A Novel Pathogenic Frameshift Variant Associated With Holt-Oram Syndrome: A Case Report.

Holt-Oram syndrome is an autosomal dominant disorder characterized by congenital heart defects and distal upper-limb abnormalities. Pathogenic variants in TBX5, located on chromosome 12q24.1, cause Holt-Oram syndrome. We report a 10-year-old boy with bilateral thumb anomalies, a large secundum atrial septal defect, and sinus bradycardia who was found to carry a maternally inherited TBX5 frameshift variant, c.130del; p.(Ala44ProfsTer22). This early truncating variant is predicted to cause loss of function through protein truncation or nonsense-mediated decay. To the best of our knowledge, this specific variant has not previously been described in the peer-reviewed literature. Detailed electrocardiographic and ambulatory rhythm findings further characterize the conduction phenotype associated with this variant.