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.