DSP – Hypertrophic Cardiomyopathy

Desmoplakin (DSP) is a key desmosomal cytolinker (HGNC:3052) most commonly implicated in arrhythmogenic cardiomyopathy. Emerging data suggest that rare DSP variants may also contribute to the pathogenesis of hypertrophic cardiomyopathy (MONDO:0005045). Although evidence is currently limited, several genetic studies have detected DSP alterations in HCM cohorts, warranting further investigation.

A targeted 46‐gene next‐generation sequencing panel applied to 13 consecutive cardiomyopathy patients identified one hypertrophic cardiomyopathy case carrying a heterozygous DSP missense variant, c.740C>T (p.Ala247Val) (PMID:25979592). This variant co‐occurred with a TTN mutation in a digenic context in a patient with unexplained left ventricular hypertrophy, suggesting a possible contributory role of DSP in HCM pathogenesis.

In a familial co‐inheritance study, double heterozygotes for DSP and MYBPC3 variants displayed variable clinical expression of hypertrophic cardiomyopathy. Two members of Family A carrying both a DSP allele and a pathogenic MYBPC3 variant were diagnosed with HCM, demonstrating segregation of DSP in an autosomal dominant pattern within a multiplex pedigree (PMID:28699631).

A large case–control cohort study screened 1,000 HCM patients and 761 controls for deleterious rare desmosomal variants, including DSP, and found a significant enrichment in the HCM group (2.4% vs. 0.66%, P=0.004) (PMID:34500006). Although the specific contribution of individual DSP mutations was not detailed, this burden analysis supports a potential pathogenic role for DSP in a subset of HCM cases.

Overall, hypertrophic cardiomyopathy due to DSP variants appears to follow an autosomal dominant inheritance mode. Segregation data are limited, with at least two affected relatives carrying DSP risk alleles in one family. Only three unrelated DSP‐variant probands with HCM have been reported to date, and functional follow-up specific to HCM is lacking.

Clinical Validity

Category: Limited

Rationale: Identification of DSP variants in 3 HCM probands with minimal segregation; early burden data showing enrichment but absence of replication or functional corroboration.

Genetic Evidence (ClinGen Tier: Limited)

Rationale: 3 probands from two independent cohorts (PMID:25979592, PMID:28699631); segregation in 2 affected relatives; variant spectrum limited to missense.

Functional Evidence (ClinGen Tier: Limited)

Rationale: No functional assays directly linking DSP variants to myocardial hypertrophy; burden study suggests association but lacks mechanistic data.

Key Take-home: DSP should be considered in genetic testing panels for HCM, but current evidence is insufficient for definitive clinical interpretation.

References

• Molecular and Cellular Probes • 2015 • Targeted 46-gene and clinical exome sequencing for mutations causing cardiomyopathies. PMID:25979592
  
• European Journal of Human Genetics • 2017 • Co-inheritance of mutations associated with arrhythmogenic cardiomyopathy and hypertrophic cardiomyopathy. PMID:28699631
  
• The Canadian Journal of Cardiology • 2022 • Deleterious Rare Desmosomal Variants Contribute to Hypertrophic Cardiomyopathy and Are Associated With Distinctive Clinical Features. PMID:34500006

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