DSP (Desmoplakin)
Details
DSP encodes desmoplakin, the most abundant protein of the cardiac desmosome and the obligate linker between desmosomal armadillo proteins (PKP2, JUP) and the intermediate filament network (desmin). Unlike most desmosomal ARVC genes that predominantly produce right-dominant phenotypes, pathogenic DSP variants are a major cause of ALVC (left-dominant arrhythmogenic cardiomyopathy) and biventricular forms.
Key Facts
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Desmosomal role: DSP connects desmosomal plaques to type III intermediate filament desmin; its N-terminal domain interacts with PKP2 and JUP, while the C-terminal domain binds desmin. This ~1000-amino-acid-per-domain protein is essential for mechanical coupling of adjacent cardiomyocytes. (sources/acm-hrs-2019)
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Variant profile: Truncating variants predominate for cardiac disease (signal-to-background T 19.8, EF 0.95); nontruncating variants less commonly pathogenic (NT 2.1, EF 0.52). Recessive DSP variants cause Carvajal syndrome (cardiomyopathy + woolly hair + palmoplantar keratoderma). (sources/acm-hrs-2019)
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Phenotypic range: DSP-related disease spans from isolated ALVC to biventricular ACM to cardiocutaneous syndromes. Dominant DSP variants may present with hair/skin abnormalities (often florid in recessive disease). (sources/acm-hrs-2019)
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LGE as early marker: LGE on CMR (subepicardial or mid-wall LV distribution) may be the sole imaging abnormality in patients with DSP variants who have LV arrhythmia, normal LVEF, and normal ECG — making CMR essential for early diagnosis in DSP disease. (sources/acm-hrs-2019)
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LV dysfunction risk: DSP variants are associated with absent to severe LV dysfunction; sudden death can occur even with mild or no LV impairment. 50% of DSP index patients and 17% of family members have arrhythmic phenotype with LV dysfunction. (sources/acm-hrs-2019)
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ICD risk: DSP-related ALVC carries significant SCD risk; LGE burden on CMR is a potential imaging marker for risk stratification (formal threshold not yet defined in current guidelines).
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NDLVC archetype: ESC 2023 explicitly cites DSP variants as the archetype of the NDLVC phenotype: ring-like and/or subepicardial LGE pattern on CMR is characteristic. DSP-related disease is the worked example in the guideline for illustrating the NDLVC diagnostic pathway (DSP Trp180* in a 17-year-old with palpitations and family SCD). (sources/esc-cmp-2023)
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Myocarditis-like episodes: DSP variants cause a unique form of cardiomyopathy with high prevalence of LV fibrosis and recurrent myocardial inflammatory episodes (elevated CRP, myocarditis-like events). (sources/esc-cmp-2023)
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ICD in NDLVC: DSP is a high-risk NDLVC genotype; ICD should be considered even with LVEF >35% if additional risk factors are present (Class IIa, Level C). (sources/esc-cmp-2023)
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18F-FDG-PET: Patients with DSP variants may show myocardial FDG uptake, potentially mimicking cardiac sarcoidosis — this diagnostic pitfall should be recognized. (sources/esc-cmp-2023)
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Muller 2025 — DSP-cardiomyopathy (genotype-specific review): LP/P DSP variants are typically associated with biventricular or left-dominant cardiomyopathy. Rare right precordial TWI; left precordial (V4–V6) TWI with LV disease. "Ring-like" LGE on CMR; reduced LVEF in late stage. VAs frequently RBBB morphology (may also have LBBB). (sources/ACM-Genotype-Mx-JCE-2024, rating: high)
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"Hot phases": Acute episodes of myocardial injury with myocarditis-like symptoms (chest pain, elevated troponin, no CAD) — thought to be immune-mediated. Associated with increased VA risk. No consensus on treatment (conservative/symptomatic vs immunosuppression). (sources/ACM-Genotype-Mx-JCE-2024)
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Female sex risk factor: Unlike PKP2-ARVC where male sex is a risk factor, female sex is associated with penetrant DSP-cardiomyopathy. Impact of exercise on penetrance is uncertain. (sources/ACM-Genotype-Mx-JCE-2024)
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Inadequacy of 2010 TFC for DSP: 2010 TFC perform poorly in DSP-cardiomyopathy — patients can present with VAs without fulfilling current diagnostic criteria. Padua criteria (2020) yield better diagnostic potential for DSP carriers. (sources/ACM-Genotype-Mx-JCE-2024)
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DSP risk calculator (Carrick 2024): Gene-specific VA risk calculator usable in DSP variant carriers irrespective of clinical phenotype status. ARVC risk calculator (2019) performs poorly in DSP-ARVC. (sources/ACM-Genotype-Mx-JCE-2024)
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Exercise in DSP: The impact of exercise on DSP penetrance is uncertain — in contrast to the established exercise-penetrance relationship in PKP2. (sources/ACM-Genotype-Mx-JCE-2024)
Contradictions / Open Questions
- FDG-PET mimicking sarcoidosis — diagnostic pitfall with management consequences: DSP variants can cause recurrent myocarditis-like inflammatory episodes with FDG-PET myocardial uptake, indistinguishable from cardiac sarcoidosis on imaging. The management implications differ significantly — sarcoidosis is treated with corticosteroids, which are not indicated in DSP cardiomyopathy. A misdiagnosis of sarcoidosis in a DSP patient could lead to inappropriate immunosuppression while the true arrhythmogenic risk goes unaddressed with ICD/genotype-guided therapy. (sources/esc-cmp-2023)
- ARVC Task Force Criteria not designed for DSP-ALVC: The 2010 ARVC Task Force Criteria are optimized for right-dominant ARVC and have poor sensitivity for left-dominant DSP disease, which lacks the epsilon waves, RVOT findings, and RV structural criteria that drive scoring. Many DSP patients with significant LV arrhythmia risk will be missed by ARVC TFC and require NDLVC-based diagnostic reasoning instead. (sources/acm-hrs-2019, sources/esc-cmp-2023)
- ICD threshold in DSP with LVEF >35% — weak evidence base: The recommendation to consider ICD in DSP/NDLVC patients with LVEF >35% when additional risk factors are present is Class IIa, Level C — the weakest level of evidence. No randomized trial exists and registry data are limited by small cohort size and referral bias. The risk-benefit threshold for ICD in patients with preserved LVEF and DSP variants is therefore poorly calibrated. (sources/esc-cmp-2023)
Connections
- Related to concepts/Desmosome
- Related to entities/ARVC
- Related to entities/ALVC
- Related to concepts/Arrhythmogenic-Cardiomyopathy
- Related to entities/PKP2
- Related to entities/NDLVC
- Related to concepts/Late-Gadolinium-Enhancement
- Related to sources/ACM-Genotype-Mx-JCE-2024