| Summary: | Mutations in Dentin Sialophosphoprotein (<i>DSPP</i>) are known to cause, in order of increasing severity, dentin dysplasia type-II (DD-II), dentinogenesis imperfecta type-II (DGI-II), and dentinogenesis imperfecta type-III (DGI-III). <i>DSPP</i> mutations fall into two groups: a 5′-group that affects protein targeting and a 3′-group that shifts translation into the −1 reading frame. Using whole-exome sequence (WES) analyses and Single Molecule Real-Time (SMRT) sequencing, we identified disease-causing <i>DSPP</i> mutations in 12 families. Three of the mutations are novel: c.53T>C/p.(Val18Ala); c.3461delG/p.(Ser1154Metfs*160); and c.3700delA/p.(Ser1234Alafs*80). We propose genetic analysis start with WES analysis of proband DNA to identify mutations in <i>COL1A1</i> and <i>COL1A2</i> causing dominant forms of osteogenesis imperfecta, 5′-<i>DSPP</i> mutations, and 3′-<i>DSPP</i> frameshifts near the margins of the <i>DSPP</i> repeat region, and SMRT sequencing when the disease-causing mutation is not identified. After reviewing the literature and incorporating new information showing distinct differences in the cell pathology observed between knockin mice with 5′-<i>Dspp</i> or 3′-<i>Dspp</i> mutations, we propose a modified Shields Classification based upon the causative mutation rather than phenotypic severity such that patients identified with 5′-<i>DSPP</i> defects be diagnosed as DGI-III, while those with 3′-<i>DSPP</i> defects be diagnosed as DGI-II.
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