ACTA1 Novel Likely Pathogenic Variant in a Family With Dilated Cardiomyopathy
2018; Wolters Kluwer; Volume: 11; Issue: 10 Linguagem: Inglês
10.1161/circgen.118.002243
ISSN2574-8300
AutoresNosheen Reza, Ankit Garg, Shana L. Merrill, Jessica L. Chowns, Sriram Rao, Anjali Owens,
Tópico(s)Congenital heart defects research
ResumoHomeCirculation: Genomic and Precision MedicineVol. 11, No. 10ACTA1 Novel Likely Pathogenic Variant in a Family With Dilated Cardiomyopathy Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBACTA1 Novel Likely Pathogenic Variant in a Family With Dilated Cardiomyopathy Nosheen Reza, MD, Ankit Garg, MD, PhD, Shana L. Merrill, MS, LCGC, Jessica L. Chowns, MS, LCGC, Sriram Rao, MBBS and Anjali Tiku Owens, MD Nosheen RezaNosheen Reza Nosheen Reza MD, Division of Cardiovascular Medicine, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, 11 S Pavilion, Room 11–134, 3400 Civic Center Blvd, Philadelphia, PA 19104, email E-mail Address: [email protected] Division of Cardiovascular Medicine, Department of Medicine, Center for Inherited Cardiovascular Disease (N.R., S.L.M., J.L.C., A.T.O.), Perelman School of Medicine at the University of Pennsylvania, Philadelphia. , Ankit GargAnkit Garg Department of Medicine (A.G.), Perelman School of Medicine at the University of Pennsylvania, Philadelphia. , Shana L. MerrillShana L. Merrill Division of Cardiovascular Medicine, Department of Medicine, Center for Inherited Cardiovascular Disease (N.R., S.L.M., J.L.C., A.T.O.), Perelman School of Medicine at the University of Pennsylvania, Philadelphia. , Jessica L. ChownsJessica L. Chowns Division of Cardiovascular Medicine, Department of Medicine, Center for Inherited Cardiovascular Disease (N.R., S.L.M., J.L.C., A.T.O.), Perelman School of Medicine at the University of Pennsylvania, Philadelphia. , Sriram RaoSriram Rao Division of Cardiovascular Medicine, Department of Medicine (S.R.), Perelman School of Medicine at the University of Pennsylvania, Philadelphia. and Anjali Tiku OwensAnjali Tiku Owens Anjali Tiku Owens, MD, Division of Cardiovascular Medicine, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, 11 S Pavilion, Room 11–181, 3400 Civic Center Blvd, Philadelphia, PA 19104, email E-mail Address: [email protected] Division of Cardiovascular Medicine, Department of Medicine, Center for Inherited Cardiovascular Disease (N.R., S.L.M., J.L.C., A.T.O.), Perelman School of Medicine at the University of Pennsylvania, Philadelphia. Originally published11 Oct 2018https://doi.org/10.1161/CIRCGEN.118.002243Circulation: Genomic and Precision Medicine. 2018;11:e002243Skeletal myopathies because of variants in the α-skeletal isoform of actin, ACTA1 (Actin, alpha skeletal muscle), are widely reported; however, associated cardiomyopathies are exceedingly rare. We present a unique case of a dominant cardiomyopathy without functional skeletal myopathy associated with a novel variant in ACTA1. This case highlights the implications of a dysfunctional skeletal muscle–enriched protein causing a predominant cardiac phenotype.A 36-year-old man (III-5) was admitted after experiencing syncope while playing basketball. Family history was notable for his father's (II-3) sudden cardiac death at age 56 (Figure [A]). Imaging revealed a moderately dilated left ventricle (LV) with ejection fraction 38%. An electrophysiological study showed easily inducible polymorphic ventricular tachycardia to which his syncope was attributed. He was discharged with an implantable cardioverter defibrillator and on medical therapy. During the next 5 years, he experienced multiple appropriate implantable cardioverter defibrillator shocks and progressive LV dysfunction necessitating continuous inotropic support. He ultimately underwent cardiac transplantation 7 years after his initial presentation. Explanted cardiac histology was notable for myocyte hypertrophy and interstitial fibrosis (Figure [B]).Download figureDownload PowerPointFigure. Molecular to Clinical Impact of ACTA1.A, Pedigree of ACTA1 p.Arg256His family. Squares and circles represent males and females, respectively, while the diamond represents unknown sex. Generations are labeled by Roman numerals while individuals are labeled with Arabic numerals. Slashes denote deceased family members. The proband, III-5, is denoted with an arrow. III-5, III-6, and IV-2 were confirmed variant carriers and are thus labeled ACTA1 ±. II-2 was confirmed not to have the variant and is thus labeled ACTA1 +/+. Red coloring denotes individuals with dilated cardiomyopathy (DCM). Green denotes individuals who experienced ventricular tachycardia (VT). Blue denotes individuals with reduced ejection fraction (REF). B. Explanted heart histology showing hematoxylin and eosin stain (left) demonstrating well-preserved myocytes with box cart nuclei (denoted by arrow) consistent with cardiac hypertrophy and trichrome stain (right) showing