Broad Genetic Testing in a Clinical Setting Uncovers a High Prevalence of Titin Loss-of-Function Variants in Very Early Onset Atrial Fibrillation

HomeCirculation: Genomic and Precision MedicineVol. 12, No. 11Broad Genetic Testing in a Clinical Setting Uncovers a High Prevalence of Titin Loss-of-Function Variants in Very Early Onset Atrial Fibrillation Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBBroad Genetic Testing in a Clinical Setting Uncovers a High Prevalence of Titin Loss-of-Function Variants in Very Early Onset Atrial Fibrillation William R. Goodyer, MD, PhD, Kyla Dunn, MS, Colleen Caleshu, MS, Mary Jackson, BS, Jennifer Wylie, MS, Tia Moscarello, MS, Julia Platt, MS, Chloe Reuter, MS, Allysonne Smith, NP, Anthony Trela, NP, Scott R. Ceresnak, MD, Kara S. Motonaga, MD, Euan Ashley, MD, PhD, Phillip Yang, MD, Anne M. Dubin, MD, FHRS and Marco Perez, MD William R. GoodyerWilliam R. Goodyer Cardiovascular Institute, Stanford University (W.R.G., E.A., P.Y., M.P.). Division of Pediatric Cardiology, Department of Pediatrics, Lucille Packard Children’s Hospital (W.R.G., A.T., S.R.C., K.S.M., A.M.D.). Search for more papers by this author , Kyla DunnKyla Dunn Stanford Center for Inherited Cardiovascular Disease (K.D., C.C., M.J., J.W., T.M., J.P., C.R., A.S., E.A., M.P.). Search for more papers by this author , Colleen CaleshuColleen Caleshu Stanford Center for Inherited Cardiovascular Disease (K.D., C.C., M.J., J.W., T.M., J.P., C.R., A.S., E.A., M.P.). Search for more papers by this author , Mary JacksonMary Jackson Stanford Center for Inherited Cardiovascular Disease (K.D., C.C., M.J., J.W., T.M., J.P., C.R., A.S., E.A., M.P.). Search for more papers by this author , Jennifer WylieJennifer Wylie Stanford Center for Inherited Cardiovascular Disease (K.D., C.C., M.J., J.W., T.M., J.P., C.R., A.S., E.A., M.P.). Search for more papers by this author , Tia MoscarelloTia Moscarello Stanford Center for Inherited Cardiovascular Disease (K.D., C.C., M.J., J.W., T.M., J.P., C.R., A.S., E.A., M.P.). Search for more papers by this author , Julia PlattJulia Platt Stanford Center for Inherited Cardiovascular Disease (K.D., C.C., M.J., J.W., T.M., J.P., C.R., A.S., E.A., M.P.). Search for more papers by this author , Chloe ReuterChloe Reuter Stanford Center for Inherited Cardiovascular Disease (K.D., C.C., M.J., J.W., T.M., J.P., C.R., A.S., E.A., M.P.). Search for more papers by this author , Allysonne SmithAllysonne Smith Stanford Center for Inherited Cardiovascular Disease (K.D., C.C., M.J., J.W., T.M., J.P., C.R., A.S., E.A., M.P.). Search for more papers by this author , Anthony TrelaAnthony Trela Division of Pediatric Cardiology, Department of Pediatrics, Lucille Packard Children’s Hospital (W.R.G., A.T., S.R.C., K.S.M., A.M.D.). Search for more papers by this author , Scott R. CeresnakScott R. Ceresnak Division of Pediatric Cardiology, Department of Pediatrics, Lucille Packard Children’s Hospital (W.R.G., A.T., S.R.C., K.S.M., A.M.D.). Search for more papers by this author , Kara S. MotonagaKara S. Motonaga Division of Pediatric Cardiology, Department of Pediatrics, Lucille Packard Children’s Hospital (W.R.G., A.T., S.R.C., K.S.M., A.M.D.). Search for more papers by this author , Euan AshleyEuan Ashley Cardiovascular Institute, Stanford University (W.R.G., E.A., P.Y., M.P.). Stanford Center for Inherited Cardiovascular Disease (K.D., C.C., M.J., J.W., T.M., J.P., C.R., A.S., E.A., M.P.). Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, CA (E.A., P.Y., M.P.). Search for more papers by this author , Phillip YangPhillip Yang Cardiovascular Institute, Stanford University (W.R.G., E.A., P.Y., M.P.). Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, CA (E.A., P.Y., M.P.). Search for more papers by this author , Anne M. DubinAnne M. Dubin Division of Pediatric Cardiology, Department of Pediatrics, Lucille Packard Children’s Hospital (W.R.G., A.T., S.R.C., K.S.M., A.M.D.). Search for more papers by this author and Marco PerezMarco Perez Marco Perez, MD, 300 Pasteur Dr, MC 5773, Stanford, CA 94305. Email E-mail Address: [email protected] Cardiovascular Institute, Stanford University (W.R.G., E.A., P.Y., M.P.). Stanford Center for Inherited Cardiovascular Disease (K.D., C.C., M.J., J.W., T.M., J.P., C.R., A.S., E.A., M.P.). Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, CA (E.A., P.Y., M.P.). Search for more papers by this author Originally published22 Oct 2019https://doi.org/10.1161/CIRCGEN.119.002713Circulation: Genomic and Precision Medicine. 2019;12:e002713Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: October 22, 2019: Ahead of Print Atrial fibrillation (AF) is the most common sustained arrhythmia, affecting ≈34 million worldwide.1 The pathophysiology of AF remains incompletely understood but is clearly complex with multiple underlying genetic, physiological, and environmental factors. Very early onset AF (vEAF; defined here as onset <45 years and without significant comorbidities), while rare (only ≈0.5%–3% of AF cases), is highly heritable, with a greater prevalence of rare variants in genes previously associated with AF.2 Patients with vEAF, therefore, represent an ideal population for discovering novel genes involved in the underlying genetic basis of AF. Notably, the Framingham study showed that patients with AF without comorbidities have a 3-fold higher risk for heart failure.3 Conversely, several forms of inherited cardiomyopathy have been strongly associated with AF4 suggestive of a shared cause.In this study, we investigated a rare cohort of patients with vEAF having otherwise normal cardiac structure and function using comprehensive genetics evaluations, including broad clinical genetic testing. Exclusion criteria included congenital heart disease or traditional AF risk factors including hyperthyroidism, heart failure, significant valvular disease, hypertension, diabetes mellitus, myocardial ischemia, morbid obesity, concurrent infection, alcohol, stimulant abuse, chronic obstructive pulmonary disease, and pulmonary hypertension. We hypothesized that the prevalence of rare genetic variation in genes associated with cardiomyopathy would be higher in this cohort.Specifically, we assessed a cohort of consecutive patients referred to the Stanford Center for Inherited Cardiovascular Diseases for evaluation of vEAF between 2014 and 2018. This retrospective chart review was approved by the Stanford University Institutional Review Board. Patients were included if they had normal cardiac function and a structurally normal heart by initial echocardiogram as well as no other significant comorbidities. Each patient received genetic counseling and a detailed 3 to 4 generation family history was collected by a cardiovascular genetic counselor. We identified 25 families with vEAF. This includes 23 unrelated patients with vEAF and 2 unrelated patients with AF onset <60 years with a first-degree family member with vEAF (Probands 2 and 17). The mean age of AF diagnosis was 27.2 years (SD 13.5) and 76% of patients were male (Table). All patients at the time of their AF diagnosis had structurally normal hearts with the exception of the probands of Family 2 and 21, who initially had tachycardia-induced cardiac dysfunction but soon after exhibited restoration of normal ventricular ejection fraction following rhythm control. Notably, 