Abstract 4877: Clinical Phenotypes and Outcome of 101 LMNA Gene Mutation Carriers
Purpose To analyze the cardiac phenotype and long-term follow-up of dilated cardiolaminopathies. Lamin A/C (LMNA) gene mutations cause a variety of phenotypes. In the cardiologic setting, patients diagnosed with idiopathic dilated cardiomyopathy (DCM) plus atrio-ventricular block (AVB) constitute the majority of reported cases.
Methods This was a longitudinal retrospective observational study conducted in 32 consecutive families in which LMNA gene defects were identified in the probands, sharing DCM phenotype.
Results Of the 171 family members, 101 were carriers of LMNA gene mutations. Sixty-five of 101 (64 %) were phenotypically affected while 36 (36 %) were only genotypically affected, including 5 with preclinical signs. The 65 patients had DCM with AVB (n=44), DCM with Ventricular Tachycardia/Fibrillation (VT/VF) (n=12), DCM with AVB and Emery-Dreifuss Muscle Dystrophy type 2 (EDMD2) (n=6), AVB plus EDMD2 (n=2), magnetic resonance imaging signs of arrhythmogenic right ventricular dysplasia associated with mild left ventricular dilation and VT (n=1). The disease was proven to be familial autosomal dominant (AD) in 23 of the 32 families; likely familial AD (based on pedigree and family history) in 8; and associated with a de novo mutation in 1. During a median follow-up of 57.4 months (interquartile range 26 –115 months) we observed 54 events in 47 DCM patients (7 had a later event excluded from the analysis) whereas no event was observed among the 36 non-affected carriers. The events were related to heart failure (HF) [15 heart transplants, 2 death from end-stage HF] and ventricular arrhythmias [17 sudden cardiac deaths (SCD) and 13 appropriate implantable cardioverter defibrillator (ICD) interventions]. By multivariable analysis, NYHA class III–IV and competitive sport ≥10 years were independent predictors of total events. By a bivariable Cox model, splice site mutations and competitive sport predicted SCD.
Conclusions DCMs caused by LMNA gene defects are highly penetrant, adult-onset, malignant diseases characterized by high rate of HF and life-threatening arrhythmias predicted by NYHA class, competitive sport activity and type of mutation.