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Identification of new mutations in the TBX5 gene in patients with Holt-Oram syndrome

Holt-Oram syndrome (HOS) (MIM 142900), first described by Holt and Oram in 1960, is characterised by malformations of the upper limbs involving mainly the pre-axial ray and variable cardiac defects, most of them septation defects. This autosomal dominant inherited condition occurs in approximately 1 in 100 000 live births and shows high penetrative and variable intrafamilial and interfamilial clinical expression.

The gene locus for HOS was mapped to chromosome 12q24.1. Mutations in the TBX5 gene (MIM *601620) were delineated as the underlying defect in HOS.1–5 TBX5 is a member of the T-box transcription factor family. It plays an indispensable role in development of heart and upper limbs during embryogenesis. To date there have been 34 different mutations at DNA level described in families with HOS; these mutations are spread over all the coding exons of the TBX5 gene.1–5

The patients for our study were recruited by a circular letter to human geneticists, experts in dysmorphology, and child cardiologists throughout Germany, Austria, Hungary, and Switzerland. The participating colleagues were asked to summarise the clinical data of their patients (all presenting with a combination of variable congenital heart defects and upper limb malformations) in a standardised format. DNA samples of all patients and their first degree relatives were collected after …