Abstract
Holt-Oram syndrome (HOS; OMIM 142900) is a rare autosomal dominant disorder, typically involving upper limb anomalies and cardiac septal defects. HOS is caused by mutations in the TBX5 gene, which encodes a T-box transcription factor. We report a Japanese family with a novel TBX5-Q469* nonsense variant that exhibited atypical HOS characteristics, including early-onset sick sinus syndrome (SSS), but no apparent upper limb abnormalities. The proband required a pacemaker implantation at age 44 for SSS and repeated catheter ablation procedures for atrial fibrillation (AF). His daughter experienced AF with pauses, requiring catheter ablation and a pacemaker. Neither exhibited upper limb abnormalities or cardiac structural defects. However, the 28-year-old granddaughter of the proband, who did not undergo genetic testing, had a surgically corrected atrial septal defect at the age of 5. She also exhibits mild shortening of the fifth finger and sinus bradycardia. This study expanded the phenotypic spectrum of HOS, emphasizing the potential for a TBX5 variant to present as familial early-onset SSS without overt skeletal anomalies. These findings highlighted the need for genetic screening for TBX5 variants in cases of early-onset familial SSS and congenital heart defects. Genetic screening may enhance early diagnosis and guide individualized management strategies. LEARNING OBJECTIVE: Genetic testing for the TBX5 gene, the causal gene for Holt-Oram syndrome, should be considered in patients with a high prevalence of early-onset familial sick sinus syndrome and history of congenital heart disease. Even in atypical cases without obvious abnormalities of the upper extremities, this could enhance the diagnosis of Holt-Oram syndrome and guide individualized management strategies.