Only a minority of children who seek medical attention for short stature can be given a precise mechanistic diagnosis such as growth hormone deficiency. More often the term “idiopathic short stature” is applied. For many of these children, the short stature is due to a primary disorder of the skeletal growth plate. This project will investigate the underlying genetic causes responsible for idiopathic growth failure. We plan to carefully characterize undiagnosed patients with growth disorders and use advanced genetic and bioinformatic methods to identify the causative genetic variants. Such mutations will thereafter be tested functionally using in vitro models of growth plate chondrogenesis and genetically modified mice to elucidate the pathogenic mechanisms. Ultimately, based on our data, potential genes or functions that could be suitable targets for novel treatment strategies will be tested in animals. This research will have immediate benefit for the patients suffering from genetic growth disorders as it will identify the underlying genetic diagnosis, thus enabling more accurate information about the cause, mode of inheritance, and prospects of improving their medical care. Understanding skeletal development, physiology, and pathology would offer novel treatment strategies for growth and skeletal diseases. It is highly important for several other large patient groups including children with inflammatory diseases and children treated for cancer who often develop growth problems.