40% of patients (10 of 25) had a first- or second-degree relative with vEAF, while 36% (9 of 25) had first- or second-degree relatives with either early onset (<50 years) idiopathic cardiomyopathy (20%, 5 of 25), unexplained sudden death (20%, 5 of 25), and strokes (12%, 3 of 25).Table. Demographics and Testing ResultsFamilyAF Onset, ySexRace/EthnicityRare Genetic VariantsVariant ClassFamily Hx 120FAARBM20 p.Arg634GlnPathogenic*†‡† 258FWhiteTTN p.Arg31606XLikely pathogenic*†‡†§† 316MWhiteANK2 p.Asp905AsnVUS 421MWhiteSCN5A p.Thr1779MetVUS 527MWhiteFKRP p.Ala13ThrVUS*† 640MAsianRBM20 p.Cys417TyrVUS 743MWhiteTTN p.Gly17311ValfsX46Likely pathogenic 838MWhiteBAG3 p.Arg45CysVUS*† 939MWhiteANK2 p.Gly1439CysVUS, probably benign 1030MAsianSCN5A p.Asp1156GlyVUS, probably benignANK2 p.Ala373ValVUS, probably benign 1116MHispanicTTN p.Lys17359Asnfs*9Likely pathogenic*†‡KCNT1 p.Pro546LeuVUSNEXN p.Tyr640Thrfs*14VUSRBM20 p.Gly583AspVUS, probably benignSCN10A p.Val1024MetVUS, probably benign 1214MWhiteCACNA1C p.Phe1226LeuVUSDEPDC5 p.Ala1091ValVUS 1340MWhiteABCC9 p.Leu1524Lysfs*5VUSALMS1 p.Arg3239CysVUS, probably benign 1430FWhiteALMS1 p.Ile486ValVUS, probably benign‖ 1520MWhiteDMD p.Gly2609AspVUS‖FKRP p.Ser152ArgVUS 1619MWhiteKCNQ1 p.Arg231HisPathogenic*†LAMP2 p.Ile379ValVUS 1753MWhiteFKRP p.Pro358LeuVUS*†§ANK2 p.Arg2506GlnVUS 1844MWhiteCAV3 p.Arg148TrpVUS, probably benign 1916MHispanicKCNA5 p.Gly182ArgVUS, probably benign§‖SCN10A p.Arg814HisVUS, probably benign 2010FAAACADVL p.Glu643AspVUS, probably benign*†‡MYBPC3 p.Gly1093GlyVUS, probably benignMYLK2 c.1425-6C>A (Intronic)VUS 2125FHispanicTTN p.Arg19624*Likely pathogenic 2216MWhiteDSP p.Val495MetVUS, probably benign 2317MHispanicNoneNone 2414FWhiteANK2 p.Ser3446GlyVUS*DTNA p.Arg536TrpVUSRYR2 c.1292+3A>G (Intronic)VUS 2515MWhiteRYR2 p.Glu4431LysVUS*†‡‖DSC2 p.Leu294IleVUS, probably benignGenetic variants detailed with amino acid variation only for simplicity. AA indicates African American; AF Onset, atrial fibrillation onset of proband; and VUS, variant of unknown significance.*vEAF (<45 y).†Further denotes disease process in first-degree relative.‡Cardiomyopathy (<50 y).§Stroke (<50 y).‖Sudden death (<50 y).Patients underwent genetic testing using inherited arrhythmias and cardiomyopathy panels (73 to 149 genes) from CLIA and CAP approved commercial laboratories. The majority of patients (21 of 25) received the Arrhythmia and Cardiomyopathy Comprehensive Panel (Invitae, San Francisco. 149 genes). Variant classifications reported here are based on re-assessment by our team in 2019 using contemporary gene- and disease-specific classification approaches. Genetic testing identified at least one rare variant in a cardiomyopathy-associated gene in 85% or 21 of 25 patients, while 1 proband had no rare variants detected and the remaining 3 had rare variants in known AF-related genes. Notably, 6 of the 25 patients (24%) had actionable variants deemed likely pathogenic or pathogenic. Four of these 6 patients had likely pathogenic, loss-of-function variants in the sarcomeric gene Titin (p.Gly17311ValfsX46 [c.51930delT] in exon 241; p.Lys17359Asnfs*9 [c.52077_52078delinsT] in exon 273; p.Arg19624* [c.58870C>T] in exon 300; and p.Arg31606X [c.94816C>T] in exon 341). Truncating A-band variants such as these are significantly overrepresented in patients with dilated cardiomyopathy and are considered to be likely pathogenic for that disease. Notably, these 4 Titin truncation variants represented 16% of the cohort, larger than previously reported.5,6 Additionally, another pathogenic variant was detected in another sarcomere-related gene, RBM20 (Proband 1).To date, 11 patients have received further