Molecular basis of the clinical features of Holt–Oram syndrome resulting from missense and extended protein mutations of the TBX5 gene as well as TBX5 intragenic duplications

•We review the phenotypes of non-truncated protein mutations of Holt–Oram syndrome.•Interactions of the T-box domain with NKX2-5 and GATA4 explain the cardiac defects.•The pathogenesis of radial ray deficiency is through two limb bud pathways of TBX5.•Other bone abnormalities (chest, face, spine) are related to TBX5-CX40 interactions.

This paper reviews the molecular basis of the clinical features of Holt–Oram syndrome resulting from missense and extended protein mutations of the TBX5 gene as well as TBX5 intragenic duplications. First, we review all previously reported cases with these mutations, and then describe the pathogenesis of the clinical features in the heart and upper limb. Special emphasis is given to ‘non-classic’ upper limb features which are known to occur with these mutations. Finally, the molecular basis of other concurrent anomalies (chest wall, craniofacial, vertebral, and lung anomalies) is reviewed.