title: Copy number variants in association with type 1 collagenopathy: Atypical osteogenesis imperfecta.
abstract: We report a sibling-pair and a 4-year old child from two families with an atypical presentation in Osteogenesis imperfecta (OI). In the sib-pair, the older sibling initially came to medical attention due to a fracture history (Patient 1) and she was shown to have a COL1A2 mutation. In addition, she also had developmental delay, facial dysmorphism, and a history of frequent infections which led to a search for an alternate diagnosis. ArrayCGH revealed a 4.3 Mb duplication on chromosome 19q13.42q13.43, which was confirmed by FISH analysis. On further familial analysis, the younger sibling who had no previous fracture history was also found to have the COL1A2 mutation and tested positive for the 19q13.42q13.43 duplication (Patient 2). The 19q13 duplication appears to be the cause of intellectual disability in these siblings but given that this is a chromosomal duplication, it is still possible that there is an as yet unidentified cause that may account for the combined phenotype in this family. Patient 3 was a 4-year old child presenting with a femoral fracture, blue sclerae, developmental delay, and joint hypermobility. Genetic analyses confirmed a COL1A2 mutation but also revealed an 8.8 Mb deletion of 11q24.2q25, confirmed by G-band chromosome analysis. We discuss the differing phenotypes in patients presenting with atypical OI and stress the need to consider ancillary investigations in individuals presenting with heterogeneous phenotypic symptoms, not entirely attributable to OI.
authors.affiliation: Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, United Kingdom.
authors.forename: Meena
authors.initials: M
authors.lastname: Balasubramanian
authors.affiliation: Sheffield Diagnostic Genetics Service, Sheffield Children's NHS Foundation Trust, United Kingdom.
authors.forename: Ashley
authors.initials: A
authors.lastname: Cartwright
authors.affiliation: Sheffield Diagnostic Genetics Service, Sheffield Children's NHS Foundation Trust, United Kingdom.
authors.forename: Kath
authors.initials: K
authors.lastname: Smith
authors.affiliation: Academic Unit of Child Health, University of Sheffield, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Arundel
authors.affiliation: Academic Unit of Child Health, University of Sheffield, United Kingdom.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Bishop
mesh_terms: D000293:Adolescent; D002675:Child, Preschool; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D024042:Collagen Type I / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D005260:Female; D005820:Genetic Testing; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D009154:Mutation / Q000235:genetics*; D010013:Osteogenesis Imperfecta / Q000235:genetics* / Q000473:pathology*
chemical_list: C000601279:COL1A2 protein, human; D024042:Collagen Type I
keywords: COL1A1; COL1A2; ancillary investigations; array comparative genomic hybridisation; osteogenesis imperfecta