evaluation by magnetic resonance imaging or computed tomography (mean interval time after echocardiogram 817 days, SD: 1194 days), with 8 revealing reduced ventricular function, chamber enlargement, borderline LV noncompaction, or late gadolinium enhancement not appreciated on presenting echocardiogram consistent with either interval disease development or possibly increased sensitivity of detection.Overall, in a cohort of 25 patients with vEAF but otherwise normal heart structure and function at presentation, clinical genetic evaluations revealed not only a high rate of familial vEAF but also cardiomyopathy within the pedigrees. Consistently, genetic testing using expanded clinical gene panels uncovered a high burden of rare variation in cardiomyopathy-related genes, most notably in loss-of-function, truncation variants of Titin. These results were coupled with new structural findings by cardiac MRI in some that had previously not manifested at presentation. Together, these data suggest an association between vEAF and rare variants in Titin before the clinical onset of cardiomyopathy. While additional studies with larger clinical cohorts are clearly needed to translate these findings into clinical practice, our study would argue for a more thorough clinical evaluation and longitudinal follow-up in this unique subpopulation of patients.AcknowledgmentsWe acknowledge the support of the National Institutes of Health and collaborative efforts of the entire SCICD. Any additional data that support the findings of this study not present in this letter format are available from the corresponding author on request.Sources of FundingThis work was supported by the Stanford Cardiovascular Institute, the Stanford Division of Cardiovascular Medicine, Department of Medicine, American Heart Association (Fellow to Faculty Award), and the Robert Wood Johnson Foundation Harold Amos Faculty Development Award (Dr Perez). This was also supported by the Department of Pediatrics and Division of Pediatric Cardiology at Lucille Packard Children’s Hospital and the Training Grant (T32) entitled Research Training in Myocardial Biology at Stanford (NIH 2 T32 HL094274; Dr Goodyer).DisclosuresC. Caleshu is stockholder at Personalis, Inc (Menlo Park, CA) and advisor at Phosphorus, Inc (NY, NY). Dr Ashley is co-founder at Personalis, Inc (Menlo Park, CA). The other authors report no conflicts.FootnotesMarco Perez, MD, 300 Pasteur Dr, MC 5773, Stanford, CA 94305. Email [email protected]eduReferences1. Chugh SS, et al. Worldwide epidemiology of atrial fibrillation: a global burden of disease 2010 study.Circulation. 2014; 129:837–847. doi: 10.1161/CIRCULATIONAHA.113.005119LinkGoogle Scholar2. Olesen MS, et al. Very early-onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation.Heart Rhythm. 2014; 11:246–251. doi: 10.1016/j.hrthm.2013.10.034CrossrefMedlineGoogle Scholar3. Kim EJ, et al. Atrial fibrillation without comorbidities: prevalence, incidence and prognosis (from the Framingham Heart Study).Am Heart J. 2016; 177:138–144. doi: 10.1016/j.ahj.2016.03.023CrossrefMedlineGoogle Scholar4. Santhanakrishnan R, et al. Atrial fibrillation begets heart failure and vice versa: temporal associations and differences in preserved versus reduced ejection fraction.Circulation. 2016; 133:484–492. doi: 10.1161/CIRCULATIONAHA.115.018614LinkGoogle Scholar5. Choi SH, et al; DiscovEHR study and the NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium. Association between titin loss-of-function variants and early-onset atrial fibrillation.JAMA. 2018; 320:2354–2364. doi: 10.1001/jama.2018.18179CrossrefMedlineGoogle Scholar6. Ahlberg G, et al. Rare truncating variants in the sarcomeric protein titin associate with familial and early-onset atrial fibrillation.Nat Commun. 