High Burden of Ventricular Arrhythmias and Cardiac Conduction Disease in Pediatric Patients with Pathogenic Desmin (DES) Variants

BackgroundPathogenic variants in the desmin gene (DES) are implicated in diverse cardiomyopathy and skeletal myopathy phentoypes with high rates of major adverse cardiac events (MACE). Although pediatric cases have been reported, the genetic profile, clinical features and outcomes in affected children remain poorly defined. This study aimed to comprehensively characterize these aspects in the pediatric population. MethodsWe conducted a systematic review and individual patient data meta-analysis of Medline (PubMed) and Embase, including patients with pathogenic or likely pathogenic DES variant(s) diagnosed before age 21. MACE were defined as cardiac conduction disease (CCD) requiring device implantation, sustained ventricular arrhythmias (VA), and heart failure (HF) events. ResultsFifty-one pediatric patients were included (58.8% male; 64.7% probands; median age at first evaluation: 14.0 years [IQR 11.0-17.0], median follow-up: 5.0 years [1.0-11.5]). Among probands, 60.6% (20/33) had a heterozygous variant (20 non-frameshift/non-truncating and 2 frameshift/truncating), while the remaining 11 (33.3%) harbored biallelic genotypes (homozygous (n=8), compound heterozygous (n=3)). At presentation, 54.9% (28/51) patients had cardiomyopathy and 54.9% had skeletal myopathy. CCD occurred in 39.2% (median age: 19.0 years), sustained VA in 21.6% (median age: 18.0 years), and HF events in 37.3% (median age: 19.0 years). In total, 64.7% experienced MACE (median age: 17.0 years [13.0-19.0]), and 19.6% died during follow-up (median age: 23.5 years [14.8-28.0]). Rates of cardiomyopathy diagnosis, CCD, VA and HF events as well as composite MACE were similar between those with a heterozygous and biallelic variants (p>0.05 for all), but the latter group had nearly twice higher rate of skeletal myopathy (43.6% vs 83.3%, p=0.016). ConclusionPediatric DES-associated disease is characterized by heterogeneous cardiomyopathy phenotypes and substantially high MACE burden. Probands were more likely than genotype-positive relatives to develop CCD and HF events, while sustained VA rates were similar and substantial in both groups. Cardiomyopathy rates and outcomes were comparable between patients with heterozygous and biallelic variants. WHAT IS KNOWN?O_LIDesmin (DES)-associated cardiomyopathy is a rare genetic disorder characterized by variable cardiac and skeletal muscle involvement, typically presenting in adulthood with conduction system disease, ventricular arrhythmias, or heart failure. C_LIO_LIWhile case reports suggest that pediatric onset is possible, the clinical features, genetic landscape, and outcomes in children remain poorly characterized. C_LI WHAT THE STUDY ADDSO_LIIn pediatric patients with DES variants, cardiac phenotype expression can commence in early childhood and rapidly progresses with age, with two-thirds of patients experiencing major adverse cardiac events by young adulthood, highlighting the critical need for initiation of comprehensive cardiac evaluation in early childhood in patients with DES variants. C_LIO_LICardiac conduction disease and heart failure were the most common events in pediatric DES patients, especially in probands, though arrhythmic risk was present, and substantial, both in probands and relatives. C_LIO_LIMultisystem involvement, including skeletal muscle symptoms, was common in pediatric DES patients, particularly those with biallelic variants, underscoring the importance of early genetic testing and longitudinal, multidisciplinary surveillance in at-risk children, regardless of family history. C_LI