Key result
Novel NKX2-5 variant is linked to familial atrial septal defect and concurrent conduction system disease.
Why the study?
Familial atrial septal defects with conduction system disease occur and carry a 10% risk of transmission to offspring, but genetic causes need further characterization.
Case Report (n=3)
A novel pathogenic NKX2-5 variant was identified in a family with atrial septal defects and conduction disease, highlighting the importance of genetic testing for this specific phenotype.
May inform genetic evaluation in familial ASD-conduction cases; extends NKX2-5 spectrum but remains hypothesis-generating.
BACKGROUND: Most atrial septal defects (ASDs) occur sporadically, but familial cases can occur and carry a 10% risk of transmission to offspring. CASE SUMMARY: We describe a 3-generation family with autosomal dominant secundum ASD and conduction system disease related to a novel NKX2-5 variant (c.300del; p.Asp101Thrfs∗75). The index patient, a 58-year-old woman with prior ASD repair and mitral valve replacement, presented with chronotropic incompetence, atrial fibrillation, left bundle branch block, and prolonged pauses, leading to pacemaker implantation. Her mother had an ASD, atrial fibrillation, left bundle branch block, and pulmonary arterial hypertension. The proband's daughter also had an ASD. Genetic testing revealed a novel NKX2-5 pathogenic variant in all 3 patients. REVIEW SUMMARY: The combination of an ASD and conduction system disease represents the most common phenotype in patients with pathogenic NKX2-5 variants. TAKE-HOME MESSAGE: A thorough family history and genetic testing are needed when evaluating patients with ASD and concurrent conduction system abnormalities.
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Srivatsav et al. (2026) conducted a case report in Familial atrial septal defect and conduction system disease (n=3). NKX2-5 variant (c.300del; p.Asp101Thrfs∗75) was evaluated on Atrial septal defect and conduction system disease phenotype. A novel NKX2-5 pathogenic variant was associated with familial atrial septal defect and concurrent conduction system abnormalities in all 3 members of a 3-generation family.
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