mild interstitial fibrosis (denoted by arrow). Scale bar (bottom left) represents 75 µm. C, Apical 4-chamber views (systole and diastole) of the proband's brother's (III-6) initial transthoracic echocardiogram at our institution. Left ventricle was normal in size but calculated left ventricle with ejection fraction was 34%. D, ACTA1 expression in multiple human tissues using data from the Human Protein Atlas (HPA; www.proteinatlas.org) from the HPA dataset located at https://www.proteinatlas.org/ENSG00000143632-ACTA1/tissue. Several nonexpressing tissues were excluded for figure simplicity: thyroid gland, parathyroid gland, adrenal gland, appendix, bone marrow, lymph node, tonsil, gallbladder, pancreas, salivary gland, duodenum, rectum, urinary bladder, testis, prostate, epididymis, seminal vesicle, fallopian tube, breast, cervix, endometrium, ovary, adipose tissue, and skin. E, ACTA1 (Actin, alpha skeletal muscle) protein showing the spatial relationship of p.Arg256His (R256H; colored red and with red arrow) compared with previously reported DCM-associated variant, p.Trp358C (W358C; colored magenta and with magenta arrow). Graphic generated using University of California, San Francisco Chimera package and the Protein Data Bank 1J6Z atomic coordinate file.1 TPM indicates transcripts per million.His brother (III-6) was referred for clinical screening soon after the proband's (III-5) diagnosis. The initial echocardiogram at our institution showed LV with ejection fraction 34% (Figure [C]). Medical therapy was initiated, but he was lost to follow-up. He re-presented 15 years later after experiencing symptomatic ventricular tachycardia and underwent implantable cardioverter defibrillator implantation. Three years later, his LV with ejection fraction fell to 20%, and implantable cardioverter defibrillator interrogation revealed >1000 premature ventricular contractions per hour. After antiarrhythmic therapy failure, he underwent successful premature ventricular contraction ablations. A paternal half-first cousin once removed (IV-2) was diagnosed with severe dilated cardiomyopathy at age 15 and soon thereafter underwent LV assist device placement.Clinical screening of affected individuals' first-degree relatives was recommended. The proband had 2 children (IV-4, IV-5) who were found to have mild LV dysfunction in their late teenage years. The proband's teenage niece (IV-6) had LV dilation with borderline LV function. Individuals III-5, III-6, and their children were physically active without limitations and did not have other symptoms consistent with known inherited cardiomyopathies including intellectual disability, skeletal muscle weakness, lipodystrophy, or atrial arrhythmias.The proband underwent sequencing of 78 genes associated with cardiomyopathy and arrhythmia through a commercial laboratory (GeneDx, Gaithersburg, MD). Individuals IV-2 and IV-4 had sequencing for cardiomyopathy-associated genes through different commercial laboratories (Laboratory for Molecular Medicine, Cambridge, Massachusetts). No pathogenic variants were identified on any test.Duo whole exome sequencing of the proband and affected cousin was performed (Personalis, Menlo Park, CA) for variant discovery given the suspicion for familial disease and the potential for higher yield with the ability to test distant affected relatives. A sample from the proband's mother (II-4) was submitted to serve as a proxy for the proband's deceased affected father's genotype. Indexed genomic libraries and enrichment were performed with proprietary kits. Sequencing was performed on Illumina sequencers using paired-end reads (Illumina, San Diego, CA). Base calling, alignment, variant calling, annotation, and quality control reporting were performed using a proprietary pipeline and were manually reviewed.A heterozygous novel variant in ACTA1, NM_001100.3: c.767G>A, p.Arg256His was detected in the proband, his brother, and his affected cousin (noted amino acid positions follow conventional amino acid numbering, that is, before any protein processing). The variant was not detected in the proband's paternal half-aunt (II-2), making the proband's father and 3 other affected intervening relatives obligate carriers. A copy number gain variant of uncertain significance, 9p22.2p22.1(18 260 501-19 340 501)×3, was identified in individual IV-2 but not in the proband and, therefore, was not thought to contribute to the cardiac phenotype as it did not track with disease. On clinical reevaluation, the screened family members did not exhibit any neuromuscular symptoms.ACTA1 is a striated muscle–specific actin with >10-fold greater expression in skeletal muscle than in heart (Figure [D]).2 There are >250 known disease-causing variants in ACTA1 that almost exclusively cause skeletal muscle myopathies.3 Only a single ACTA1 variant associated with a dilated cardiomyopathy, p.Trp358Cys, has been previously