Novel TBX5 Duplication in a Japanese Family with Holt–Oram Syndrome

Holt–Oram syndrome is an autosomal dominant disorder characterized by upper limb malformations in the preaxial radial ray and cardiac septation and/or a conduction abnormality. It has been demonstrated that Holt–Oram syndrome is caused by mutations in the T-box transcription factor gene TBX5. Numerous germline mutations (more than 90) of this gene have been reported; however, TBX5 mutations are only identified in up to 74 % of typical Holt–Oram syndrome patients. We report a Japanese family with 2 affected individuals with the typical Holt–Oram syndrome phenotype, namely bilateral asymmetrical radial ray deformities and an atrial septal defect. An array-based comparative genomic hybridization study revealed an 11-kb duplication at 12q24.1. Moreover, a multiplex ligation-dependent probe amplification study confirmed the duplication of exons 1–6 of TBX5. Although a small duplication in TBX5 (6 bases) has been reported, a large duplication of this gene has not been described previously in typical Holt–Oram syndrome patients. All typical Holt–Oram syndrome cases in which a mutation is not identified should be screened for TBX5 exon duplications.