DES – Arrhythmogenic Right Ventricular Cardiomyopathy

Desmin (DES) encodes a muscle‐specific intermediate filament that integrates the sarcomere with cell–cell junctions at the cardiac intercalated disk. Pathogenic DES variants have been implicated in rare cases of arrhythmogenic right ventricular cardiomyopathy (ARVC), presenting with ventricular arrhythmias, right ventricular dysfunction, and sudden cardiac death.

Multiple independent studies have identified heterozygous DES missense variants in ARVC probands. A de novo c.347A>G (p.Asn116Ser) variant was found in 1 of 22 ARVC patients PMID:20829228 and two additional variants (p.Lys241Glu and p.Ala213Val) were each detected in 1 of 91 index cases PMID:23168288. The novel p.Ala120Asp change segregated with an arrhythmogenic phenotype in a multi‐generation family PMID:24200904, and two missense variants (p.Asn342Asp, p.Arg454Trp) were reported in two families exhibiting ARVC-like or biventricular cardiomyopathy PMID:20423733. Only one additional affected relative was available for segregation in one pedigree PMID:20423733. Inheritance is autosomal dominant.

The DES variant spectrum in ARVC comprises exclusively missense changes clustering in the rod and tail domains; no truncating or canonical splice variants have been reported. No founder alleles have been described, and de novo occurrence has been documented for p.Asn116Ser and p.Ala120Asp.

Functional studies demonstrate dominant-negative pathogenicity of DES variants. The p.Asn116Ser mutant forms aggresomes and severely impairs filament formation in bacterial assays and SW13 cells (PMID:20829228). Desmin p.Ala120Asp disrupts filament assembly, prevents intercalated disk localization, and induces cytoplasmic aggregates in vitro and in ex vivo ventricular slices (PMID:24200904). In D7-des transgenic mice, mutant desmin causes gap junction remodeling, connexin-43 mislocalization, slowed conduction, and arrhythmogenic susceptibility (PMID:15913582).

Clinical screening of 100 Chinese ARVC patients failed to identify DES mutations, underscoring their rarity PMID:24238504. A recent ClinGen curation classified DES as having moderate evidence for ARVC causation, in contrast to the definitive status of desmosomal genes (PMID:33831308).

Integrated genetic and experimental data support a moderate gene–disease relationship. DES variants cause ARVC via a dominant-negative mechanism disrupting cytoskeletal integrity and electrical coupling. Key take-home: Rare heterozygous DES missense variants should be considered a moderate‐strength diagnostic criterion for ARVC when accompanied by supportive clinical and functional data.

References

• Human molecular genetics • 2010 • De novo desmin-mutation N116S is associated with arrhythmogenic right ventricular cardiomyopathy. PMID:20829228
• The American journal of cardiology • 2013 • Desmin mutations and arrhythmogenic right ventricular cardiomyopathy. PMID:23168288
• Circulation. Cardiovascular genetics • 2013 • The novel desmin mutant p.A120D impairs filament formation, prevents intercalated disk localization, and causes sudden cardiac death. PMID:24200904
• Heart rhythm • 2010 • Desmin mutations as a cause of right ventricular heart failure affect the intercalated disks. PMID:20423733
• Cardiovascular research • 2005 • Remodeling of gap junctions and slow conduction in a mouse model of desmin-related cardiomyopathy. PMID:15913582
• Chinese medical journal • 2013 • Screening of pathogenic genes in Chinese patients with arrhythmogenic right ventricular cardiomyopathy. PMID:24238504
• Circulation. Genomic and precision medicine • 2021 • International Evidence Based Reappraisal of Genes Associated With Arrhythmogenic Right Ventricular Cardiomyopathy Using the Clinical Genome Resource Framework. PMID:33831308

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