rs397516929 — DSP Ser987Pro

Desmoplakin Ser987Pro — A Rare Variant Linked to Fibrotic Arrhythmogenic Cardiomyopathy

Desmosomes are the mechanical rivets that hold cardiac muscle cells together under the repetitive stress of every heartbeat. Desmoplakin (DSP) is the master scaffold of the desmosome — the only structural protein that spans from the desmosome's cytoplasmic plaque all the way to the intermediate filaments inside the cell. When desmoplakin is compromised, desmosomal integrity fails under mechanical load¹¹ desmosomal integrity fails under mechanical load
DSP is the primary force transducer between the desmosome and the cytoskeleton, triggering a cascade of cellular detachment, fibrosis, and arrhythmia-prone scar tissue. The p.Ser987Pro variant at rs397516929 replaces a serine with proline at position 987 in the protein — a conservative-to-rigid substitution that likely alters the local protein conformation and mechanical resilience of the desmoplakin rod domain.

The Mechanism

The serine-987-to-proline substitution sits within the central rod domain of desmoplakin, a region critical for dimerization and mechanical resistance²² dimerization and mechanical resistance
desmoplakin functions as an antiparallel homodimer linked through its rod domain. Proline is the most conformationally constrained amino acid; its introduction into an alpha-helical region typically breaks or kinks the helix. In the context of a structural protein under cyclical mechanical stress, even partial impairment of rod domain rigidity or dimerization efficiency could reduce the desmosome's ability to maintain intercellular adhesion during high-demand periods.

Heterozygous loss-of-function in DSP causes disease through haploinsufficiency — one damaged copy reduces total desmoplakin output below the threshold required for sustained mechanical integrity in cardiomyocytes. The result is cardiomyocyte detachment, fatty-fibrous replacement, and patchy subepicardial fibrosis³³ cardiomyocyte detachment, fatty-fibrous replacement, and patchy subepicardial fibrosis
the fibrosis precedes and is disproportionate to systolic dysfunction in DSP cardiomyopathy, creating an arrhythmia-prone substrate that can trigger ventricular tachycardia and sudden cardiac death — often while left ventricular ejection fraction (LVEF) is still preserved.

DSP cardiomyopathy has a distinct inflammatory dimension absent from most heritable cardiomyopathies: 14–22% of carriers experience acute "hot phase" episodes of chest pain, troponin elevation, and new late gadolinium enhancement⁴⁴ 14–22% of carriers experience acute "hot phase" episodes of chest pain, troponin elevation, and new late gadolinium enhancement
mimicking myocarditis or acute coronary syndrome but without obstructive coronary disease. These episodes accelerate fibrosis accumulation and substantially increase subsequent arrhythmia risk.

The Evidence

DSP cardiomyopathy has been characterized in detail only in the past six years, and the Ser987Pro specific variant (ClinVar VCV000044888) has a single ClinVar submission from Mass General Brigham (2009, no assertion criteria), based on two patients with arrhythmogenic right ventricular cardiomyopathy. The variant is essentially absent from gnomAD population databases — consistent with a high-penetrance pathogenic variant under strong negative selection.

The broader DSP cardiomyopathy literature, however, is now substantial. Smith et al. (Circulation 2020) studied 107 patients with pathogenic DSP variants⁵⁵ Smith et al. (Circulation 2020) studied 107 patients with pathogenic DSP variants
Desmoplakin cardiomyopathy is a fibrotic and inflammatory form distinct from typical dilated or arrhythmogenic right ventricular cardiomyopathy. Circulation 141:1872–1884, 2020 and showed that left ventricular predominant disease occurred in 55% of DSP patients (versus 0% for PKP2 mutations), with subepicardial late gadolinium enhancement in 40% and normal LVEF preserved in 35% of imaging-positive patients — fibrosis preceding dysfunction.

Wang et al. (Europace 2022), following 91 DSP variant carriers for a median 4.3 years⁶⁶ Wang et al. (Europace 2022), following 91 DSP variant carriers for a median 4.3 years
Clinical characteristics and risk stratification of desmoplakin cardiomyopathy. Europace 24:268–277, 2022, found a sustained ventricular arrhythmia (VA) incidence of 5.9 per 100 person-years. Myocardial injury events — the "hot phase" episodes — strongly predicted both arrhythmia (HR not quantified in abstract) and heart failure (HR not quantified).

