Submission Details

Autosomal dominant

08/21/2019

The DDR2 gene is located on chromosome 1 at 1q23.3 and encodes the discoidin domain receptor tyrosine kinase 2 protein. The protein is a widely expressed transmembrane receptor which is activated by fibrillar collagen in the extracellular matrix and plays a role in cell differentiation, remodelling of the extracellular matrix and cell proliferation. DDR2 was first reported in relation to autosomal dominant Warburg-Cinotti syndrome in 2018 (30449416: Xu et al. 2018). At least two unique missense variants have been reported, Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least four probands in one publication (30449416: Xu et al. 2018 ). Variants in this gene segregated with disease in two additional family members in one family (affect offspring from an affected mother). The mechanism for disease appears to involve heterozygous gain of function (30449416: Xu et al. 2018). Of note, variants in DDR2 are also associated with spondylometaepiphyseal dysplasia, short limb-hand type, an autosomal recessive disorder associated with loss-of-function variants. These two disorders are considered distinct disease entities and will be curated separately. The gene-disease relationship is supported by expression data with the DDR2 gene displaying a high level of expression in skin especially (11375938: Labrador et al. 2001). In vitro functional assays demonstrate activation of DDR2 by collagen and a role of the protein in the proliferation of skin fibroblasts and wound healing (9659899: Vogel et al. 1997; 11375938: Labrador et al. 2001). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role; no convincing evidence has emerged that contradicts the gene-disease relationship. LUMPING AND SPLITTING CONSIDERATIONS: MIM 271665: Spondylometaepiphyseal dysplasia, short limb-hand type Per criteria outlined by the ClinGen Lumping and Splitting Working group, we found evidence of a distinct phenotypes and different modes of inheritance and mechanism of disease. Therefore, we have split curations for Warburgh-Cinotti syndrome and spodylometaepiphyseal dysplasia, short limb-hand type.

30449416 9659899 11375938