title: What every clinical geneticist should know about testing for osteogenesis imperfecta in suspected child abuse cases.
abstract: Non-accidental injury (NAI) is a major medical concern in the United States. One of the challenges in evaluation of children with unexplained fractures is that genetic forms of bone fragility are one of the differential diagnoses. Infants who present with fractures with mild forms of osteogenesis imperfecta (OI) (OI type I or OI type IV), the most common genetic form of bone disease leading to fractures might be missed if clinical evaluation alone is used to make the diagnosis. Diagnostic clinical features (blue sclera, dentinogenesis imperfecta, Wormian bones on X-rays or positive family history) may not be present or apparent at the age of evaluation. The evaluating clinician faces the decision about whether genetic testing is necessary in certain NAI cases. In this review, we outline clinical presentations of mild OI and review the history of genetic testing for OI in the NAI versus OI setting. We summarize our data of molecular testing in the Collagen Diagnostic Laboratory (CDL) from 2008 to 2014 where NAI was noted on the request for DNA sequencing of COL1A1 and COL1A2. We provide recommendations for molecular testing in the NAI versus OI setting. First, DNA sequencing of COL1A1, COL1A2, and IFITM5 simultaneously and duplication/deletion testing is recommended. If a causative variant is not identified, in the absence of a pathologic clinical phenotype, no additional gene testing is indicated. If a VUS is found, parental segregation studies are recommended.
authors.forename: Melanie G
authors.initials: MG
authors.lastname: Pepin
authors.forename: Peter H
authors.initials: PH
authors.lastname: Byers
mesh_terms: D002649:Child Abuse / Q000175:diagnosis*; D002675:Child, Preschool; D024042:Collagen Type I / Q000235:genetics; D000090602:Collagen Type I, alpha 1 Chain; D003937:Diagnosis, Differential; D050723:Fractures, Bone / Q000175:diagnosis / Q000000981:diagnostic imaging / Q000209:etiology*; D005820:Genetic Testing; D006801:Humans; D007223:Infant; D008565:Membrane Proteins / Q000235:genetics; D010013:Osteogenesis Imperfecta / Q000175:diagnosis* / Q000235:genetics; D011859:Radiography
chemical_list: C000601279:COL1A2 protein, human; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; C575746:IFITM5 protein, human; D008565:Membrane Proteins
keywords: biochemical testing osteogenesis imperfecta; child abuse; molecular testing osteogenesis imperfecta; osteogenesis imperfecta; recurrent fracture