Key result
Novel inherited TBX5 frameshift variant links to Holt-Oram syndrome with limb defects and bradycardia.
Why the study?
A specific TBX5 frameshift variant causing Holt–Oram syndrome had not been previously described in the peer-reviewed literature.
Case Report (n=1)
The identification of a novel early truncating TBX5 frameshift variant (c.130del) expands the known molecular spectrum of Holt-Oram syndrome and highlights the importance of longitudinal rhythm surveillance.
Adds novel TBX5 variant to diagnostic resources; extends the mutational spectrum of Holt-Oram syndrome.
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.
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Sarkar et al. (2026) conducted a case report in Holt-Oram syndrome (n=1). TBX5 frameshift variant c.130del; p.(Ala44ProfsTer22) was evaluated. A novel maternally inherited TBX5 frameshift variant, c.130del, was identified in a 10-year-old boy with Holt-Oram syndrome, characterized by classical upper-limb abnormalities, structural heart disease, and sinus bradycardia.
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