Genetic spectrum of familial and sporadic dilated cardiomyopathy: arrhythmic phenotypes associated with mutations in the lamin A/C (LMNA) gene

Purpose. To study the diagnostic value of cascade family screening and the spectrum of genetic variants in patients with familial and sporadic DCM, assess clinical outcomes and comparative analysis of 5-year event-free survival.

Materials and methods. The study included 156 unrelated patients with verified DCM. All patients (aged 46 [34; 57] years; 125 (80%) male; LVEF 31 [24; 38]%; LV EDD 68 [61; 74] mm; follow-up period - 77 [59; 108] months) a complex of clinical and instrumental studies (ECG, ECHO, HM, MRI), cascade family screening with genetic testing (NGS+Sanger) and segregation analysis were performed.

Results. Criteria for familial DCM were identified in 73 (46.8%) probands. The genetic cause of DCM was identified in 47 (64,4%) familial cases, while for sporadic form DCM pathogenic variants were detected in 19 (22,9%) patients. The dominant mutations were truncating variants in the titin gene (10,9%) and variants in the lamin A/C (LMNA) gene - 8,33%. As a result of the evaluation of cumulative event-free survival (Kaplan-Meier curves), LMNA carriers showed the poor 5-year prognosis for ventricular tachyarrhythmic events (x²=39.9; p=0,0001) and composite adverse outcomes (x²=12.1; p=0.001). Probands who had a familial DCM (log rang x²=38.5; p=0,0001) showed the worst prognosis and low cumulative survival when compared with patients of the sporadic DCM.

Conclusion. Cascade clinical family screening and genetic testing in the DCM cohort increased the level of diagnosis of familial DCM from 4.5% to 46.8%. Associations of LMNA mutations with life-threatening tachyarrhythmias are defined as prognostically significant, that confirms the important role of genetic stratification of arrhythmic risk.

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