published, but this individual also suffered from childhood-onset skeletal myopathy.4 This variant is not spatially related to our p.Arg256His variant and may disrupt actin function by a different molecular mechanism (Figure [E]).An unpublished p.Arg256Gly variant in the Leiden Open Variation Database also reports an individual with severe dilated cardiomyopathy though with concurrent skeletal myopathy.5 Our p.Arg256His variant is absent from multiple healthy genome datasets, including 1000 Genomes and Exome Aggregation Consortium, and in silico models (including PolyPhen-2 and Sorting Intolerant From Tolerant) predict a deleterious effect on protein function. Furthermore, p.Arg256 is conserved among 93 vertebrate species. These data indicate the importance of preserving p.Arg256 and that p.Arg256His is likely pathogenic and associated with cardiomyopathy though different amino acid substitutions may influence the degree of skeletal muscle involvement.Here, we first report a novel ACTA1 variant that is associated with a predominant dilated cardiomyopathy without clinical skeletal myopathy. Our work underscores the need to evaluate for the coexistence of inherited skeletal and cardiac myopathies and inspires future investigation into the mechanism by which cardiac muscle can be disproportionately affected by a protein predominantly expressed in skeletal muscle.Sources of FundingDr Reza is supported by the National Institutes of Health National Human Genome Research Institute Ruth L. Kirschstein Institutional National Research Service T32 Award in Genomic Medicine (T32 HG009495). Dr Owens is supported by the Winkleman Family Fund in Cardiovascular Innovation.DisclosuresNone.Footnotes*Drs Reza and Garg are joint first authors.https://www.ahajournals.org/journal/circgenNosheen Reza MD, Division of Cardiovascular Medicine, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, 11 S Pavilion, Room 11–134, 3400 Civic Center Blvd, Philadelphia, PA 19104, email nosheen.[email protected]upenn.eduAnjali Tiku Owens, MD, Division of Cardiovascular Medicine, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, 11 S Pavilion, Room 11–181, 3400 Civic Center Blvd, Philadelphia, PA 19104, email anjali.[email protected]upenn.eduReferences1. Pettersen EF, et al. UCSF Chimera–a visualization system for exploratory research and analysis.J Comput Chem. 2004; 25:1605–1612. doi: 10.1002/jcc.20084CrossrefMedlineGoogle Scholar2. Uhlén M, et al. Proteomics. Tissue-based map of the human proteome.Science. 2015; 347:1260419.CrossrefMedlineGoogle Scholar3. Sparrow JC, et al. Muscle disease caused by mutations in the skeletal muscle alpha-actin gene (ACTA1).Neuromuscul Disord. 2003; 13:519–531.CrossrefMedlineGoogle Scholar4. Gatayama R, et al. Nemaline myopathy with dilated cardiomyopathy in childhood.Pediatrics. 2013; 131:e1986–e1990. doi: 10.1542/peds.2012-1139CrossrefMedlineGoogle Scholar5. Fokkema IF, et al. LOVD v.2.0: the next generation in gene variant databases.Hum Mutat. 2011; 32:557–563. doi: 10.1002/humu.21438CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Díaz Expósito A, Robles Mezcua A, Pérez Cabeza A and García Pinilla J (2022) A new mutation in the ACTA1 gene possibly associated with dilated cardiomyopathy without concomitant myopathy, Revista Española de Cardiología (English Edition), 10.1016/j.rec.2022.03.005, Online publication date: 1-May-2022. Díaz Expósito A, Robles Mezcua A, Pérez Cabeza A and García Pinilla J (2022) Una nueva mutación en el gen ACTA1, posiblemente asociada con miocardiopatía dilatada sin miopatía concomitante, Revista Española de Cardiología, 10.1016/j.recesp.2022.03.020, Online publication date: 1-Jun-2022. Miyao N, Hata Y, Izumi H, Nagaoka R, Oku Y, Takasaki I, Ishikawa T, Takarada S, Okabe M, Nakaoka H, Ibuki K, Ozawa S, Yoshida T, Hasegawa H, Makita N, Nishida N, Mori H, Ichida F, Hirono K and Lionetti V (2020) TBX5 R264K acts as a modifier to develop dilated cardiomyopathy in mice independently of T-box pathway, PLOS ONE, 10.1371/journal.pone.0227393, 15:4, (e0227393) Matsumoto A, Tsuda H, Furui S, Kawada‐Nagashima M, Anzai T, Seki M, Watanabe K, Muramatsu K, Osaka H, Iwamoto S, Nishino I and Yamagata T (2022) A case of congenital fiber‐type disproportion syndrome presenting dilated cardiomyopathy with ACTA1 mutation , Molecular Genetics & Genomic Medicine, 10.1002/mgg3.2008 Parker F, Baboolal T and Peckham M (2020) Actin Mutations and Their Role in Disease, International Journal of Molecular Sciences, 10.3390/ijms21093371, 21:9, (3371) October 2018Vol 11, Issue 10 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCGEN.118.002243PMID: 30354303 Originally publishedOctober 11, 2018 Keywordscardiomyopathiestachycardia, ventriculargenetic testingmutationgenefamilyactinPDF download Advertisement SubjectsCardiomyopathyClinical StudiesGeneticsPrecision Medicine
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