Case report of familial sudden cardiac death caused by a DSG2 p.F531C mutation as genetic background when carrying with heterozygous KCNE5 p.D92E/E93X mutation

Abstract

Background: Sudden cardiac death (SCD) induced by malignant ventricular tachycardia (MVT) among young adults with right ventricular cardiomyopathy/dysplasia (ARVC/D) is a devastating event. Parts of ARVC/D patients have a mutation in genes encoding components of cardiac desmosomes, such as desmoglein-2 (DSG2), plakophilin-2 and desmoplakin.

Case presentation: Here we report a potentially pathogenic mutation in the DSG2 gene, which was identified in a family with ARVC/D using Whole Exome Sequencing (WES) and Sanger Sequencing. In all, Patient III:1 with ARVC/D carried the compound heterozygous mutations of DSG2 p.F531C and KCNE5 p.D92E/E93X, which were both inherited from her mother (II:2), who died of SCD. Carriers of DSG2p.F531C showed various phenotypes, such as ARVC/D, SCD, MVT and dilated cardiomyopathy. For III:1, there were significant low-voltage regions in the inferior-apical, inferior-lateral wall of the right ventricular epicardium and outflow tracts of the right ventricle. Under the guidance of a three-dimensional mapping system, MVT was successfully ablated with an epicardial-endocardial approach targeting for late, double or fragmental potentials after implantable cardioverter-defibrillator (ICD) electrical storms. No VT recurrence was observed during the one year of follow-up.

Conclusions: When coexisting with heterozygous KCNE5 p.D92E/E93X, heterozygous DSG2 p.F531C as a genetic background was found to predispose to ARVC/D, SCD and MVT, which were successfully ablated using an epicardial-endocardial approach.

Keywords: Arrhythmogenic right ventricular cardiomyopathy/dysplasia; Electrical storm; Genetics; Sudden cardiac death; Ventricular tachycardia.

Fig. 1

Pedigree Charts

Fig. 2

ECGs characteristics of III:1 patient. a Inversion of T wave (V₁-V₃ leads) in sinus rhythm; Pairs of ventricular premature beat origin from right ventricular tract; cardiac counterclockwise transposition. b Clinical episode of persistent and malignant ventricular tachycardia origin from the inflow-free wall of right ventricle. c–d Ventricular programed stimulation induced short episode of ventricular tachycardia origin from the inflow-free wall (c) and outflow tract of right ventricle (d), during first ablation in the other hospital

Fig. 3

Cardiac CT images of III:1 patient. Four-chamber view of non-enhanced image (a) and enhanced image (b). Thinning of the anterior wall of the right ventricle with extensive fatty infiltration (arrow) could be noted. The short-axis view (c) demonstrated dilation of the right ventricle (star). Enlargement of the right atrium (stars) was shown on the axial view (d)

Fig. 4

Pathogenic mutations in the DSG2 protein and structure of KCNE5 mutations. a secondary structure of DSG2 protein (NP_001934.2), which consists of 1118 amino acids. The pathogenic mutation related to ARVC/D, hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) were displayed according to PubMed ClinVar and recent reports from PubMed. b-d primary (b) and tertiary (c–d) structure changes of KCNE5 p.D92E/E93X mutation and wildtype of KCNE5, constructed by Swiss-model. *, stop-gain

Fig. 5

Electrical and anatomical mapping with guidance of CARTO system. a Endocardial mapping of both ventricles, showed in anterior-posterior position. b Endocardial mapping of both ventricles, showed in posterior–anterior positions. c–d Epicardial mapping indicated that there were obvious low-voltage regions or scars with significant late, double or fragmented potentials, around the tricuspid annulus, in inferior-lateral-apex and inferior-apex walls (c–d), and outflow tract (e) of right ventricle. Line and lamellar ablation was performed across the scars (red points). F, in the mid-septum of endocardium in the right ventricle, the pacing mapping suggested potential targets, as ECG characteristics of pacing similar to that of short episodes of clinical VT. This region was mapped with significant late potentials and ablated (red points)