Variants in MHY7 Gene Cause Arrhythmogenic Cardiomyopathy

Abstract

Background: Arrhythmogenic Cardiomyopathy (ACM) is a disease of the cardiac muscle, characterized by frequent ventricular arrhythmias and functional/ structural abnormalities, mainly of the right ventricle. To date, 20 different genes have been associated with ACM and the majority of them encode for desmosomal proteins. In this study, we describe the characterization of two novel variants in MHY7 gene, segregating in two ACM families. MYH7 encodes for myosin heavy chain β (MHC-β) isoform, involved in cardiac muscle contractility.

Method and results: In family A, the autopsy revealed ACM with biventricular involvement in both the proband and his father. In family B, the proband had been diagnosed as affected by ACM and implanted with implantable cardioverter defibrillator (ICD), due to ECG evidence of monomorphic ventricular tachycardia after syncope. After clinical evaluation, a molecular diagnosis was performed using a NGS custom panel. The two novel variants identified predicted damaging, located in a highly conserved domain: c. 2630T>C is not described while c.2609G>A has a frequency of 0.00000398. In silico analyses evaluated the docking characteristics between proteins using the Haddock2.2 webserver.

Conclusions: Our results reveal two variants in sarcomeric genes to be the molecular cause of ACM, further increasing the genetic heterogeneity of the disease; in fact, sarcomeric variants are usually associated with HCM phenotype. Studies on the role of sarcomere genes in the pathogenesis of ACM are surely recommended in those ACM patients negative for desmosomal mutation screening.

Keywords: MYH7 gene; arrhythmogenic cardiomyopathy; hypertrophic cardiomyopathy; sudden cardiac death; targeted gene panel.

Figure 1

(A) Pedigree structure of family A, arrow indicates the proband affected (III-2); Met877Thr is the variant identified within MYH7 gene; (B) basal ECG of the proband; (C) transthoracic echocardiography of the proband, the arrow shows aneurysm of right ventricular outflow tract (RVOT); (D) 24-h ambulatory ECG monitoring showing NSVT.

Figure 2

(A) Pedigree structure of family B, arrow indicates the proband affected (II-3); R870H is the variant identified within the MYH7 gene; (B) 12-lead ECG showing a wide QRS complex tachycardia; (C) basal ECG of the proband.

Figure 3

(A) MYH7 domain; (B) identification of variant M877T in MYH7; (C) identification of variant R870H in MYH7. The arrows indicate the position of the variants identified in heterozygosity.

Figure 4

(A) The image (made with UCSF Chimera of the myosin dimer (PDB code 3dtp) with the mutation (M877T) colored in red; a close-up of the affected region is reported on the right. The mutations map at the interface between the two long α helices. (B) Global and closeup view of the MYH7 dimer (PDB code 3dtp) of the mutation site (R870H in blue). The involved residue positions map on the interaction interface between two α helices of the homodimer.