Natural History, Phenotype Spectrum, and Clinical Outcomes of Desmin ()-Associated Cardiomyopathy.

Background: Pathogenic/likely pathogenic (LP) desmin () variants cause heterogeneous cardiomyopathy and skeletal myopathy phenotypes. Limited data suggest a high incidence of major adverse cardiac events (MACEs), including cardiac conduction disease, sustained ventricular arrhythmias (VA), and heart failure (HF) events (HF hospitalization, left ventricular assist device/cardiac transplant, HF-related death) in patients with pathogenic/LP variants. However, pleiotropic presentation and small cohort sizes have limited clinical phenotype and outcome characterization. We aimed to describe the natural history, phenotype spectrum, familial penetrance and outcomes in patients with pathogenic/LP variants through a systematic review and individual patient data meta-analysis using published reports.

Methods: We searched Medline (PubMed) and Embase for studies that evaluated cardiac phenotypes in patients with pathogenic/LP variants. Cardiomyopathy diagnosis or occurrence of MACE was considered evidence of cardiac involvement/penetrance. Lifetime event-free survival from cardiac conduction disease, sustained VA, HF events, and composite MACE was assessed.

Results: Of the 4212 screened publications, 71 met the inclusion criteria. A total of 230 patients were included (52.6% male, 52.2% probands, median age: 31 years [22.0-42.8] at first evaluation, median follow-up: 3 years [0-11.0]). Overall, 124 (53.9%) patients were diagnosed with cardiomyopathy, predominantly dilated cardiomyopathy (14.8%), followed by restrictive cardiomyopathy (13.5%), whereas other forms were less common: arrhythmogenic cardiomyopathy (7.0%), hypertrophic cardiomyopathy (6.1%), arrhythmogenic right ventricular cardiomyopathy (5.2%), and other forms (7.4%). Overall, 132 (57.4%) patients developed MACE, with 96 (41.7%) having cardiac conduction disease, 36 (15.7%) sustained VA, and 43 (18.7%) HF events. Familial penetrance of cardiac disease was 63.6% among relatives with pathogenic/LP variants. Male sex was associated with an increased risk of sustained VA (hazard ratio, 2.28; =0.02) and HF events (hazard ratio, 2.45; =0.008).

Conclusions: cardiomyopathy exhibits heterogeneous phenotypes and a distinct natural history, characterized by high familial penetrance and a substantial MACE burden. Male patients face a higher risk of sustained VA events.