A novel NKX2-5 mutation causing atrial septal defect and high-degree atrioventricular block in a Chinese family

Familial congenital heart disease associated with NKX2-5 gene variants represents an important inherited cardiac condition. In this study, we evaluated a multigenerational Chinese family presenting with recurrent structural heart defects. The proband, a 35-year-old woman who underwent surgical repair of a defect of the atrial septum at age twenty-six, later developed intermittent high-grade impairment of atrioventricular conduction requiring implantation of a leadless ventricular pacemaker, followed by episodes of paroxysmal irregular atrial rhythm treated with catheter ablation. Systematic assessment of her relatives identified defects of the atrial septum in six additional family members across two generations, while no carriers exhibited ventricular arrhythmias, myocardial disease, or unexpected sudden death. Genetic testing revealed a heterozygous frameshift variant in NKX2-5 (c.604_605del; p.L202Gfs*49), confirmed by Sanger sequencing and absent from population databases. The variant was present in all relatives with structural heart defects and absent in unaffected tested individuals, supporting strong segregation. On the basis of established genetic criteria, this variant is considered likely pathogenic for defects of the atrial septum. The conduction abnormalities observed in the proband cannot be conclusively attributed to the variant because they were not present in other carriers. This novel variant broadens the spectrum of NKX2-5 related familial congenital heart disease and highlights the importance of genetic evaluation in families with inherited structural cardiac conditions.