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ACTN2 Variant Associated with a Cardiac Phenotype Suggestive of Left-Dominant Arrhythmogenic Cardiomyopathy

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ACTN2 Variant Associated with a Cardiac Phenotype Suggestive of Left-Dominant Arrhythmogenic Cardiomyopathy ACTN2 variant associated with a cardiac phenotype suggestive of left-dominant arrhythmogenic cardiomyopathy Jean-Marc Good, MD, PhD,* Florence Fellmann, MD, PhD,* Zahurul A. Bhuiyan, MBBS, PhD, FESC,* Samuel Rotman, MD,† Etienne Pruvot, MD,‡ Jurg€ Schl€apfer, MD‡ From the *Department of Genetic Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland, †Service of Clinical Pathology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland, and ‡Department of Cardiology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. Introduction Arrhythmogenic cardiomyopathy (ACM) is a heritable heart KEY TEACHING POINTS disease characterized by fibrofatty replacement of the cardio- The variant p.Tyr473Cys in the ACTN2 gene, coding myocytes. It can result in life-threatening arrhythmias and for the Z-disk protein alpha-actinin-2, leads to a sudden cardiac death (SCD). Arrhythmogenic right ventricu- dominantly inherited phenotype suggestive of left- lar dysplasia/cardiomyopathy (ARVD/C) is the most com- dominant arrhythmogenic cardiomyopathy (ACM). mon form of ACM, while left-dominant or biventricular This implies that analysis of ACTN2 might be ACM is less frequent.1 Genes involved in ACM pathology mainly encode desmosomal protein,2 but anomalies in other considered in patients with ACM in whom genetic genes have been described.3,4 screening was inconclusive. Variants in the alpha-actinin-2 (ACTN2) gene have been The signal for plakoglobin was markedly reduced in associated with different cardiac manifestations, including the myocardial biopsy of our index case. This hypertrophic cardiomyopathy (HCM), dilated cardiomyopa- 5–9 6 further supports the concept that plakoglobin thy (DCM), atrial arrhythmia, left ventricular noncom- fi fi de ciency may be a common feature of ACMs, paction (LVNC), idiopathic ventricular brillation, and independently of their molecular origin. SCD.7 Alpha-actinin-2, the protein encoded by ACTN2, is a major component of the sarcomere Z-disc expressed in The decreased signal for plakoglobin in the the cardiac and skeletal muscle. Its supposed role is to bind myocardial biopsy of our index case suggests a link actin filaments and to stabilize the muscle contractile appa- between Z-disc proteins and the desmosome. This 10,11 ratus. Changes in its scaffolding function have been pro- remains to be investigated. posed to be pathogenic and lead to DCM and HCM. Additionally, alpha-actinin-2 interacts with several signaling proteins and ion channels.11,12 Some speculate that mutant alpha-actinin-2 affects the localization and function of car- Case reports diac ion channels and thus might contribute to arrhythmic The female proband (II-2 in Figure 1B) presented with poly- phenotypes. We describe here 4 members of a Swiss family morphic ventricular premature beats at age 25 years. At age in which a missense ACTN2 variant cosegregates with a car- 62, she experienced tiredness, dyspnea, and thoracic discom- diomyopathy suggestive of left-dominant ACM. fort. The electrocardiogram revealed low voltage in periph- eral leads and T-wave inversion in lead V5 and V6 (Figure 2A). Coronary angiography showed no evidence of coronary artery disease. The cardiovascular magnetic reso- KEYWORDS ACTN2; Alpha-actinin-2; Arrhythmia; Left-dominant nance demonstrated a diffusely hypokinetic nondilated left arrhythmogenic cardiomyopathy; Next-generation sequencing; Plakoglobin (Heart Rhythm Case Reports 2020;6:15–19) ventricle with a reduced ejection fraction (41%) and wide- spread areas of late gadolinium enhancement predominantly Address reprint requests and correspondence: Dr Jean-Marc Good, Department of Genetic Medicine, Lausanne University Hospital (CHUV), in the inferior and anterolateral walls (Figure 2B). The right Av. Pierre Decker 5, 1011 Lausanne, Switzerland. E-mail address: ventricle was considered normal. A metabolic positron emis- [email protected]. sion tomography scan did not reveal any inflammatory 2214-0271/© 2019 Heart Rhythm Society. Published by Elsevier Inc. This is an open access article https://doi.org/10.1016/j.hrcr.2019.10.001 under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 16 Heart Rhythm Case Reports, Vol 6, No 1, January 2020 Figure 1 Genetic investigations. A: Sanger sequence confirmation of the ACTN2 variant c.1418A.G (p.Tyr473Cys). B: Family pedigree. Lines through sym- bols indicate deceased subject; arrow indicates proband; red symbols indicate heterozygous carriers of p.Tyr473Cys in ACTN2 and affected by left-dominant arrhythmogenic cardiomyopathy. component (Figure 2C). A left ventricle endomyocardial