rs397516943 — DSP

Pathogenic DSP nonsense variant creating a premature stop codon at position 160 (p.Arg160Ter), causing desmoplakin haploinsufficiency and desmoplakin-associated arrhythmogenic cardiomyopathy with predominantly left ventricular fibrosis

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Desmoplakin p.Arg160Ter — When the Cardiac Glue Breaks

Your heart muscle is held together by molecular anchors called desmosomes11 desmosomes
protein complexes at the intercalated discs between cardiomyocytes — they transmit mechanical force and maintain cell-cell adhesion during every heartbeat. Desmoplakin (DSP) is the largest desmosomal protein and acts as the structural linchpin, connecting desmosomal cadherins at the cell surface to the intermediate filament cytoskeleton deep inside the cell. Without functional desmoplakin, cardiac cells cannot hold together under the mechanical stress of beating, leading to cell death, fibrofatty replacement of the myocardium, and the substrate for life-threatening arrhythmias.

The p.Arg160Ter mutation (c.478C>T, NM_004415.4) converts arginine at position 160 into a premature stop codon. The resulting truncated mRNA is targeted for nonsense-mediated decay22 nonsense-mediated decay
a cellular quality-control mechanism that degrades mRNA transcripts containing premature stop codons, preventing production of toxic truncated proteins — meaning the mutant allele produces essentially no functional desmoplakin protein. The result is haploinsufficiency: only one functional DSP allele remains to supply desmoplakin to every intercalated disc in every cardiomyocyte, leaving the heart structurally vulnerable.

This variant is classified Pathogenic/Likely pathogenic by 10 major genetic testing laboratories in ClinVar (VCV000044922), including GeneDx, Mayo Clinic Laboratories, Ambry Genetics, Labcorp Genetics, and the Stanford Center for Inherited Cardiovascular Disease — the highest possible evidence tier for rare disease variants.

The Mechanism

The p.Arg160Ter variant sits in the N-terminal head domain of DSP, upstream of the plakin domain and both spectrin repeat rod domains. A stop codon this early in the protein eliminates the entire functional architecture of desmoplakin. Recent experimental work33 Recent experimental work
Smith et al., bioRxiv 2025 demonstrated that truncating DSP variants reduce DSP protein levels by 23–62% of normal in patient-derived cardiomyocytes. Under conditions of heightened contractile stress (simulated by endothelin-1 exposure), DSP-haploinsufficient cardiomyocytes showed 75% adhesion failure versus only 8% in controls. At baseline contractile load, adhesion was intact — explaining why carriers can appear clinically normal for decades before disease manifests during physiological or pathological stress (intense exercise, myocarditis, pregnancy).

The loss of desmosomal integrity triggers a cascade: cardiomyocytes detach and die, the immune system responds with inflammation, and myofibroblasts replace the lost muscle with fibrous and fatty tissue. This fibrofatty replacement creates late gadolinium enhancement44 late gadolinium enhancement
a signal on cardiac MRI that indicates fibrous scar tissue, where gadolinium contrast agent persists because normal cardiomyocytes wash it out but scar tissue cannot visible on cardiac MRI and provides the electrical substrate for reentrant ventricular tachycardia and ventricular fibrillation.

The Evidence

DSP cardiomyopathy is now recognized as a distinct entity from classical arrhythmogenic right ventricular cardiomyopathy (ARVC). The landmark multicenter study by Smith et al., Circulation 202055 multicenter study by Smith et al., Circulation 2020
107 DSP and 81 PKP2 patients established that DSP mutations produce left-dominant disease in 55% of patients (versus 0% for PKP2), with LV late gadolinium enhancement in 40% and acute myocardial injury episodes — a myocarditis-like inflammatory flare — in 15%. Right ventricular cardiomyopathy was present in only 14% of DSP patients, meaning classical ARVC diagnostic criteria systematically miss DSP disease.

The largest outcomes study to date, Gasperetti et al., Eur Heart J 202566 Gasperetti et al., Eur Heart J 2025
800 patients with pathogenic DSP variants across 26 international institutions, found that 17.4% of DSP carriers experienced sustained ventricular arrhythmias (3.9%/year). Myocardial injury episodes — which 8.8% of carriers experienced — dramatically amplified subsequent risk: hazard ratio 2.394 for sustained VA and 5.064 for heart failure hospitalization.

For variants specifically triggering nonsense-mediated decay of both major DSP isoforms77 nonsense-mediated decay of both major DSP isoforms
both DSP-I (ubiquitous isoform) and DSP-II (heart-enriched shorter isoform) are eliminated, maximizing the desmoplakin deficit in cardiac tissue — as p.Arg160Ter does — the Hoorntje et al., Circ Genom Precis Med 202388 Hoorntje et al., Circ Genom Precis Med 2023
170 DSP patients from an international cohort study found these individuals were dramatically overrepresented among clinically affected patients versus unaffected carriers (83.6% vs 16.4%, p<0.0001). Ventricular arrhythmia occurred in 33% of affected individuals in this cohort.

Genotype-phenotype analysis confirms that DSP non-missense variants (truncating, frameshift, splice site — all producing haploinsufficiency) carry substantially worse LV involvement than missense variants: LV dysfunction in 76.5% vs 10%99 LV dysfunction in 76.5% vs 10% (p=0.001) and LV MRI involvement in 92% vs 22% (p=0.001).

