P88 CARDIAC INVOLVEMENT IN FOUR NOVEL NESPRIN–1 GENETIC VARIANTS

Abstract

Abstract Background Nesprins are proteins encoded by synaptic nuclear envelope (SYNE)–1 and –2 genes, that concur, together with lamin A/C and emerin, to nuclear envelope function. Almost 140 disease–related variants were identified, mostly resulting in central nervous system and skeletal muscle disorders; only a few were associated with cardiomyopathy, mostly with relatively late onset and no specific arrhythmic profile. Purpose To describe cardiac involvement in 4 novel SYNE1 variants. Methods 189 patients underwent genetic analysis in our center (2019–2022) for suspected genetic cardiomyopathy (TruSight Cardio panel, Illumina); 72% had a positive genetic report, including pathogenic/likely pathogenic or variants of undetermined significance (VUS). Among them, 4 (2%) males presented with a sole SYNE1 heterozygous VUS (figure). Results None had muscle or neurological involvement. Patients 1 and 2 had negative family history (FH) and underwent pacemaker implantation under 50 years old for high–grade atrioventricular block (AVB). Transthoracic echocardiography (TTE) and cardiac magnetic resonance (CMR) showed a mildly impaired left ventricular ejection fraction (LVEF) without oedema or fibrosis. During 3 and 6 years of follow–up (FU), several non–sustained episodes of fast ventricular tachycardia (VT) and of atrial tachycardia occurred. Patient 3 is a 55–year–old man with negative FH and a left bundle branch block (LBBB) known since the age of 45.In 2021, while playing football, he suffered a cardiac arrest due to ventricular fibrillation treated with two DC shocks; ECG showed first–degree AVB and LBBB; TTE and CMR revealed a mildly impaired LVEF without oedema or fibrosis. A subcutaneous ICD was implanted, which recorded 3 atrial fibrillation episodes in a 1–year FU. Patient 4 is a 49–year–old man, with FH of sudden death (mother’s brothers at 40 and 50 years) and of polycystic kidney, who underwent renal transplant. He had left anterior fascicular block and suffered 2 episodes of sustained monomorphic VT from the right ventricle treated with ablation. TTE and CMR showed mild LV concentric hypertrophy with normal LVEF, segmental abnormalities in right and LV strain, no fibrosis. Conclusions SYNE1 genetic variants were found to be associated with a complex cardiac phenotype, including early onset conduction disease, atrial and ventricular arrhythmias, and cardiomyopathy. Further studies are needed to determine the functional significance of the variants.