Similarly, natural occurrences of limblessness in humans and zebrafish have been attributed to mutations in tbx5. In humans, most tbx5 mutations are found in the highly conserved DNA-binding Tbox region and result in Holt-Oram syndrome (HOS), characterized by reduction of the forelimbs and associated heart anomalies [9]. This evidence concerns the gene TBX5 and Holt-Oram syndrome.