Spondylo-Meta-Epiphyseal Dysplasia, Short Limb-Hand Type (SMED-SL) via the DDR2 Gene

Spondylo-meta-epiphyseal dysplasia with short limb and abnormal calcification (SMED-SL; OMIM 271665) is a growth disorder characterized by disproportionate short stature, short limbs, short broad fingers, abnormal metaphyses and epiphyses, platyspondyly, and premature calcifications (Borochowitz et al. Am J Med Genet 45:320-326, 1993; Langer et al. Am J Med Genet 45:488-500, 1993; Bargal et al. Am J Hum Genet 84:80-84, 2009; Ali et al. Hum Mol Genet 19:2239-2250, 2010). Additional findings include a short nose with wide nasal bridge and wide nostrils, a long philtrum, ocular hypertelorism, retro/micrognathia, and a narrow chest (Borochowitz et al. 1993; Langer et al. 1993).

Spondylo-meta-epiphyseal dysplasia with short limb and abnormal calcification is an autosomal recessive disorder caused by variants in the DDR2 gene (Bargal et al. 2009). The DDR2 gene encodes a cell-surface receptor known as discoidin domain receptor 2 (DDR2), a member of the receptor tyrosine kinase family (Bargal et al. 2009). The DDR2 receptor is mainly expressed in mesenchymal cells and consists of extracellular domains, including the discoidin domain and the stalk domain, and intracellular domains, including the juxtamembrane domain and the cytosolic tyrosine kinase domain (Ali et al. 2010). The binding of the discoidin domain of the DDR2 receptor to fibrillar collagen is crucial for the activation of the tyrosine kinase signal transduction (Bargal et al. 2009; Ali et al. 2010). The DDR2 receptor has an important role in fundamental processes including cell proliferation, adhesion, and migration as well as extracellular matrix remodeling (Ali et al. 2010). A mix of missense and splicing variants have been reported in DDR2 gene (Bargal et al. 2009; Ali et al. 2010).

The prevalence of the DDR2 variants is currently unknown.

This test provides full coverage of all coding exons of the DDR2 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).

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).