Lamin A/C cardiomyopathy in children

Abstract

Abstract Background Lamin A/C gene (LMNA) variants cause familial dilated cardiomyopathy (DCM) with a malignant cardiac phenotype characterized by atrioventricular (AV) block and supraventricular and ventricular arrhythmias, often preceding cardiac dilatation and dysfunction. Current guidelines recommend genetic and clinical screening of family members, starting at 10-12 years of age. However, children with LMNA variants are underrepresented in research publications and data are lacking on both the onset of a cardiac phenotype and the prevalence of cardiac events in this population. Purpose The study aimed to investigate the prevalence of cardiac events in LMNA genotype positive children and penetrance of LMNA cardiac phenotype in genotype positive paediatric relatives. Methods We conducted a longitudinal cohort study including consecutive genotype-positive LMNA patients and genotype positive relatives, all ≤18 years of age, followed between 2009 and 2022. The patients were examined by electrocardiography, Holter monitoring, and echocardiography. A cardiac phenotype was defined as the presence of either atrioventricular (AV) block, prolonged sinus arrest, atrial fibrillation/ flutter (AF), ventricular tachycardia (VT), or echocardiographic DCM. Cardiac events were defined as AF, VT, cardiac syncope, sudden cardiac arrest (SCA) or heart transplantation (Htx). Childhood-onset disease was defined as the presence of a cardiac phenotype ≤12 years of age. Results Among 44 LMNA genotype-positive children (age 10.4 [IQR 6.5-12.9] years, 34 relatives), 12 (27 %) became phenotype-positive at a median age of 12.8 [IQR 7.9-14.1] years, of which 7 (58 %) had childhood-onset disease (Figure 1). Nine (18 %) of the children experienced a cardiac event and 44 % of these were ≤12 years of age (Figure 2). Three children had AF, 5 had VT, and one had cardiac syncope. Htx was performed in two unrelated children, at 6 and 8 years of age, respectively. Among the 34 genotype-positive paediatric relatives, 21 % (n=7) became phenotype-positive at a median age of 10.9 [IQR 7.5-15.1] years, of which 57 % (n=4) had childhood-onset disease. Conclusions In a cohort of LMNA genotype children, there was a high prevalence of cardiac events and 44 % of these occurred in children ≤12 years of age. The penetrance of LMNA cardiac phenotype in genotype positive paediatric relatives was 21 %, highlighting the importance of early family screening and cardiological follow-up.