c.1418A.G, p.Tyr473Cys was identified in heterozygosity biopsy showed diffuse fibrosis without fatty replacement (Figure 1A). No variants were found in the other genes of (Figure 3A). Immunofluorescence staining revealed a mark- the panel, notably in JUP, encoding plakoglobin. For the rea- edly diminished signal for plakoglobin (Figure 3B), while the sons explained in the discussion section (below), the variant signal level was preserved for other desmosomal proteins. p.Tyr473Cys in ACTN2 was considered likely pathogenic The diagnosis of left-dominant ACM was strongly suspected and causative of the familial left-dominant ACM. based on the ventricular arrhythmias, T-wave inversions in the precordial leads, diffuse hypokinesia with late gadolin- ium enhancement, and the diffuse areas of fibrosis. Following Discussion some episodes of symptomatic nonsustained ventricular Several ACTN2 mutations located in different regions of the tachycardia, a cardioverter-defibrillator was implanted. protein, including the actin binding, spectrin-like, and The offspring (III-1, III-2, III-3; Figure 1B) of the proband calmodulin-like domains, have been associated to HCM.5,6,8 (II-2), aged 44, 36, and 35 years, respectively, all presented Among them, the p.Thr495Met variant, located in the second with right bundle branch block morphology ventricular pre- spectrin-like domain similarly as p.Tyr473Cys, was observed mature beats. They reported fatigue, dyspnea, and/or palpita- in 3 different families.5,8 The spectrin-like domain of alpha- tions. Their electrocardiograms were all characterized by low actinin-2 is known to interact with different structural and voltages in peripheral leads, T-wave inversion in lateral leads signaling proteins.11 Less frequently, ACTN2 mutations have (III-1), incomplete right bundle branch block (III-3), and been associated with the phenotype of DCM, as for example otherwise normal traces (III-2). Cardiovascular magnetic in carriers of the p.Gln9Arg variant.9 In addition, members resonance was suggestive of a left-dominant ACM in all 3. of 2 families with variants in the actin binding domain of The ejection fractions were reduced in III-1 (ventricle left: alpha-actinin-2 presented with a more complex and heteroge- 47%, right: 49%) and preserved in III-2 and III-3. Areas of nous cardiac phenotype: the p.Ala119Thr variant was linked late gadolinium enhancement restricted to the left ventricle to DCM, LVNC, idiopathic ventricular fibrillation, and were observed with a predominance for the subepicardial SCD,7 and the p.Met228Thr variant cosegregated with layer of the heart basal regions in the anteroseptal, anterolat- HCM, early-onset supraventricular arrhythmias, and atrioven- eral, inferior, and inferoseptal walls (III-1); anteroseptal, infe- tricular block, as well as with LVNC.6 Finally, an association rior, and inferoseptal walls (III-2); and anterior, anteroseptal, between ACTN2 and ARVD/C has already been reported in and anterolateral walls (III-3). the ClinVar database (unpublished; p.Glu829Ter, Given the familial nature of the cardiomyopathy, high- SCV000740535). In summary, heterozygous missense muta- throughput DNA sequencing (using TruSight One panel tions of ACTN2 are associated with a range of cardiac pheno- from Illumina, San Diego, CA) was performed to screen 10 types, including structural and rhythmic disorders with a genes (ACTN2, DSG2, DSC2, PKP2, DSP, LDB3, JUP, highly variable expressivity, even for a given variant. RYR2, TGFb3, TMEM43) involved in arrhythmogenic and The variant p.Tyr473Cys has been recently reported related cardiomyopathies. In the proband (II-2) and in the 3 in association with a phenotype of DCM/HCM but was children (III-1, III-2, III-3), the ACTN2 missense variant considered of “uncertain significance” owing to insufficient Good et al ACTN2 Variant and Arrhythmogenic Cardiomyopathy 17 Figure 2 Cardiologic investigations in subject II-2. A: Electrocardiogram showing low voltage in peripheral leads and T-wave inversion in lead V5 and V6. B: Magnetic resonance imaging showing late gadolinium enhancement. C: Metabolic positron emission tomography scan showing no inflammatory component. evidence to determine its role in the disease (unpublished; this amino acid substitution has not been observed in the pub- reported in the ClinVar database, SCV000834859). Howev- lic database gnomAD as of April 2019. For these reasons, we er, several arguments suggest a pathogenic role. First, consider p.Tyr473Cys as likely pathogenic even in the p.Tyr473Cys segregates with the phenotype of left- absence of direct functional proof. dominant ACM in 4 members of our family. Second, the The phenotype in affected members of our family is Tyr473 residue is highly conserved across various species, homogenous and corresponds well with left-dominant ACM and its replacement with cysteine
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