rs397516923 — DSP DSP Q72Ter

Rare truncating variant in desmoplakin that creates a premature stop codon at position 72, disrupting cardiac desmosomal integrity and predisposing carriers to arrhythmogenic cardiomyopathy with predominantly left ventricular involvement.

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Desmoplakin's Hidden Role in the Heart — When the Cellular Glue Fails

Desmoplakin is the molecular anchor that holds heart muscle cells together. Encoded by the DSP gene11 DSP gene
Desmoplakin, chromosome 6p24.3; encodes the largest desmosomal protein at 2,871 amino acids, it forms the cytoplasmic half of desmosomes22 desmosomes
Specialized cell-cell junctions that anchor intermediate filaments across adjacent cells, providing tensile strength in tissues under repeated mechanical stress. In the heart, where each cell is pulled and squeezed with every beat, intact desmosomes are not optional — they are structural lifelines. The rs397516923 variant (c.214C>T) creates a premature stop codon at position 72 of the desmoplakin protein (p.Gln72Ter), truncating the protein before it can serve any structural function. The resulting haploinsufficiency — one broken copy in a dominant condition — is sufficient to compromise cardiac desmosomal integrity and predispose carriers to a fibrotic, inflammatory form of cardiomyopathy.

The Mechanism

Normally, desmoplakin bridges between the desmosomal plaque proteins (plakophilin, plakoglobin) and the intermediate filament cytoskeleton (desmin), anchoring the cellular scaffold across the gap junction. When one DSP allele carries a nonsense variant33 nonsense variant
A single-nucleotide change that converts an amino acid codon into a stop codon, terminating translation prematurely; here at residue 72 of 2,871, leaving over 97% of the protein unproduced, the truncated mRNA is typically eliminated by nonsense-mediated mRNA decay (NMD)44 nonsense-mediated mRNA decay (NMD)
A cellular surveillance mechanism that degrades mRNAs containing premature stop codons, usually preventing production of a truncated protein that might interfere with the normal copy. The remaining wild-type allele produces only half the normal desmoplakin, insufficient to maintain normal desmosomal density. The consequence is progressive replacement of cardiomyocytes with fibrofatty tissue — particularly in the left ventricular subepicardium — along with arrhythmogenic scarring.

Notably, DSP-related cardiomyopathy differs from classic arrhythmogenic right ventricular cardiomyopathy (ARVC): DSP truncating variants cause predominantly left ventricular or biventricular disease. A landmark study found 55% of DSP variant carriers55 55% of DSP variant carriers
Smith et al. Circulation 2020 — 107 patients with pathogenic DSP mutations versus 81 PKP2-mutation patients showed left ventricular predominance, compared to 0% of PKP2 mutation carriers. This LV-centric phenotype means the condition is frequently misdiagnosed as myocarditis or dilated cardiomyopathy.

The Evidence

ClinVar classifies rs397516923 as pathogenic (VCV000044872.7), supported by functional and clinical evidence that loss-of-function variants in DSP cause arrhythmogenic cardiomyopathy. The p.Gln72Ter truncation is among the earliest-terminating DSP nonsense variants documented in clinical cohorts, and variant location matters: Hoorntje et al. 202366 Hoorntje et al. 2023
Circ Genomic and Precision Medicine — 170 DSP truncating variant carriers, mean age at diagnosis 43 years found that variants triggering NMD of both major DSP isoforms occurred in 83.6% of high-arrhythmic-risk cases versus only 16.4% of low-risk cases (p<0.0001), and 33% of carriers overall experienced sustained ventricular arrhythmia during follow-up.

The largest outcomes dataset to date enrolled 800 DSP variant carriers across 34 institutions77 800 DSP variant carriers across 34 institutions
Gasperetti et al. Eur Heart J 2025 — multinational registry, median follow-up 3.7 years: 17.4% developed sustained ventricular arrhythmia at 3.9% per year; 9% required hospitalization for heart failure. Left ventricular ejection fraction (LVEF) below 50% was independently associated with both arrhythmic risk (HR 1.645) and heart failure risk (HR 3.879). Acute myocardial injury episodes — occurring in 8.8% of patients — doubled subsequent arrhythmia risk and raised heart failure risk five-fold.

In pediatric carriers, the condition is particularly aggressive: a 34-patient pediatric cohort88 34-patient pediatric cohort
Choi et al. Circ Arrhythm Electrophysiol 2024 found 50% of ICD recipients received appropriate shocks, and the condition mimicked myocarditis at presentation in half of symptomatic patients — elevating the risk of delayed or missed diagnosis.

The inheritance pattern is autosomal dominant with reduced penetrance. Not all carriers develop overt disease, but the pathogenic classification of this specific variant reflects documented co-segregation with cardiomyopathy in affected families.

