The diagnosis of OI is usually made based on clinical findings alone. The presence of fractures, together with short stature, bone deformity, blue sclerae, dentino-genesis imperfecta, or a family history of OI, is usually sufficient for diagnosis. However, it is important to rule out diseases and other reasons that can cause fractures of bones in children. Most patients with types I-IV OI have private mutation; therefore extensive analysis of the COL1A1 (18,000 bp) and COL1A2 (38,000 bp) genes must be undertaken to define the mutations. Most investigators have developed a two-step experimental strategy to detect mutations. In the first step, an attempt is made to localize a region in collagen gene that may contain a mutation by procedures such as analysis of the type I collagen synthesized by cultured skin fibroblasts and cyanogen bromide peptide mapping. After the region containing the mutation is identified, the mutation is defined by sequencing cDNA or genomic DNA from the region. However, only some mutations cause overmodi-fication of collagen chains, resulting in delayed electro-phoretic mobility that can be detected by analysis of the protein, and no current procedure for scanning mRNA or DNA for mutations has been shown to detect all single base substitutions. An automated procedure of cDNA sequencing for the procollagen chains with sequencing primer information was described. In the diagnosis of type I OI with no detectable biochemical abnormality of type I collagen, a 4-bp insertion polymorphism in the 3' untranslated region of the COL1A1 gene is highly informative for null allele testing and can be used in prenatal diagnosis.
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