Patients with atrial septal defects (ASD) have increased mortality and morbidity. This can only be partly explained by hemodynamic changes caused by the ASD, suggesting additional underlying causes. Patients with an ASD have an increased burden of pathogenic gene variants in ASD related genes, indicating genetics as an important etiologic factor. Inheritance of genetic variants with high impact can cause ASD in relatives (familial ASD). In this study we present a family with ASD and diverse cardiac morbidity and Holt-Oram syndrome.

Methods: We included patients with a familial ASD in an exome sequencing project. In this cohort we identified a unique family with 12 family members with ASD. We performed whole exome sequencing in 5 family members to identify the disease-causing gene variant. To confirm the inherited gene variant, we used Sanger sequencing in the rest of the family members with ASD and age >18 years. Medical data was collected from hospital records and clinical examination with x-ray of upper-limbs and Holter monitoring.

Results: We identified a novel pathogenic variant the F232L in TBX5 in all 10 affected family members with an ASD and age >18 years. Two patients were children and therefore not investigated yet. The family members presented with diverse cardiac phenotypes including heart failure, tachyarrhythmias, AV-block and bradycardia, of which 2 needed a pacemaker. Clinical examination showed bilateral short fingers in all affected family members. X-ray was performed in 1 patient showing an abnormal scaphoid bone. These findings suggest a dominant inherited disorder: Holt-Oram syndrome.

Conclusion: We identified a novel variant in TBX5 (F232L). Holt-Oram syndrome with mild skeletal malformations might be under diagnosed. Severe arrhythmias with pacemaker need are associated with Holt-Oram syndrome. Hence, clinical awareness of family history, arrhythmias, and heart failure in patients with familial ASD may lead to timely treatment and uncover patients with Holt-Oram Syndrome.