TBX5 and Holt-Oram syndrome: In particular, TBX5 gene defects were shown to be responsible for the most common prototypical heart–hand syndrome type I, or Holt-Oram syndrome (HOS, MIM1 142900) characterized by cardiac septal defects, conduction system disease and radial ray anomaly of forelimb skeleton (Basson et al., 1997; Li et al., 1997).