Patellar dysplasia (PD) can cause patellar dislocation and subsequent osteoarthritis (OA) development. Herein, a novel ABCA6 mutation contributing to a four-generation family with familiar patellar dysplasia (FPD) is identified. In this study, whole exome sequencing (WES) and genetic linkage analysis across a four-generation lineage presenting with six cases of FPD are conducted. A disease-causing mutation in ABCA6 is identified for FPD. Further analyses reveal a consistent correlation between ABCA6 expression downregulation and PD occurrence, chondrocyte degeneration, and OA onset. Moreover, ABCA6-KO mice demonstrate severe knee joint degeneration and accelerated OA progression. Besides, synovial mesenchymal stem cells (SMSCs) are extracted from WT, ABCA6