The largest cohort to date, Gasperetti et al. (Eur Heart J 2025), enrolled 800 patients from 26 institutions⁷⁷ Gasperetti et al. (Eur Heart J 2025), enrolled 800 patients from 26 institutions
Clinical features and outcomes in carriers of pathogenic desmoplakin variants. Eur Heart J 46:362–376, 2025. Over 3.7-year follow-up, 17.4% developed sustained VA (3.9%/year) and 9.0% required heart failure hospitalization (1.8%/year). Independent VA predictors included female sex (aHR 1.547), prior non-sustained VT (aHR 1.721), prior sustained VA (aHR 1.923), LVEF ≤50% (aHR 1.645), and myocardial injury episodes (HR 2.394). Critically, 32.5% of patients met no conventional diagnostic criteria for ARVC, DCM, or NDLVC — underscoring that standard phenotypic thresholds miss many DSP carriers.

Bariani et al. (Heart Rhythm 2022), 73 Italian DSP carriers⁸⁸ Bariani et al. (Heart Rhythm 2022), 73 Italian DSP carriers
Clinical profile and long-term follow-up of a cohort of patients with desmoplakin cardiomyopathy. Heart Rhythm 2022, found major ventricular arrhythmias in 29% overall, with males experiencing dramatically worse outcomes: 52% arrhythmia vs 24% in females (p=0.036), and 31% cardiac death in males vs 0% in females (p<0.001). Females showed preferential left ventricular involvement.

The DSP Risk Score (Carrick et al., Eur Heart J 2024)⁹⁹ DSP Risk Score (Carrick et al., Eur Heart J 2024)
A novel tool for arrhythmic risk stratification in desmoplakin gene variant carriers. Eur Heart J 45:2968, 2024 integrates five clinical parameters — female sex, non-sustained VT history, PVC burden, LVEF <50%, and moderate-to-severe RV dysfunction (HR 6.0) — into a validated risk model with c-statistic 0.782, stratifying patients into low (<5%), intermediate (5–20%), and high-risk (>20%) five-year arrhythmia categories.

Practical Actions

DSP cardiomyopathy is actionable precisely because it is heritable (autosomal dominant, each child of a carrier has 50% risk), penetrant but variable in timing, and progressive in proportion to cumulative fibrosis. Carriers who are identified before symptoms emerge have the greatest window for preventive monitoring.

Cardiac magnetic resonance imaging (CMR) is the cornerstone of evaluation — echocardiography misses subepicardial fibrosis detectable only as late gadolinium enhancement. Ambulatory ECG monitoring quantifies PVC burden, one of the five parameters in the validated DSP risk score. Competitive sports restriction is recommended for carriers with confirmed disease phenotype, as exercise-induced myocardial stress can trigger "hot phase" episodes and accelerate fibrosis. For those progressing to high VA burden or reduced LVEF, ICD consideration follows standard ESC/AHA heart failure guidelines — though the LVEF <35% threshold used in dilated cardiomyopathy is insensitive for DSP disease, where arrhythmia risk is elevated even with preserved ejection fraction.

First-degree relatives of confirmed carriers should undergo clinical and genetic evaluation. Cascade genetic testing identifies pre-symptomatic carriers before fibrosis has accumulated.

Interactions

DSP cardiomyopathy shares phenotypic overlap with PKP2 (plakophilin-2) and DSG2 (desmoglein-2) variants — all desmosomal genes whose proteins form the macromolecular complex at the intercalated disc. Compound heterozygosity or digenic combinations with PKP2 variants have been reported and may produce more severe phenotypes with earlier onset and biventricular involvement, though systematic data on specific genotype combinations are limited. SCN5A variants (sodium channel) have been found as potential modifiers of arrhythmia severity in some desmosomal cardiomyopathy families. Carriers with concurrent hypertension or obesity face accelerated fibrosis progression due to increased hemodynamic wall stress amplifying desmosomal vulnerability.