Molecular Genetics of Holt–Oram Syndrome

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.

Keywords: Holt–Oram syndrome; TBX5; transcription factor; DNA‐binding; limb malformation; cardiac defects

Figure 1.

Overview of the TBX5 protein and its various domains: T‐box, nuclear localisation signals (NLS), nuclear export signal (NES) and activation domain (AD). Mutations that have been molecularly tested and are present in the T‐box have been highlighted.

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Further Reading

Mckusick VA and O'neill MJF (1997) T‐BOX5. http://omim.org/entry/601620.

Stoll C, Dott B, Alembik Y et al. (2013) Associated malformations among infants with radial ray deficiency. Genetic Counseling 24(2): 223–234.

Sunagawa S, Kikuchi A, Sano Y et al. (2009) Prenatal diagnosis of Holt‐Oram syndrome: role of 3‐D ultrasonography. Congenital Anomalies 49(1): 38–41.

Tsai TC, Lu JK, Choo SL et al. (2012) The paracrine effect of exogenous growth hormone alleviates dysmorphogenesis caused by tbx5 deficiency in zebrafish (Danio rerio) embryos. Journal of Biomedical Science 19: 63.

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Barnett, Phil, and Postma, Alex V(Jun 2014) Molecular Genetics of Holt–Oram Syndrome. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024329]