PO10 Truncating PLN variant associated with a hypertrophic cardiomyopathy phenotype and low arrhythmic risk

Background Pathogenic variants in the phospholamban (PLN) gene show diverse phenotypes. Non-truncating variants, with p.Arg14del being the most frequent and best characterized, are usually associated with dilated or arrhythmogenic cardiomyopathy with high arrhythmic risk. In contrast, truncating variants are rarely reported and may present with a hypertrophic cardiomyopathy (HCM) phenotype, with an uncertain arrhythmic risk. Purpose We report a case of HCM due to a truncating PLN variant to highlight the phenotypic variability and challenges in risk stratification. Methods A 37-year-old male, with no relevant family history, presented with atypical chest pain. The physical examination was unremarkable. A comprehensive diagnostic workup was performed, including ECG, biomarker assessment (hs-cTnI, NT-proBNP), echocardiography, coronary angiography, cardiac magnetic resonance (CMR), 24-hour Holter ECG monitoring, and genetic testing (next-generation sequencing using a cardiomyopathy panel of 180 genes). Clinical follow-up extended over four years. Results ECG showed ST elevation in V1-V3 and T-wave inversions in DI, aVL, V2-V3 (Figure 1). Echocardiography revealed severe asymmetric LVH with anteroseptal hypokinesia. Biomarkers showed a mildly elevated NT-proBNP (207 pg/ml) and normal troponin. Coronary angiography showed normal coronary arteries. CMR confirmed HCM with a septal thickness of 31 mm, an accessory anterolateral papillary muscle, and extensive late gadolinium enhancement (>15% of LV mass) involving the most hypertrophied regions, predominantly the anteroseptal and anterior basal/mid segments (Figure 1). LVEF was 55%, likely reflecting the impact of extensive fibrosis. A 24-hour Holter ECG monitoring detected only one brief episode of ventricular bigeminy, with RBBB morphology. Genetic testing identified a pathogenic heterozygous variant in the PLN gene: NM_002667.5:c.116T>G p.(Leu39*). This nonsense variant introduces a premature stop codon at position 39 of the 52-amino acid phospholamban protein. The truncated protein is degraded by the proteasome, causing haploinsufficiency and loss of SERCA2a (sarcoplasmic/endoplasmic reticulum Ca2+-ATPase) inhibition, which enhances SR Ca2+ reuptake and has been shown experimentally to promote hypercontractility [1,2], with subsequent hypertrophic remodeling. Given the patient’s low blood pressure and biomarker profile, treatment with beta-blockers, low-dose ACE inhibitors, and trimetazidine was initiated. At four-year follow-up, the patient remained asymptomatic, with stable LVEF and no significant ventricular arrhythmias. Estimated 5-year SCD risk was 2.56%, below the ICD threshold. Conclusions This case illustrates a rare PLN phenotype, where a truncating variant leads to hypertrophy and fibrosis but low arrhythmic risk, underscoring the need for tailored risk stratification in PLN-associated cardiomyopathies.