Gain-of-function vs. loss-of-function effects of DES variants on cardiodesminopathy phenotypes

Abstract Introduction Genetic cardiomyopathies result from pathogenic variants in validated disease genes. However, different defects in the same gene can lead to cardiomyopathy heterogeneity. For instance, variants in the DES gene have been associated with restrictive cardiomyopathy (RCM), hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), and non-dilated left ventricular cardiomyopathy (NDLVC). The phenotypic heterogeneity associated with DES complicates the interpretation of novel or rare variants in this gene. Purpose This study aims to elucidate the genetic basis of phenotypic heterogeneity associated with DES variants and to assign precise clinical phenotypes to different types of DES defects. Methods We analyzed clinical phenotypes, myocardial pathology, family screening data, disease progression, and outcomes in patients with RCM, DCM, ARVC, NDLVC, and HCM carrying DES variants. DES variants were classified according to ACMG criteria to assess their impact on cardiac phenotypes. Results We identified two distinct groups of pathogenic variants: in-frame variants and truncating variants. Carriers of VUS were excluded. First Group: 20 patients carrying 12 pathogenic rare missense and in-frame splice variants exhibited a uniform phenotype characterized by early primary RCM and progressive atrioventricular block (AVB). All showed intramyocyte myofibrillar desmin accumulation at electron microscopy study. Family segregation analysis revealed both autosomal dominant and recessive inheritance patterns. The prognosis was poor: 11 patients underwent heart transplantation; 6 patients died while on the transplant waiting list, and 2 non-listed died for heart failure; 1 patient is alive on the waiting list. Second group: 6 patients carrying loss-of-function (LoF) truncating variants showed late onset NDLVC at cardiac magnetic resonance examination; the endomyocardial biopsy study excluded intramyocyte desmin accumulation. All patients remained clinically stable; one patient underwent ICD implantation, with one recorded discharge. Conclusions Rare missense and in-frame splice DES variants with gain-of-function effects can lead to desmin misfolding, resulting in a distinct phenotype characterized by RCM, AVB, and intramyocyte myofibrillar desmin aggregates. The presence of this specific clinical and pathological signature is sufficient to establish the pathogenic role of in-frame DES variants. Conversely, heterozygous truncating variants with LoF effect are associated with NDLVC phenotype, with a more favorable prognosis.