Practical Actions

Carriers of pathogenic DSP variants require cardiomyopathy-specialist care, not routine cardiology follow-up. The standard ARVC Task Force Criteria are specifically less sensitive for DSP disease because they prioritize right ventricular findings — a cardiac MRI protocol looking for subepicardial LV late gadolinium enhancement is the key diagnostic test.

Risk stratification now has a validated clinical tool: the DSP risk score integrates female sex, NSVT history, PVC burden, LVEF, and RV function to stratify 5-year VA risk as low (<5%), intermediate (5–20%), or high (>20%). Patients in the high-risk category should be considered for ICD implantation regardless of whether they have had a documented arrhythmic event. Patients who experience a myocardial injury episode (acute troponin rise with myocarditis- like presentation) should be urgently re-evaluated, as this dramatically escalates risk.

First-degree family members (parents, siblings, children) each carry a 50% risk of inheriting this variant. Cascade genetic testing and cardiac imaging of all adult relatives is standard of care.

Interactions

The R160* variant eliminates both major DSP isoforms (DSP-I and DSP-II) through nonsense-mediated decay — this biallelic isoform impact distinguishes early-truncating variants from variants that spare the heart-enriched DSP-II isoform and may explain the particularly high clinical penetrance observed.

DSP haploinsufficiency can interact with physiological demands that stress desmosomal integrity: intense endurance or resistance exercise, viral myocarditis, and pregnancy have all been associated with acute myocardial injury episodes (inflammatory flares) in DSP cardiomyopathy carriers. These events — detectable by troponin elevation — independently predict subsequent arrhythmia and heart failure and should prompt immediate cardiac evaluation.

Among desmosomal gene variants, double-variant carriers (a pathogenic DSP variant plus a pathogenic variant in PKP2, DSG2, or DSC2) show substantially worse outcomes than single-variant carriers in the desmosomal cardiomyopathy cohort data. If additional desmosomal variants are identified on clinical genetic testing, this escalates management urgency.

Genotype Interpretations

What each possible genotype means for this variant.

CC No DSP R160* Mutation Normal

No p.Arg160Ter DSP mutation — not at elevated risk from this variant

You carry two copies of the normal DSP allele at this position and do not have the p.Arg160Ter desmoplakin mutation. You are not at elevated risk for DSP-associated arrhythmogenic cardiomyopathy from this specific variant. More than 99.99% of the general population shares this result — the T allele has not been observed in large population databases including gnomAD and the ALFA consortium (0/10,680 chromosomes). Note that other DSP variants and other desmosomal gene mutations (PKP2, DSG2, DSC2, JUP) can cause similar conditions; this result addresses only the p.Arg160Ter mutation.

CT DSP R160* Carrier High Risk

Carries one copy of the pathogenic p.Arg160Ter DSP mutation — significant risk of arrhythmogenic cardiomyopathy

Desmoplakin (DSP) is the structural linchpin of cardiac desmosomes — the intercellular junctions that hold cardiomyocytes together during mechanical loading. The p.Arg160Ter mutation creates a premature stop codon at amino acid 160, so early in the protein that the resulting truncated mRNA is eliminated by nonsense-mediated decay. The affected allele produces no functional DSP protein. Because the normal allele produces only roughly half the normal desmoplakin complement, cardiac desmosomes are structurally weakened.

Under conditions of elevated mechanical stress — vigorous exercise, myocarditis, hemodynamic burden of pregnancy — desmoplakin-deficient cardiomyocytes are 75-fold more likely to fail adhesion than normal cells (75% vs 8% adhesion failure in experimental models). Repeated cycles of cardiomyocyte detachment, death, and fibrofatty replacement create the arrhythmic substrate: reentrant circuits within fibrotic scar tissue generate sustained ventricular tachycardia. The fibrosis is predominantly subepicardial in distribution and left-ventricular dominant — distinguishing DSP cardiomyopathy from classical right-ventricular ARVC caused by PKP2 mutations.

Disease may remain subclinical for decades. Initial presentation is often either incidental LV late gadolinium enhancement on cardiac MRI, frequent premature ventricular contractions on Holter monitoring, or an acute myocardial injury episode (troponin elevation with a myocarditis-like clinical syndrome). The myocarditis-like flares can be provoked by viral illness, extreme exercise, or pregnancy. Each such episode significantly worsens the arrhythmic and heart failure prognosis.

Risk stratification using the validated DSP risk score (integrating sex, NSVT, PVC burden, LVEF, and RV function) identifies patients at 5-year VA risk from <5% (low) to >20% (high). High-risk patients warrant primary prevention ICD consideration even without a prior arrhythmic event.

First-degree relatives (children, siblings, parents) each have a 50% probability of carrying this variant. Cascade genetic testing with cardiac evaluation of positive relatives is the standard of care and has demonstrated benefit in identifying preclinical disease before a sentinel arrhythmic event.

TT Homozygous DSP R160* Homozygous

Two copies of the pathogenic DSP p.Arg160Ter mutation — extremely rare, severe desmoplakin deficiency

You carry two copies of the DSP p.Arg160Ter mutation. This is an extremely rare genotype — both the heterozygous CT state and the homozygous TT state are essentially absent from population databases. Homozygous truncating DSP variants are associated with very early-onset and severe arrhythmogenic cardiomyopathy, and in some contexts with the Carvajal syndrome phenotype (arrhythmogenic cardiomyopathy with woolly hair and palmoplantar keratoderma), since DSP is also expressed in skin. This genotype requires immediate emergency cardiac evaluation.