DSP-Related Cardiomyopathy as a Distinct Clinical Entity? Emerging Evidence from an Italian Cohort

Abstract

Variants in desmoplakin gene (DSP MIM *125647) have been usually associated with Arrhythmogenic Cardiomyopathy (ACM), or Dilated Cardiomyopathy (DCM) inherited in an autosomal dominant manner. A cohort of 18 probands, characterized as heterozygotes for DSP variants by a target Next Generation Sequencing (NGS) cardiomyopathy panel, was analyzed. Cardiological, genetic data, and imaging features were retrospectively collected. A total of 16 DSP heterozygous pathogenic or likely pathogenic variants were identified, 75% (n = 12) truncating variants, n = 2 missense variants, n = 1 splicing variant, and n = 1 duplication variant. The mean age at diagnosis was 40.61 years (IQR 31-47.25), 61% of patients being asymptomatic (n = 11, New York Heart Association (NYHA) class I) and 39% mildly symptomatic (n = 7, NYHA class II). Notably, 39% of patients (n = 7) presented with a clinical history of presumed myocarditis episodes, characterized by chest pain, myocardial enzyme release, 12-lead electrocardiogram abnormalities with normal coronary arteries, which were recurrent in 57% of cases (n = 4). About half of the patients (55%, n = 10) presented with a varied degree of left ventricular enlargement (LVE), four showing biventricular involvement. Eleven patients (61%) underwent implantable cardioverter defibrillator (ICD) implantation, with a mean age of 46.81 years (IQR 36.00-64.00). Cardiac magnetic resonance imaging (CMRI) identified in all 18 patients a delayed enhancement (DE) area consistent with left ventricular (LV) myocardial fibrosis, with a larger localization and extent in patients presenting with recurrent episodes of myocardial injury. These clinical and genetic data confirm that DSP-related cardiomyopathy may represent a distinct clinical entity characterized by a high arrhythmic burden, variable degrees of LVE, Late Gadolinium Enhancement (LGE) with subepicardial distribution and episodes of myocarditis-like picture.

Keywords: arrhythmogenic cardiomyopathy; desmoplakin; dilated cardiomyopathy.

Figure 1

Family Pedigree of Patient ID 2. Black circle and squares indicate individuals with a clinical diagnosis of dilated cardiomyopathy. Black arrow indicates the proband. Black lines at the top indicate individuals who underwent to genetic testing. Black lines at the bottom indicate individuals without offspring. WPW: Wolf Parkinson White syndrome, ✥ Sudden Cardiac Death (SCD) at the age of 51 years. * Q833X heterozygous carrier, ⍭ Aortic dissection.

Figure 2

Family Pedigree of Patient ID 6. Black circle and squares indicate individuals with Arrhythmogenic cardiomyopathy. Black arrow indicates the proband. Black lines at the top indicate individuals who underwent to genetic testing. Black lines at the bottom indicate individuals without offspring. Little black square indicates lung cancer, * E1068Vfs*19 heterozygous carrier, + Breast cancer, ^ Bilateral hypoacusia, probably due to a meningitis infection on her 6th month of life.

Figure 3

Family Pedigree of Patient ID 7. Black circle and squares indicate individuals with a clinical diagnosis of dilated cardiomyopathy. Black arrow indicates the proband. Black lines at the top indicate individuals who underwent to genetic testing. Black lines at the bottom indicates individuals without offspring. * G1737Dfs*16 heterozygous carrier.

Figure 4

Schematic representation of the main structural domains of the desmoplakin protein and relative position of the genetic variants reported in this study. Splicing variant reported in italics. SRD:Spectrin repeat domain; PRD:plakin repeat domains; GSR:glycine/serine/arginine-rich domain.