B-PO05-208 PATHOGENIC VARIANTS AS A RED HERRING: A CASE OF PREMATURE VENTRICULAR CONTRACTION-TRIGGERED VENTRICULAR FIBRILLATION WITH AN INCIDENTAL PATHOGENIC VARIANT IN LMNA-ENCODED LAMIN A/C

Abstract

Pathogenic variants in LMNA-encoded lamin A/C can cause cardiomyopathies and cardiac conduction abnormalities. While genetic testing is a hallmark diagnostic tool critical in assessing inherited arrhythmia syndromes and cardiomyopathies, careful variant interpretation is of utmost importance. Describe a case that highlights the ongoing need for caution when interpreting genetic test results for inherited arrhythmia syndromes and cardiomyopathies and demonstrate that when faced with marked genotypic/phenotypic discordance, it is best to view the phenotype as the most important. N/A This is a case of a 16-year-old male with out of hospital sudden cardiac arrest secondary to ventricular fibrillation (VF) initially attributed to a maternally-inherited pathogenic/likely pathogenic frameshift variant annotated as c.1961dup; p.T655NfxX49 in LMNA. However, cardiac imaging demonstrated a hemodynamically and structurally normal heart in the patient. Furthermore, while three first-degree relatives had this variant, their cardiac evaluations were normal. The family was recommended to receive prophylactic implantable cardiac defibrillators and thus sought out a second opinion. Since the clinical and genetic information was incongruent with the diagnosis, subsequent electrophysiology (EP) study revealed premature ventricular contraction (PVC)-triggered VF that was ablated successfully. This case presents an interesting conundrum in which a pathogenic/likely pathogenic frame-shift variant was identified in LMNA, a gene that when mutated is normally thought to be associated with high penetrance and substantial risk of SCA. However, the phenotype was consistent with a non-genetic etiology and the pathogenic variant deemed to be a coincidental but irrelevant finding. Careful clinical assessment and genetic evaluation allowed the correct diagnosis to be made and unnecessary ICD implants in the family members to be avoided. In a patient with a pathogenic LMNA variant, LMNA-mediated sudden cardiac arrest in the setting of a pristine cardiac evaluation is unlikely. Therefore, before rendering such a conclusion, search for alternative explanations such as non-genetic, PVC-triggered VF.