2018; 9:4316. doi: 10.1038/s41467-018-06618-yCrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Rudaka I, Vilne B, Isakova J, Kalejs O, Gailite L and Rots D (2023) Genetic Basis of Early Onset Atrial Fibrillation in Patients without Risk Factors, Journal of Cardiovascular Development and Disease, 10.3390/jcdd10030104, 10:3, (104) Tremblay-Gravel M, Ichimura K, Picard K, Kawano Y, Dries A, Haddad F, Lakdawala N, Wheeler M and Parikh V (2022) Intrinsic Atrial Myopathy Precedes Left Ventricular Dysfunction and Predicts Atrial Fibrillation in Lamin A/C Cardiomyopathy, Circulation: Genomic and Precision Medicine, 16:1, (e003480), Online publication date: 1-Feb-2023. Kandola M, Kulm S, Kim L, Markowitz S, Liu C, Thomas G, Ip J, Lerman B, Elemento O and Cheung J (2023) Population-Level Prevalence of Rare Variants Associated With Atrial Fibrillation and its Impact on Patient Outcomes, JACC: Clinical Electrophysiology, 10.1016/j.jacep.2022.11.022, Online publication date: 1-Jan-2023. Wilde A, Semsarian C, Márquez M, Shamloo A, Ackerman M, Ashley E, Sternick E, Barajas-Martinez H, Behr E, Bezzina C, Breckpot J, Charron P, Chockalingam P, Crotti L, Gollob M, Lubitz S, Makita N, Ohno S, Ortiz-Genga M, Sacilotto L, Schulze-Bahr E, Shimizu W, Sotoodehnia N, Tadros R, Ware J, Winlaw D, Kaufman E, Aiba T, Bollmann A, Choi J, Dalal A, Darrieux F, Giudicessi J, Guerchicoff M, Hong K, Krahn A, MacIntyre C, Mackall J, Mont L, Napolitano C, Ochoa J, Peichl P, Pereira A, Schwartz P, Skinner J, Stellbrink C, Tfelt-Hansen J and Deneke T (2022) European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases, EP Europace, 10.1093/europace/euac030, 24:8, (1307-1367), Online publication date: 1-Sep-2022. Pensa A, Baman J, Puckelwartz M and Wilcox J (2022) Genetically based atrial fibrillation: Current considerations for diagnosis and management, Journal of Cardiovascular Electrophysiology, 10.1111/jce.15446, 33:8, (1944-1953), Online publication date: 1-Aug-2022. Wilde A, Semsarian C, Márquez M, Sepehri Shamloo A, Ackerman M, Ashley E, Sternick Eduardo B, Barajas‐Martinez H, Behr E, Bezzina C, Breckpot J, Charron P, Chockalingam P, Crotti L, Gollob M, Lubitz S, Makita N, Ohno S, Ortiz‐Genga M, Sacilotto L, Schulze‐Bahr E, Shimizu W, Sotoodehnia N, Tadros R, Ware J, Winlaw D, Kaufman E, Aiba T, Bollmann A, Choi J, Dalal A, Darrieux F, Giudicessi J, Guerchicoff M, Hong K, Krahn A, Mac Intyre C, Mackall J, Mont L, Napolitano C, Ochoa Juan P, Peichl P, Pereira A, Schwartz P, Skinner J, Stellbrink C, Tfelt‐Hansen J and Deneke T (2022) European Heart Rhythm Association ( EHRA )/Heart Rhythm Society ( HRS )/Asia Pacific Heart Rhythm Society ( APHRS )/Latin American Heart Rhythm Society ( LAHRS ) Expert Consensus Statement on the state of genetic testing for cardiac diseases , Journal of Arrhythmia, 10.1002/joa3.12717, 38:4, (491-553), Online publication date: 1-Aug-2022. Reddy Y, Borlaug B and Gersh B (2022) Management of Atrial Fibrillation Across the Spectrum of Heart Failure With Preserved and Reduced Ejection Fraction, Circulation, 146:4, (339-357), Online publication date: 26-Jul-2022. Wilde A, Semsarian C, Márquez M, Sepehri Shamloo A, Ackerman M, Ashley E, Sternick E, Barajas-Martinez H, Behr E, Bezzina C, Breckpot J, Charron P, Chockalingam P, Crotti L, Gollob M, Lubitz S, Makita N, Ohno S, Ortiz-Genga M, Sacilotto L, Schulze-Bahr E, Shimizu W, Sotoodehnia N, Tadros R, Ware J, Winlaw D, Kaufman E, Aiba T, Bollmann A, Choi J, Dalal A, Darrieux F, Giudicessi J, Guerchicoff M, Hong K, Krahn A, MacIntyre C, Mackall J, Mont L, Napolitano C, Ochoa