Submission Details

The DDR2 gene is located on chromosome 1 at 1q23.3 and encodes the discoidin domain receptor tyrosine kinase 2, a receptor tyrosine kinase predominantly 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 dominant Warburg-Cinotti syndrome (MONDO:0032579) has been curated separately. DDR2 was first reported in relation to autosomal recessive spondyloepimetaphyseal dysplasia-short limb-abnormal calcification syndrome (SMED-SL/AC) in 2009 after homozygosity mapping of three unrelated individuals with a clinical diagnosis of SMED-SL/AC (Bargal et al., PMID: 19110212). Since then several families have been identified with homozygous DDR2 mutations (missense, truncating, and splice site variants) and a clinical diagnosis of SMED-SL/AC. This curation includes 10 variants across 16 families and seven publications (PMID: 19110212, Ali et al., 2010, PMID: 20223752, Al-Kindi et al., 2014, PMID 24725993, Gupta et al., 2019, PMID 31406622, Heidari et al., 2021, PMID 33953858, Urel-Demir et al., 2018, PMID 29884795, Gulec et al., 2022, PMID 35221872). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function with supporting functional evidence of 5 patient variants (4 missense and 1 frameshift) showing defective kinase phosphorylation. Included in the modeled patient variants is a p.Arg752Cys founder variant, which was the originally identified variant by homozygosity mapping and ultimately found in all affected individuals across more than six families. This gene-disease relationship is also supported by several mouse models (Labrador et al., 2001, PMID: 11375938), expression studies, and protein interaction studies (Konitsiotis et al., 2008, PMID: 18201965) demonstrating an essential role for DDR2 in skeletal growth and chondrocyte function. In summary, DDR2 is definitively associated with autosomal recessive spondyloepimetaphyseal dysplasia-short limb-abnormal calcification syndrome (SMED-SL/AC). This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders Gene Curation Expert Panel on the meeting date 10/21/2022 (SOP Version 9.0).