Spectrum of Rare and Common Genetic Variants in Arrhythmogenic Cardiomyopathy Patients

Abstract

Arrhythmogenic cardiomyopathy (ACM) is a rare inherited disorder, whose genetic cause is elusive in about 50-70% of cases. ACM presents a variable disease course which could be influenced by genetics. We performed next-generation sequencing on a panel of 174 genes associated with inherited cardiovascular diseases on 82 ACM probands (i) to describe and classify the pathogenicity of rare variants according to the American College of Medical Genetics and Genomics both for ACM-associated genes and for genes linked to other cardiovascular genetic conditions; (ii) to assess, for the first time, the impact of common variants on the ACM clinical disease severity by genotype-phenotype correlation and survival analysis. We identified 15 (likely) pathogenic variants and 66 variants of uncertain significance in ACM-genes and 4 high-impact variants in genes never associated with ACM (ABCC9, APOB, DPP6, MIB1), which deserve future consideration. In addition, we found 69 significant genotype-phenotype associations between common variants and clinical parameters. Arrhythmia-associated polymorphisms resulted in an increased risk of arrhythmic events during patients' follow-up. The description of the genetic framework of our population and the observed genotype-phenotype correlation constitutes the starting point to address the current lack of knowledge in the genetics of ACM.

Keywords: arrhythmogenic cardiomyopathy; cardiovascular genetics; common variants; desmosomal genes; genotype-phenotype correlation; rare variants.

Figure 1

Classification of rare variants according to the association of the relative gene with ACM: definitive evidence (PKP2, DSP, DSG2, DSC2, JUP, and TMEM43), with moderate evidence (DES and PLN), with limited evidence (SCN5A, LMNA, CDH2, CTNNA3, TGFB3, TTN, TJP1, MYH7, MYBPC3 and MYL3), with no evidence (TNNC1, TNNI3, TNNT2, TPM1, ACTC1 and MYL2) and refuted/disputed (RYR2 and LDB3) [7].

Figure 2

Distribution of carriers of rare variants in genes associated with ACM (with definite, moderate and limited evidence), identified in our cohort. Abbreviations: P: pathogenic; LP: likely pathogenic; VUS: variant of uncertain significance.

Figure 3

Manhattan plots representing the genotype-phenotype correlation. The 69 significant associations (p < 0.005) are shown in the graphs: 62 different genetic variables distributed over 29 (in red) of the 69 clinical parameters considered. For simplicity, variants are indicated by the name of the gene in which they have been identified. For polymorphism details, see Tables S3 and S4. “MAE” included SVT, syncope and VF. Abbreviations: BMI: body mass index; EPS: electrophysiological study; ECHO: echocardiogram; TAPSE: tricuspid annular plane systolic excursion; RVOT: right ventricular outflow tract; PSAX: parasternal short-axis; PLAX: parasternal long-axis; FAC: fractional area change; LV: left ventricle; EDV: end-diastolic volume; EF: ejection fraction; TCF: task force criteria.

Figure 4

Kaplan–Meier curves representing the arrhythmic events-free survival during follow-up time in association with MYBPC3:c.2308+18C>G variants (A), CASQ2:c.1194T>C (B) and MYBPC3:c.3288G>A (C). Kaplan-Meier curves representing the MAE-free survival during follow-up time in association with MYBPC3:c.2308+18C>G (D) and MYL2:c.132T>C (E) variants. “MAE” includes syncope, sustained ventricular tachycardia and ventricular fibrillation. “Arrhythmic event” includes NSVT, syncope, SVT and VF.