An essential initiator of forelimb development is the transcription factor Tbx5. Loss of Tbx5 in mice results in the complete absence of forelimb development, but normal hindlimb development and mutation of TBX5 in humans result in Holt-Oram syndrome characterized by upper limb and heart defects15–17. The gene discussed is TBX5; the disease is Holt-Oram syndrome.