*3.4. Phenotypic Di*ff*erences in Missense versus Non-Missense LMNA Variant Carriers*

We assessed clinical differences among non-missense and missense variant carriers at last follow-up. Of interest, missense variant carriers had LBBB more frequently (54.5% vs. 14.3%, *p* = 0.017) and more advanced cardiomyopathy with regard to left ventricular size and function (Table 4). Of note, all subjects with elevated CK activity were found among non-missense variant carriers ( supplementary Table S4). Other variables were comparable; in particular, we found no significant differences with regard to cardiac biomarkers' concentrations.


**Table 4.** Clinical Characteristics of *LMNA* variant carriers at last follow-up.

Legend: Number of subjects is expressed as *n* (%). Continuous variables are shown as mean ± SD or median and quartiles (Q1:25th–Q2:75th percentiles). RF ablation: radiofrequency ablation; VA: ventricular arrhythmia.

#### *3.5. Follow-Up and Risk Stratification Including Biomarkers*

Mean follow-up was 1769 days, median 1522 (Q1: 771–Q3: 2564). During the follow-up period, 14/53 (26.4%) patients developed end-stage HF: three (5.6%) of them died, and eleven (20.8%) were transplanted. There was one SCD, while another patient had SCA with successful resuscitation.

At the end of follow-up only 19/53 (36%) patients remained free of ICD (including a patient who refused to have an ICD implanted and died suddenly). Of the 34/53 (64%) patients with ICD, 10/34 (29%) experienced adequate ICD discharge.

The disease progressed to end-stage HF only in patients with DCM/HNDC. MVA occurred in 41% of them and in 19% of patients with indeterminate status ( supplementary Table S5).

The comparison of clinical data of probands and relatives between the initial and last follow-up visits confirmed progressive character of *LMNA*-related disease both with regard to HF and to arrhythmia (Table 2 and supplementary Table S6).

The influence of prespecified risk factors on the risk of MVA assessed from the date of the initial evaluation in the subgroup of 44 patients with no history of SCA or sVT and, on the risk of end-stage HF and MVA during lifespan in the whole cohort of 53 patients, is summarized in the Table 5.


**Table 5.** Potential risk factors affecting MVA-free and HTX-free survival.

Legend: AV block: atrioventricular block; CI: confidence interval; HF: heart failure; hsTnT: high-sensitive Troponin T; HTX: heart transplantation; LVEF: left ventricular ejection fraction; MVA: malignant ventricular arrhythmia; NA: not applicable; nsVT: non-sustained ventricular tachycardia; NT-proBNP: N-terminal prohormone brain natriuretic peptide.