Practical Actions

For carriers of this variant, cardiac evaluation is the priority. Standard ARVC risk calculators perform poorly in DSP carriers (c-statistic 0.558 for LV-predominant disease), making individual assessment by a cardiomyopathy specialist essential. Key monitoring elements include cardiac MRI with late gadolinium enhancement (the primary test for subepicardial LV fibrosis), Holter monitoring for ventricular ectopy, and periodic echocardiography for ejection fraction surveillance.

High-intensity competitive sports should be avoided, as exercise-induced ventricular ectopy is more frequent in desmosomal mutation carriers and endurance exercise accelerates the fibrofatty remodeling that drives arrhythmic risk. First-degree relatives (parents, siblings, children) should undergo genetic cascade testing and, if variant-negative, clinical surveillance screening every 1-3 years from age 10 given the condition's age-dependent penetrance.

Interactions

DSP-related cardiomyopathy may interact with other desmosomal gene variants. Compound heterozygosity for two DSP alleles (one from each parent) produces a more severe phenotype with earlier onset and dermatologic manifestations (woolly hair, palmoplantar keratoderma) as seen in Carvajal syndrome. Variants in co-desmosomal proteins — PKP2, DSG2, DSC2, JUP — have independent pathogenic roles and may compound with DSP haploinsufficiency in rare cases. Family members sharing additional desmosomal variant burden appear to have worse clinical trajectories than those carrying only the DSP truncating allele.

Genotype Interpretations

What each possible genotype means for this variant.

CC Non-Carrier Normal

No DSP truncating variant detected

You carry two copies of the common C allele at rs397516923 and do not carry this pathogenic DSP truncating variant. The T allele that creates the p.Gln72Ter premature stop codon is absent from your genome. Fewer than 1 in 10,000 people carry this variant in population databases, and it has not been detected in any of the major population sequencing projects (gnomAD, TOPMED, ALFA). Your standard cardiac risk assessment is not modified by this SNP.

CT Pathogenic Carrier Carrier

One copy of this pathogenic DSP truncating variant — cardiac evaluation warranted

The p.Gln72Ter truncation is one of the earliest-terminating pathogenic DSP variants documented in clinical cohorts. The premature stop at residue 72 (out of 2,871) means the mRNA is almost certainly eliminated by nonsense-mediated decay, leaving only the wild-type allele to produce desmoplakin. This haploinsufficiency results in reduced desmosomal density in cardiomyocytes, progressive fibrofatty infiltration of the myocardium (predominantly subepicardially in the left ventricle), and arrhythmogenic scarring.

Clinically, DSP-related cardiomyopathy is distinct from classical ARVC: in one cohort of 107 patients with pathogenic DSP mutations, 55% had left ventricular predominant involvement, 40% had subepicardial late gadolinium enhancement on cardiac MRI, and 15% experienced acute myocardial injury episodes. Myocarditis-like presentations are documented in approximately 50% of symptomatic pediatric patients and are a recognized feature in adults as well.

Risk stratification should not rely on standard ARVC risk calculators, which perform poorly in DSP carriers (c-statistic 0.558). Gene-specific risk factors include prior non-sustained VT (HR 2.097), prior sustained ventricular arrhythmia (HR 1.923), and LVEF ≤50% (HR 1.645). Myocardial injury episodes are particularly ominous: they are associated with doubled arrhythmia risk and five-fold heart failure risk in subsequent follow-up.

TT Homozygous (Extremely Rare) Homozygous

Two copies of this pathogenic truncating variant — associated with severe early-onset cardiomyopathy and dermatologic features

Homozygous DSP truncating variants eliminate functional desmoplakin production from both alleles. Desmoplakin is an obligate desmosomal component — cells lacking it cannot form functional desmosomes, resulting in catastrophic structural failure of intercellular junctions in mechanically stressed tissues (heart, skin, hair follicles). Case reports and small cohorts of compound DSP heterozygotes and homozygotes document early-onset severe biventricular cardiomyopathy with a high rate of sudden cardiac death and heart failure, often with the triad of cardiomyopathy, woolly/sparse hair, and palmoplantar keratoderma (Carvajal syndrome, Naxos disease-like phenotype).

Pediatric cohort data (Choi et al. 2024) found that homozygous or compound heterozygous DSP variants correlated with earlier presentation (before age 13), severe biventricular disease, and dermatologic features in all cases. The cardiomyopathy in biallelic carriers is not amenable to standard ARVC management — it requires aggressive heart failure therapy, early ICD consideration, and specialist evaluation for transplant eligibility.

Given the extreme rarity of the TT genotype, this result should be confirmed by repeat testing and interpreted in consultation with a clinical geneticist and cardiomyopathy specialist.