DSP c.6310delA p.(Thr2104Glnfs*12) associates with arrhythmogenic cardiomyopathy, increased trabeculation, curly hair, and palmoplantar keratoderma

Abstract

BackgroundPathogenic variants in DSP associate with cardiac and cutaneous manifestations including arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, curly or wavy hair, and palmoplantar keratoderma (PPK). Episodes of myocardial inflammation associated with DSP cardiomyopathy might be confused in clinical work with myocarditis of other etiologies such as viral. Cardiac magnetic resonance imaging (CMR) may help in differential diagnosis.Methods and resultsThis study comprised 49 Finnish patients: 34 participants from families with suspected DSP cardiomyopathy (9 index patients and 25 family members) and 15 patients with myocarditis. All 34 participants underwent genetic testing and cardiac evaluation, and 29 of them also underwent CMR. Participants with the DSP variant, numbering 22, were dermatologically examined. The 15 patients with myocarditis underwent CMR and were evaluated during their hospitalization.A heterozygous truncating DSP c.6310delA p.(Thr2104Glnfs*12) variant was confirmed in 29 participants. Only participants with the DSP variant had pacemakers and life-threatening ventricular arrhythmias. Of the participants with the DSP variant, 24% fulfilled cardiomyopathy criteria, and the median age at diagnosis was 53. Upon CMR, myocardial edema was found to be more common in patients with myocarditis. Both groups had a substantial percentage of late gadolinium enhancement (LGE). A ring-like LGE and increased trabeculation were observed only in participants with the DSP variant. All the studied participants with the DSP variant had PPK and curly or wavy hair. Hyperkeratosis developed before the age of 20 in most patients.ConclusionsThe DSP c.6310delA p.(Thr2104Glnfs*12) variant associates with curly hair, PPK, and arrhythmogenic cardiomyopathy with increased trabeculation. Cutaneous symptoms developing in childhood and adolescence might help recognize these patients at an earlier stage. CMR, together with dermatologic characteristics, may help in diagnosis.

Decoding common genetic alterations between Barrett's esophagus and esophageal adenocarcinoma: A bioinformatics analysis

“…The DSP gene is responsible for encoding the protein desmoplakin, which is crucial in anchoring intermediate filaments to desmosomal plaques and is an essential component of functional desmosomes. Additionally, desmosomes are believed to be involved in other crucial cellular functions, including chemical signaling pathways, cellular differentiation, and apoptosis [ 26 ].

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Cardiac Inflammation in Adult-Onset Genetic Dilated Cardiomyopathy

“…We did not find a significant association between specific genes and cardiac inflammation, i.e., there was no enrichment of a gene in the group of patients with DCM and cardiac inflammation. Desmoplakin ( DSP ) is, by far, most associated with inflammation among all the DCM-associated genes, and episodes of myocardial inflammation associated with DSP cardiomyopathy might be confused with (viral) cardiomyopathy [ 14 , 21 ]. DSP links other desmosomal proteins (desmocollin-2 and desmoglein-2), that are by themselves anchored in the plasma membrane, to desmin, which is a structural protein anchoring multiple structures (e.g., Z-disc, mitochondria) within the cytoplasm [ 22 , 23 ].…”

“…Cardiac specific overexpression of desmocollin-2 led to acute inflammation and biventricular cardiomyopathy in a transgenic mouse model [ 23 ]. The cardiac inflammation is most often diagnosed by observing myocardial edema on cardiac magnetic resonance imaging (MRI) that may suggest an inflammatory process [ 21 , 24 ], and is present together with episodes of chest pain associated with elevated cardiac enzymes [ 25 ]. Myocardial inflammation has become a key feature of arrhythmogenic cardiomyopathy, mainly in the young, where the inflammation might resemble a ‘hot-phase’ of the disease [ 26 ].…”

Plantar keratoderma and curly hair as a diagnostic clue of cardiomyopathy risk

“…Desmosomes are intercellular junctions that function to resist mechanical stress and present in both epidermal and myocardial tissue. DSP is associated with heterogeneous phenotypes comprising varying skin and hair abnormalities, as well as desmoplakin‐related heart disease, including arrhythmogenic and dilated cardiomyopathy, ventricular arrhythmias, and myocarditis‐like episodes 1–3 . Cardiac examinations performed in the family members showed normal results at the time of evaluation.…”