Whole-Exome Sequencing Identifies a Novel Mutation (p.L320R) of Alpha-Actinin 2 in a Chinese Family with Dilated Cardiomyopathy and Ventricular Tachycardia

Abstract

Dilated cardiomyopathy (DCM) is a severe cardiovascular disease which can lead to heart failure and sudden cardiac death (SCD). The typical feature of DCM is left ventricular enlargement or dilatation. In some conditions, DCM and arrhythmia can occur concurrently, apparently promoting the prevalence of SCD. According to previous studies, mutations in more than 100 genes have been detected in DCM and/or arrhythmia patients. Here, we report a Chinese family with typical DCM, ventricular tachycardia, syncope, and SCD. Using whole-exome sequencing, a novel, likely pathogenic mutation (c.959T>G/p.L320R) of actinin alpha 2 (ACTN2) was identified in all affected family members. This novel mutation was also predicted to be disease-causing by MutationTaster, SIFT, and Polyphen-2. Our study not only expands the spectrum of ACTN2 mutations and contributes to the genetic diagnosis and counseling of the family, but also provides a new case with overlap phenotype that may be caused by the ACTN2 variant.

Case Report: Novel Likely Pathogenic ACTN2 Variant Causing Heterogeneous Phenotype in a Korean Family With Left Ventricular Non-compaction

“…Molecular coupling of a Ca 2+ -activated K + channel to Ltype Ca 2+ channels via alpha-actinin2 has been reported (30). Previous studies reported that the ACTN2 mutation may lead to diverse cardiomyopathy, including dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, and LVNC, as well as arrhythmia, such as idiopathic ventricular fibrillation, juvenile atrial arrhythmias, and sudden unexplained death (28,(31)(32)(33)(34). Notably, the variant ACTN2 c.683T>C (p.Met228Thr) was described by Girolami et al (28) in a family with familial hypertrophic cardiomyopathy and juvenile atrial arrhythmias.…”

Mono- and bi-allelic protein truncating variants in alpha-actinin 2 cause cardiomyopathy through distinct mechanisms

“…There are several recent papers suggesting that only a core set of genes, not including ACTN2, are causative of cardiomyopathy 53,54 . However, there are a growing number of publications that have associated genetic variants in ACTN2 with cardiomyopathy [15][16][17][18][19] , as well as a regulatory element of ACTN2 that was recently associated with heart failure 22 . We believe that the previous associations, in combination with the evidence presented here for how two protein-truncating variants, one dominant negative and one recessive, cause cardiac disease with variable pathological presentation supports inclusion of ACTN2 as a disease-causing gene for cardiomyopathy in humans.…”

“…A missense mutation in ACTN2 was first identified in a patient with dilated cardiomyopathy (DCM) in 2003 14 . Since then, additional studies have reported heterozygous missense mutations in ACTN2 that co-segregate with both dilated and hypertrophic cardiomyopathy (HCM) [15][16][17][18][19][20][21] . Common genetic variation in a regulatory element modulating ACTN2 expression was recently associated with heart failure with reduced ejection fraction 22 .…”

In search of markers useful for evaluation of graft patency - molecular analysis of ‘muscle system process’ for internal thoracic artery and saphenous vein conduits

“…Chiu et al on the other hand, reported 3 more mutations: Thr495Met, Glu583Ala and Glu628Gly in patients from other 4 families [23]. Mutations in this gene may also lead to DCM, idiopathic ventricular fibrillation, juvenile atrial arrhythmias, restrictive cardiomyopathy, and left ventricular failure and sudden unexplained death [24]. Currently, there are numerous new reports on the discovery of mutations in the ACTN2 gene associated with cardiac diseases [24], as well as their impact on the phenotype of a given disease [25].…”