The DDR2 gene is located on chromosome 1 at 1q23.3 and encodes the discoidin domain receptor tyrosine kinase 2 protein, a receptor tyrosine kinase widely expressed in cells of mesenchymal origin and activated by fibrillar collagen in the extracellular matrix. The protein is involved in cell adhesion, proliferation and extracellular matrix remodeling.Variants in DDR2 have been associated with multiple disorders: spondyloepimetaphyseal dysplasia-short limb-abnormal calcification syndrome (MONDO:0010077) and Warburg-Cinotti syndrome (MONDO:0032579). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found sufficient differences in heritability and phenotype to support splitting these disorders into two distinct disease entities. The role of DDR2 in autosomal recessive Spondyloepimetaphyseal dysplasia-short limb-abnormal calcification syndrome (MONDO:0010077) has been curated separately. DDR2 was first reported in relation to autosomal-dominant Warburg-Cinotti syndrome (MONDO:0032579) in 2018 (Xu et al., PMID: 30449416). This publication reports two recurrent missense variants in six individuals across four families, including segregation in three affected family members in one family (affected mother with two affected offspring). Affected individuals displayed the clinical features of progressive corneal neovascularization, keloid formation, flexion contractures of the fingers, and acro-osteolysis. The proposed mechanism is activating gain-of-function with experimental evidence showing sustained ligand-independent kinase activity in patient fibroblasts carrying both p.Leu610Pro and p.Tyr740Cys variants (PMID: 30449416). This gene-disease relationship is also supported by expression and in vitro functional assays showing a role of DDR2 in tissue remodeling. (Vogel et al., 1997, PMID: 9659899). Since only two missense variants have been described with Warburg-Cinotti syndrome, other variants would need very careful consideration. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Syndromic Disorders Gene Curation Expert Panel on the meeting date 10/21/2022 (SOP Version 9.0).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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