole exome sequencing.
abstract: Osteogenesis imperfecta (OI) and Ehlers-Danlos syndrome (EDS) are variable genetic disorders that overlap in different ways [Cole 1993; Grahame 1999]. Here, we describe a boy presenting with severe muscular hypotonia, multiple fractures, and joint hyperflexibility, features that are compatible with mild OI and hypermobility type EDS, respectively. By whole exome sequencing, we identified both a COL1A1 mutation (c.4006-1G > A) inherited from the patient's mildly affected mother and biallelic missense variants in TNXB (p.Val1213Ile, p.Gly2592Ser). Analysis of cDNA showed that the COL1A1 splice site mutation led to intron retention causing a frameshift (p.Phe1336Valfs*72). Type 1 collagen secretion by the patient's skin fibroblasts was reduced. Immunostaining of a muscle biopsy obtained from the patient revealed a clear reduction of tenascin-X in the extracellular matrix compared to a healthy control. These findings imply that the combination of the COL1A1 mutation with the TNXB variants might cause the patient's unique phenotype.
authors.affiliation: Institute of Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany.|Faculty of Medicine Carl Gustav Carus, Institute for Clinical Genetics, Dresden, Germany.
authors.forename: Luisa
authors.initials: L
authors.lastname: Mackenroth
authors.affiliation: Institute of Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany.|Max-Planck-Institut für Molekulare Genetik, Berlin, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Fischer-Zirnsak
authors.affiliation: Institute of Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Egerer
authors.affiliation: Institute of Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Hecht
authors.affiliation: Department of Pediatric Pneumology and Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Tilmann
authors.initials: T
authors.lastname: Kallinich
authors.affiliation: Institute for Neuropathology, Charité, Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Stenzel
authors.affiliation: Department of Radiology, Charité, Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Spors
authors.affiliation: Children's Hospital, DRK-Kliniken Westend, Berlin, Germany.
authors.forename: Arpad
authors.initials: A
authors.lastname: von Moers
authors.affiliation: Institute of Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany.|Max-Planck-Institut für Molekulare Genetik, Berlin, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Mundlos
authors.affiliation: Institute of Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany.|Max-Planck-Institut für Molekulare Genetik, Berlin, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Kornak
authors.affiliation: Department of Pediatric Pneumology and Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Gerhold
authors.affiliation: Institute of Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Denise
authors.initials: D
authors.lastname: Horn
mesh_terms: D000483:Alleles; D024042:Collagen Type I / Q000235:genetics* / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D004252:DNA Mutational Analysis; D004535:Ehlers-Danlos Syndrome / Q000175:diagnosis* / Q000235:genetics*; D059472:Exome; D006579:Heterozygote; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D008297:Male; D009154:Mutation; D010013:Osteogenesis Imperfecta / Q000175:diagnosis* / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D019063:Tenascin / Q000235:genetics*
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D019063:Tenascin; C081865:tenascin X
keywords: COL1A1; Ehlers-Danlos syndrome; TNXB; osteogenesis imperfecta; whole exome sequencing