Red herring pathogenic variants: a case report of premature ventricular contraction-triggered ventricular fibrillation with an incidental pathogenic LMNA variant

Abstract

Background: Pathogenic variants in the lamin A/C gene (LMNA) can lead to a wide range of phenotypes from dilated and arrhythmogenic cardiomyopathies and conduction abnormalities to partial lipodystrophies. This case highlights a coincidental pathogenic LMNA variant identified in a patient with sudden cardiac arrest (SCA). We demonstrate the need for careful interpretation of pathogenic variants identified in cardiomyopathy genes by highlighting a case in which a coincidental pathogenic LMNA variant was found in a patient with premature ventricular complex (PVC)-induced ventricular fibrillation (VF).

Case summary: We present the case of a 16-year-old male with SCA secondary to VF. Genetic testing identified a maternally inherited pathogenic variant in LMNA annotated c.1961dup; p.T655Nfs*49. The patient received an implantable cardiac defibrillator and was discharged on nadolol. The patient's two brothers were also variant-positive. However, the patient and both brothers had normal chamber dimensions on echocardiogram and no late gadolinium enhancement on cardiac magnetic resonance imaging. The family members with the variant were recommended to have prophylactic implantable cardiac defibrillators and thus sought a second opinion. The patient received an appropriate shock and device interrogation identified PVCs. Electrophysiology study identified PVC-induced VF which was ablated with no recurrent ventricular arrhythmias/implantable cardioverter defibrillator therapies over 8 months of follow-up. Although the variant in LMNA could lead to cardiac arrest, the clinical phenotype was consistent with a non-genetic aetiology. The family members were told to have periodic cardiac evaluation.

Discussion: This case demonstrates the identification of a coincidental pathogenic variant in a cardiomyopathy gene in a patient with cardiac arrest. Although this variant could lead to cardiomyopathy, it appears the cardiac arrest was not due to the pathogenic variant. This highlights the need to consider the clinical phenotype when interpreting genetic test results for cardiomyopathies even in the presence of a positive genetic test result.

Keywords: Cardiomyopathy; Case report; Cryogenic ablation; Genetic testing; LMNA; Lamin A/C.

Figure 1

Family pedigree with structural imaging. The 16-year-old proband (black arrow) and all first-degree relatives with the p.T655NfsX49-LMNA variant (blue star) had structurally normal hearts with unremarkable echocardiogram with no late gadolinium enhancement on cardiac magnetic resonance imaging. Parasternal long-axis view at end-diastole and short-axis cardiac magnetic resonance imaging are displayed.

Figure 2

Electrocardiogram obtained on a patient showing sinus bradycardia with a PR interval of 114 ms, QRS duration of 84 ms, and QTc of 380 ms not showing any signs of conduction disease.

Figure 3

An implantable cardioverter defibrillator tracing demonstrating short-coupled premature ventricular complexes (≤350 ms) inducing polymorphic ventricular tachycardia that degenerates to ventricular fibrillation. Premature ventricular complexes are identified on the marker strip (red ovals) with coupling intervals of 250 and 350 ms.

Figure 4

(A) The patient’s clinical premature ventricular complex with a left bundle branch block pattern, late precordial transition, and a left superior axis originating from the moderator band. (B) During the premature ventricular complex, the Purkinje potential proceeds the QRS by 24 ms (white oval).

Figure 5

A voltage map of the right ventricle demonstrating normal voltage. The areas outlined in purple indicate the high-voltage zone (>1.5 mV), indicating that there is no area of fibrosis/mild disease in the right ventricle. The grey area in this voltage map was not assessed.