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This article has been peer reviewed. It is the authors' final version prior to publication in Journal of Bone and Mineral Research May 29, 2013

The published version is available at DOI: 10.1002/jbmr.1999. Copyright © Wiley


Developmental Dysplasia of the Hip (DDH) is a debilitating condition characterized by incomplete formation of the acetabulum leading to dislocation of the femur, suboptimal joint function, and accelerated wear of the articular cartilage resulting in arthritis. DDH affects 1 in 1000 newborns in the United States with well defined "pockets" of high prevalence in Japan, Italy and other Mediterranean countries. Although reasonably accurate for detecting gross forms of hip dysplasia, existing techniques fail to find milder forms of dysplasia. Undetected hip dysplasia is the leading cause of osteoarthritis of the hip in young individuals causing over 40% of cases in this age group. A sensitive and specific test for DDH has remained a desirable yet elusive goal in orthopaedics for a long time. A 72 member, four generation affected family has been recruited, and DNA from its members retrieved. Genome-wide linkage analysis revealed a 2.61 Mb candidate region (38.7-41.31 Mb from the p term of chromosome 3) co-inherited by all affected members with a maximum LOD score of 3.31. Whole exome sequencing and analysis of this candidate region in four severely affected family members revealed one shared variant, rs3732378, that causes a threonine (polar) to methionine (non-polar) alteration at position 280 in the trans-membrane domain of CX3CR1. This mutation is predicted to have a deleterious effect on its encoded protein which functions as a receptor for the ligand fractalkine. By Sanger sequencing this variant was found to be present in the DNA of all affected individuals and obligate heterozygotes. CX3CR1 mediates cellular adhesive and migratory functions and is known to be expressed in mesenchymal stem cells destined to become chondrocytes. A genetic risk factor that might to be among the etiologic factors for the family in this study has been identified, along with other possible aggravating mutations shared by 4 severely affected family members. These findings might illuminate the molecular pathways affecting chondrocyte maturation and bone formation.

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