It had been known for over a decade that heterozygous mutations within TBX5 lead to Holt-Oram syndrome in humans (Basson et al., 1997, 1999) when Smemo et al. (2012) went searching for disease-causing enhancer mutations around the TBX5 gene in families with septal defects, the predominant cardiac defect of Holt-Oram syndrome. Here, TBX5 is linked to Abnormal cardiac septum morphology.