Novel ACTN2 missense variant is associated with idiopathic ventricular fibrillation: a case report

Idiopathic ventricular fibrillation (VF) is a diagnosis of exclusion made in patients who experience VF without an attributable cause. Pathogenic variants of the ACTN2 gene encoding the sarcomeric protein alpha-actinin-2 are known to cause hypertrophic and dilated cardiomyopathy. We show that ACTN2 variants may also be associated with malignant arrhythmias in the absence of overt structural heart disease.

A 48-year-old female presented with cardiac arrest due to VF without any history of cardiovascular disease or family history of sudden cardiac death. Troponin I was elevated at 0.698 ng/mL, but coronary angiography showed no significant coronary artery disease. Substance abuse testing showed elevated benzodiazepine and sertraline levels, which she was taking for anxiety. Electrocardiogram showed normal QRS complexes without prolonged PR or QTc intervals. She underwent therapeutic hypothermia. Cardiac magnetic resonance imaging at 2 weeks showed normal biventricular function without structural abnormalities, fibrosis, or evidence of myocardial infarction. A targeted gene panel revealed a heterozygous missense variant of unknown significance (VUS) in exon 18 of the ACTN2 gene (c.2162G > A/p.R721H).

The identified VUS is located in a highly conserved residue of a spectrin-like repeat domain of alpha-actinin-2. Spectrin-like domains of alpha-actinin-2 bind and regulate the ion channels Na_v1.5, K_v1.4, and K_v1.5, which contribute to the myocardial action potential. The VUS was predicted as pathogenic by MutationTaster, Polymorphism Phenotyping v2, and Sorting Intolerant From Tolerant in silico missense prediction tools. The c.2162G > A/p.R721H alpha-actinin-2 variant may result in dysregulation of cardiac ion channels, leading to arrhythmias.