Molecular Genetics of Holt–Oram Syndrome

Abstract

Abstract The Holt–Oram syndrome (HOS) is an autosomal‐dominant hand–heart syndrome characterised by malformations of the upper limbs, mainly involving the preaxial (radial) ray, and variable cardiac defects. Mutations in TBX5, a transcription factor that regulates a wide variety of developmental processes, underlie HOS. Thus far, more than a hundred TBX5 mutations have been identified in patients with HOS. However, only the application of stringent diagnostic criteria will lead to a high sensitivity and specificity in TBX5 mutation screening. Various pathogenic mechanisms that lead to HOS have been uncovered, ranging from loss‐of‐function to gain‐of‐function. Nonetheless, in a significant minority of HOS patients, who do fulfil the strict diagnostic criteria, no TBX5 mutation is identified. This suggests that mutations in regulatory parts of TBX5 could cause disease, or mutations in genes other than TBX5 could underlie HOS. Application of exome sequencing or even whole‐genome sequencing should be pursued in those cases. Key Concepts: Holt–Oram syndrome is caused by TBX5 mutations. The majority of TBX5 mutations lead to loss‐of‐function. Application of stringent diagnostic criteria increases the yield of TBX5 mutation screening in HOS patients. In a minority of HOS patients, who fulfil the stringent diagnostic criteria, no TBX5 mutation is identified. TBX5 is involved in the specification of the mesoderm and development of the heart, vasculature and limbs.