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

BACKGROUND

Pathogenic 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.

METHODS

We 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.

RESULTS

Fifty-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).

CONCLUSION

Pediatric 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.