This study revealed a close control of TBX5 on extracellular matrix synthesis and identified novel targets of the transcription factor, as VCAN (versican), FN1 (fibronectin), and HSPG2 (perlecan) that, besides the known NPPA, TTN, and GJA5 (Connexin 43) genes, could be targeted for the treatment of Holt-Oram syndrome and associated AF [279]. Here, TBX5 is linked to Holt-Oram syndrome.