Novel TBX5 mutations in patients with Holt-Oram syndrome

Holt-Oram syndrome (MIM #142900) is an autosomal-dominant disorder characterized by radial ray deformities of the upper limb associated with cardiac septation and/or conduction defects. The disorder is caused by mutations in the transcription factor TBX5. Several studies report a rather low detection rate (range, 22-35%) of TBX5 mutations in patients with a clinical suspicion of Holt-Oram syndrome. The low detection rate is attributed to clinical misdiagnosis and genetic heterogeneity. However, a detection rate up to 74% has been reported when strict inclusion criteria for Holt-Oram syndrome are applied before genetic testing. We performed mutational analysis in a cohort of 27 unrelated patients referred with a clinical diagnosis of Holt-Oram syndrome. Seven TBX5 mutations were detected by direct sequencing. The detection rate of TBX5 mutations in this co hort of patients was 25.9% but increased to 54% when the strict phenotypical criteria were applied. No mutations were found in patients who did not meet these strict phenotypical criteria. Interestingly, we were unable to identify a TBX5 mutation in six of 13 patients who did meet the strict criteria. This study confirms TBX5 genetic testing should be reserved for patients who fulfill the strict phenotypic criteria for Holt-Oram syndrome.