Molecular Genetic and Ocular Findings in Patients with Holt-Oram Syndrome

Purpose: The autosomal dominant Holt-Oram syndrome (HOS) is characterized by upper limb and cardiac septal defects. Mutations of the TBX5 gene have been identified as the underlying gene defect in HOS. Embryonic expression of TBX5 has been found in the human retina. This is the first report of ocular findings in two unrelated families with mutations in the TBX5 gene. Methods: Six living persons affected with HOS and 10 unaffected family members were subjected to mutation analysis and complete ophthalmological examination, including electrophysiological examinations (EOG and flash ERG). Results: A heterozygous single base-pair substitution in exon 5 (408C → A) was detected in all affected patients. All examined affected patients were ophthalmologically asymptomatic with normal EOG. A scotopic elongated b-wave latency was found in affected family members who were older than 35 years. The ERG was normal in the younger patient. Conclusions: Haploinsufficiency of TBX5 alters the dorsal-ventral polarity in developing eye vesicles without any detected functional loss in humans. Slight ERG abnormalities later in life may be a result of changes induced by the inner ganglion cell layer in the inner nuclear layer.