Dentinogenesis Imperfecta (DGI) and Dentin Dysplasia (DD) via the DSPP Gene

Inherited dentin malformations are classified into three types of dentinogenesis imperfecta (DGI) and two types of dentin dysplasia (DD) (Shields et al. Arch Oral Biol 18:543-553, 1973). DGI-I (OMIM 166240): Syndromic DGI. This includes individuals afflicted with osteogenesis imperfecta. Both deciduous and permanent teeth are discolored (grey-yellowish) and worn. Pulpal obliteration is apparent both prior to and upon tooth eruption. Expressivity is variable, even within a single patient, ranging from total obliteration to normal-appearing dentin.

DGI-II (OMIM 125490): Similar to DGI-I, but penetrance is almost complete and expressivity is consistent.

DGI-III (OMIM 125500): Phenotypic variant of DGI-II, but with large pulp chambers resembling shell teeth in deciduous teeth.

DD-I (OMIM 125400): Deciduous and permanent teeth appear normal but radiologically show short roots with crescent-shaped pulpal remnant parallel to the cemento-enamel junction in the permanent teeth and total pulpal obliteration in the deciduous teeth. Non-carious teeth usually show numerous periapical radiolucencies.

DD-II (OMIM 125420): Deciduous teeth have features of DGI-II. The permanent teeth are normal, but pulp cavities show a thistle-tube deformity and commonly contain pulp stones.

DGI (opalescent dentin) is the most common heritable dentin disease. In the United States, the prevalence is estimated between 1:6,000 and 1:8,000; DGI-III may be even more predominant in the “Brandywine isolate” population of mixed White, Black, and Amerindian ancestry (see Acevedo et al. Cells Tissues Organs 189:230-236, 2009). Variants in the DSPP gene are known to cause DGI-II (Xiao et al. Nat Genet 27:201-204, 2001; Malmgren et al. Hum Genet 114:491-498, 2004), DGI-III (Kim et al. Hum Genet 116:186-191, 2005), and DD-II (Rajpar et al. Hum Mol Genet 11:2559-2565, 2002). Variants in DSPP exhibit an autosomal dominant mode of inheritance. DSPP encodes a 940 amino-acid polypeptide produced in odontoblasts that is cleaved into dentin sialoprotein (DSP) and dentin phosphoprotein (DPP) (MacDougall et al. J Biol Chem 272:835-842, 1997). DSP and DPP are noncollagenous matrix proteins that play a crucial role in dentinogenesis: most causative variants have been reported in the DSP-coding region (mainly in exons 2-3). Causative variants are distributed rather evenly among missense, nonsense, splicing, and small deletions. The DGI phenotype is also a variable feature in many other syndromes including osteogenesis imperfecta (OI) and Ehlers-Danlos syndrome (EDS), Goldblatt syndrome (OMIM 184260), and Schimke immuno-osseous dysplasia (SIOD, OMIM 242900).

No disease-causing variants outside of the DSPP gene have been identified for nonsyndromic DGI or DD.

This test provides full coverage of all coding exons of the DSPP gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Exon 5 of the gene has a large repeat element; sequencing covers the 5’ portion of the coding sequence up to the repeat and the 3’ portion after the repeat along with ~10 bp of flanking non-coding DNA on either side of this exon.

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).