DSP p.(Thr2104Glnfs12) variant presents variably with early onset severe arrhythmias and left ventricular cardiomyopathy

• Published in: BMC medical genetics Vol. 21; no. 1; p. 19
• Main Authors: Heliö, Krista, Kangas-Kontio, Tiia, Weckström, Sini, Vanninen, Sari U M, Aalto-Setälä, Katriina, Alastalo, Tero-Pekka, Myllykangas, Samuel, Heliö, Tiina M, Koskenvuo, Juha W
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 31.01.2020; BioMed Central; BMC
• Subjects: Adult; Age; Age of Onset; Aged; Aged, 80 and over; Arrhythmia; Arrhythmogenic cardiomyopathy; Arrhythmogenic Right Ventricular Dysplasia - diagnostic imaging; Arrhythmogenic Right Ventricular Dysplasia - genetics; Arrhythmogenic Right Ventricular Dysplasia - physiopathology; Cardiac arrhythmia; Cardiac patients; Cardiomyopathies; Cardiomyopathy; Cardiomyopathy, Dilated - diagnostic imaging; Cardiomyopathy, Dilated - genetics; Cardiomyopathy, Dilated - physiopathology; Cardiovascular disease; Classification schemes; Congestive cardiomyopathy; Connectin; Contrast Media - administration & dosage; Coronary artery; Coronary heart disease; Coronary vessels; desmoplakin; Desmoplakins - genetics; Diagnosis; Diagnostic imaging; Dilated cardiomyopathy; Diseases; DNA sequencing; DSP; Edema; Electrocardiography; Female; Gadolinium; Gadolinium - administration & dosage; Genes; Genetic aspects; Genetic Predisposition to Disease; Genetic variation; Genetics; Genomics; Genotype & phenotype; Health aspects; Heart; Heart diseases; Heart Ventricles - physiopathology; Hospitals; Humans; Hypertension; Inflammation; Laboratories; Left heart ventricle; Magnetic Resonance Imaging; Male; Medical records; Middle Aged; Mutation; Myocardial diseases; Myocardium; Next-generation sequencing; Patients; Pedigree; Penetrance; Phenotypes; Proteins; Rare earth metal compounds; Transplants & implants; Ventricle; Ventricular Dysfunction, Left - diagnostic imaging; Ventricular Dysfunction, Left - genetics; Ventricular Dysfunction, Left - physiopathology; Finland; DSP; desmoplakin; Cardiomyopathies; Arrhythmogenic cardiomyopathy; Mutation; Dilated cardiomyopathy
• ISSN: 1471-2350; 1471-2350
• DOI: 10.1186/s12881-020-0955-z

Dilated cardiomyopathy (DCM) is a condition characterized by dilatation and systolic dysfunction of the left ventricle in the absence of severe coronary artery disease or abnormal loading conditions. Mutations in the titin (TTN) and lamin A/C (LMNA) genes are the two most significant contributors in familial DCM. Previously mutations in the desmoplakin (DSP) gene have been associated with arrhythmogenic right ventricular cardiomyopathy (ARVC) and more recently with DCM. We describe the cardiac phenotype related to a DSP mutation which was identified in ten unrelated Finnish index patients using next-generation sequencing. Sanger sequencing was used to verify the presence of this DSP variant in the probands' relatives. Medical records were obtained, and clinical evaluation was performed. We identified DSP c.6310delA, p.(Thr2104Glnfs*12) variant in 17 individuals of which 11 (65%) fulfilled the DCM diagnostic criteria. This pathogenic variant presented with left ventricular dilatation, dysfunction and major ventricular arrhythmias. Two patients showed late gadolinium enhancement (LGE) and myocardial edema on cardiac magnetic resonance imaging (MRI) that may suggest inflammatory process at myocardium. The patients diagnosed with DCM showed an arrhythmogenic phenotype as well as SCD at young age supporting the recently proposed concept of arrhythmogenic cardiomyopathy. This study also demonstrates relatively low penetrance of truncating DSP variant in the probands' family members by the age of 40. Further studies are needed to elucidate the possible relations between myocardial inflammation and pathogenic DSP variants.