Molecular diagnosis in children with fractures but no extraskeletal signs of osteogenesis imperfecta
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In 26 of 94 individuals (28%) below 21 years of age who had a significant fracture history but did not have extraskeletal features of osteogenesis imperfecta (OI), we detected disease-causing mutations in OI-associated genes.
In children who have mild bone fragility but do not have extraskeletal features of OI, it can be difficult to establish a diagnosis on clinical grounds. Here, we assessed the diagnostic yield of genetic testing in this context, by sequencing a panel of genes that are associated with OI.
DNA sequence analysis was performed on 94 individuals below 21 years of age who had a significant fracture history but had white sclera and no signs of dentinogenesis imperfecta.
Disease-causing variants were detected in 28% of individuals and affected 5 different genes. Twelve individuals had mutations in COL1A1 or COL1A2, 8 in LRP5, 4 in BMP1, and 2 in PLS3.
DNA sequence analysis of currently known OI-associated genes identified disease-causing variants in more than a quarter of individuals with a significant fracture history but without extraskeletal manifestations of OI.
KeywordsChildren Fractures Mutations Next-generation sequencing Osteogenesis imperfecta
FR received salary support from the Chercheur-Boursier Clinicien program of the Fonds de Recherche du Québec—Santé. LMW is supported by the Research Chair program at the University of Ottawa and the Departments of Pediatrics and Surgery, Children’s Hospital of Eastern Ontario. This study was supported by the Shriners of North America.
GB performed analyses; LMW, PT and FHG contributed patient information; PM and FHG reviewed sequencing data; and FR conceptualized the project, contributed patient information, finalized the report, and accepts responsibility for the integrity of the data analysis. All authors have read and approved of the final version of the manuscript.
Compliance with ethical standards
The study was approved by the Institutional Review Board of McGill University and the Research Ethics Board at the Children’s Hospital of Eastern Ontario.
Conflicts of interest
- 11.Ogden CL, Kuczmarski RJ, Flegal KM, Mei Z, Guo S, Wei R, Grummer-Strawn LM, Curtin LR, Roche AF, Johnson CL (2002) Centers for Disease Control and Prevention 2000 growth charts for the United States: improvements to the 1977 National Center for Health Statistics version. Pediatrics 109:45–60CrossRefPubMedGoogle Scholar
- 13.Zemel BS, Kalkwarf HJ, Gilsanz V et al (2011) Revised reference curves for bone mineral content and areal bone mineral density according to age and sex for black and non-black children: results of the bone mineral density in childhood study. J Clin Endocrinol Metab 96:3160–3169CrossRefPubMedPubMedCentralGoogle Scholar
- 18.Richards S, Aziz N, Bale S et al (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17:405–424CrossRefPubMedPubMedCentralGoogle Scholar