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

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 an 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. We assessed demographic data, clinical features, and genetic analysis in members of this Iranian family. Whole genome sequencing (WGS), in silico structural and functional predictions, was also used to investigate genetic entities. Also, a mini‐review was performed across various databases to identify all disease‐causing missense variants within the DES gene. 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 appeared enriched among variants located in coil2B, while syncope was more frequently reported in variants affecting coil2B and the tail domains; however, these observations are exploratory and literature‐derived. Different domains showed varying associations with specific clinical outcomes, such as spine ankylosis in the tail domain and dysphonia in the desmin head domain. The present study reports an Iranian family exhibiting severe HCM due to a likely pathogenic DES gene variant, lacking skeletal myopathy phenotypes. Also, examination of all missense variants highlighted clinical heterogeneity and complex inheritance patterns among individuals carrying different variants in the DES gene. In this context, genetic analysis is a valuable diagnostic tool for effectively managing affected patients, identifying carriers, and facilitating future family planning decisions.