Characteristics of the p.Ser358Leu Variant in the TMEM43 Gene and Its Phenotypic Manifestations.

Introduction. The c.1073C>T (p.Ser358Leu, rs63750743) variant in the TMEM43 gene causes a rare form of arrhythmogenic cardiomyopathy type 5 (ACM5), characterized by significant fatty infiltration of the myocardium, electrical conduction abnormalities, and a high risk of sudden cardiac death (SCD) – often the first manifestation of the disease. Objective: to present the clinical case of a female patient with the p.Ser358Leu variant, initially diagnosed with idiopathic ventricular tachycardia (IVT), later reclassified as biventricular arrhythmogenic cardiomyopathy (ACM); and to describe the spectrum of phenotypic manifestations of p.Ser358Leu in other carriers. Methods. A 65-year-old female patient experienced recurrent sustained ventricular tachycardia (VT). Clinical work-up included 12-lead ECG, transthoracic echocardiogram (TTE), cardiac magnetic resonance imaging (MRI) with late gadolinium enhancement (LGE), 24-hour ECG monitoring, and coronary angiography. Genetic analysis was performed using next-generation sequencing (NGS) of a panel of 174 genes linked to inherited cardiovascular diseases. There was a family history of three male relatives who died suddenly. Results. ECG showed sinus bradycardia, reduced R-wave amplitude in V1–V3, and T-wave inversions in leads III and aVF. Holter ECG revealed isolated and paired ventricular extrasystoles, single supraventricular extrasystoles, and an episode of idioventricular rhythm. Cardiac MRI demonstrated morpho-functional abnormalities consistent with the biventricular form of ACM per the 2020 Padua criteria. Due to hemodynamically significant VT, a cardioverter-defibrillator (ICD) was implanted. The was detected in the TMEM43 gene. The pathogenic variant c.1073C>T (p.Ser358Leu, rs63750743) in TMEM43 gene was detected. Conclusion. The pathogenic p.Ser358Leu variant in TMEM43 exhibits variable phenotypic expression but is most often considered a malignant nucleotide substitution, associated with early-onset ACM and high SCD risk, especially in males. This case confirms the very high risk of SCD in p.Ser358Leu carriers and highlights the difficulty of detecting myocardial structural changes in such individuals. Therefore, screening for the p.Ser358Leu TMEM43 mutation should be included not only in patients with ACM, but also in individuals with IVT when no pathogenic variants are found in channelopathy-associated genes.

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