Unveiling New Insights: Reinterpreting DES Mutation, p.Arg383His, through a Study of an Iranian Family with Isolated Hypertrophic Cardiomyopathy, Implication for Phenotype‒Genotype Correlation Analysis

Abstract

Background Desmin, a crucial intermediate filament in muscle cells, maintains structural integrity in cardiac muscle and provides stability to striated muscle cells. Mutations in the DES gene lead to desminopathies, causing diverse cardiac and skeletal myopathies. We examine a new Iranian family with a highly penetrant p.Arg383His variant in the DES gene, resulting in severe hypertrophic cardiomyopathy (HCM) without skeletal phenotypes. Moreover, we discuss all reported disease-causing missense variants, examining their clinical manifestations across different domains. Methods We assessed demographic data, clinical characteristics, and genetic analyses of family members. Whole genome sequencing (WGS), in silico structural and functional predictions, was also used to investigate genetic entities. A comprehensive search was performed across various databases, including to identify all disease-causing missense variants within the DES gene. Results WGS identified a p.Arg383His variant in the DES gene in the Iranian family. Analyzing 119 disease-causing missense variants in desmin revealed limited correlation between variant location and phenotypes. A significant prevalence (36.9%) of conduction diseases was linked to variants in various domains. Heart failure was associated with variants in coil2B, while syncope occurred with variants in coil2B and the tail regions. Coil1B variants showed no connection with end-stage cardiac phenotypes. Different domains showed varying associations with specific clinical outcomes, such as spine ankylosis in the tail domain and dysphonia in the desmin head domain. Conclusion The present study reports an Iranian family exhibiting severe HCM due to a novel DES gene variant, lacking skeletal myopathy phenotypes. Examining all missense variants highlighted clinical heterogeneity and complex inheritance patterns among carriers. In this context, genetic analysis is a valuable diagnostic tool for effectively managing affected patients, identifying carriers, and facilitating future family planning decisions.