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Abstract
Here, we present a small Iranian family, where the index patient received a diagnosis of restrictive cardiomyopathy (RCM) in combination with atrioventricular (AV) block. Genetic analysis revealed a novel homozygous missense mutation in the DES gene (c.364T > C; p.Y122H), which is absent in human population databases. The mutation is localized in the highly conserved coil-1 desmin subdomain. In silico, prediction tools indicate a deleterious effect of the desmin (DES) mutation p.Y122H. Consequently, we generated an expression plasmid encoding the mutant and wildtype desmin formed, and analyzed the filament formation in vitro in cardiomyocytes derived from induced pluripotent stem cells and HT-1080 cells. Confocal microscopy revealed a severe filament assembly defect of mutant desmin supporting the pathogenicity of the DES mutation, p.Y122H, whereas the wildtype desmin formed regular intermediate filaments. According to the guidelines of the American College of Medical Genetics and Genomics, we classified this mutation, therefore, as a novel pathogenic mutation. Our report could point to a recessive inheritance of the DES mutation, p.Y122H, which is important for the genetic counseling of similar families with restrictive cardiomyopathy caused by DES mutations.
Highlights
Mutations in DES, encoding the muscle specific intermediate filament protein desmin, can cause myopathies, as well as different cardiomyopathies [1]
A permanent pacemaker was implanted. He was referred for an echocardiography to evaluate cardiac function as an underlying cardiomyopathy was suspected
The homozygous DES mutation, p.Y122H, was identified in an isolated index patient from a family without any obvious cosegregation, this mutation fulfills several criteria for pathogenicity according to the guidelines of the American College of Medical Genetics and Genomics (ACMG) [31]
Summary
Mutations in DES, encoding the muscle specific intermediate filament protein desmin, can cause myopathies, as well as different cardiomyopathies [1]. The spectrum of cardiac phenotypes associated with DES mutations ranges from dilated (DCM, MIM #604765) [2,3], arrhythmogenic (ACM, MIM #107970) [4,5], noncompaction (NCCM, MIM #604169) [6], hypertrophic #115197) [7] and, in rare cases, restrictive cardiomyopathies (RCM, MIM #115210) [8]. It is currently unknown, why phenotypes caused by DES mutations are diverse and include skeletal and cardiac myopathies. In addition to mutations in DES, RCM-associated mutations have been currently described in more than 15 further genes such as ACTC1
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