J, Peichl P, Pereira A, Schwartz P, Skinner J, Stellbrink C, Tfelt-Hansen J and Deneke T (2022) European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the State of Genetic Testing for Cardiac Diseases, Heart Rhythm, 10.1016/j.hrthm.2022.03.1225, 19:7, (e1-e60), Online publication date: 1-Jul-2022. Yoneda Z, Anderson K, Ye F, Quintana J, O’Neill M, Sims R, Sun L, Glazer A, Davogustto G, El-Harasis M, Laws J, Saldivar B, Crawford D, Stricker T, Wells Q, Darbar D, Michaud G, Stevenson L, Lubitz S, Ellinor P, Roden D and Shoemaker M (2022) Mortality Among Patients With Early-Onset Atrial Fibrillation and Rare Variants in Cardiomyopathy and Arrhythmia Genes, JAMA Cardiology, 10.1001/jamacardio.2022.0810, 7:7, (733), Online publication date: 1-Jul-2022. Tooley J and Perez M (2021) Role of digital health in detection and management of atrial fibrillation, Heart, 10.1136/heartjnl-2020-318262, 108:11, (834-839), Online publication date: 1-Jun-2022. Lukas Laws J, Lancaster M, Ben Shoemaker M, Stevenson W, Hung R, Wells Q, Marshall Brinkley D, Hughes S, Anderson K, Roden D and Stevenson L (2022) Arrhythmias as Presentation of Genetic Cardiomyopathy, Circulation Research, 130:11, (1698-1722), Online publication date: 27-May-2022. Ly O, Chen H, Brown G, Hong L, Wang X, Han Y, Pavel M, Sridhar A, Maienschein-Cline M, Chalazan B, Ong S, Abdelhady K, Massad M, Rizkallah L, Rehman J, Khetani S and Darbar D (2022) Mutant ANP induces mitochondrial and ion channel remodeling in a human iPSC–derived atrial fibrillation model, JCI Insight, 10.1172/jci.insight.155640, 7:7, Online publication date: 8-Apr-2022. Guo X, Qiu X, Wang J, Guo Y, Yang C, Li L, Gao R, Ke Z, Di R, Sun Y, Xu Y and Yang Y (2021) PRRX1 Loss‐of‐Function Mutations Underlying Familial Atrial Fibrillation, Journal of the American Heart Association, 10:23, Online publication date: 7-Dec-2021. Yoneda Z, Anderson K, Quintana J, O’Neill M, Sims R, Glazer A, Shaffer C, Crawford D, Stricker T, Ye F, Wells Q, Stevenson L, Michaud G, Darbar D, Lubitz S, Ellinor P, Roden D and Shoemaker M (2021) Early-Onset Atrial Fibrillation and the Prevalence of Rare Variants in Cardiomyopathy and Arrhythmia Genes, JAMA Cardiology, 10.1001/jamacardio.2021.3370, 6:12, (1371), Online publication date: 1-Dec-2021. Tomaselli G and Roy-Puckelwartz M (2021) Early-Onset Atrial Fibrillation and Heritable Heart Disease—To Test or Not to Test?, JAMA Cardiology, 10.1001/jamacardio.2021.3367, 6:12, (1359), Online publication date: 1-Dec-2021. Chalazan B, Mol D, Darbar F, Ornelas-Loredo A, Al-Azzam B, Chen Y, Tofovic D, Sridhar A, Alzahrani Z, Ellinor P and Darbar D (2021) Association of Rare Genetic Variants and Early-Onset Atrial Fibrillation in Ethnic Minority Individuals, JAMA Cardiology, 10.1001/jamacardio.2021.0994, 6:7, (811), Online publication date: 1-Jul-2021. Kany S, Reissmann B, Metzner A, Kirchhof P, Darbar D and Schnabel R (2021) Genetics of atrial fibrillation—practical applications for clinical management: if not now, when and how?, Cardiovascular Research, 10.1093/cvr/cvab153, 117:7, (1718-1731), Online publication date: 16-Jun-2021. Kim J, Chelu M and Li N (2021) Genetics of atrial fibrillation, Current Opinion in Cardiology, 10.1097/HCO.0000000000000840, 36:3, (281-287), Online publication date: 1-May-2021. Li N, Xu Y, Shi H, Yang C, Guo Y, Li R, Qiu X, Yang Y and Zhang M (2021) KLF15 Loss-of-Function Mutation Underlying Atrial Fibrillation as well as Ventricular Arrhythmias and Cardiomyopathy, Genes, 10.3390/genes12030408, 12:3, (408) Yoneda Z, Anderson K, Estrada J, Quintana J, Strickland T, Montgomery J, Michaud G, Roden D and Shoemaker M (2021) Genetic Testing for Early Onset Atrial Arrhythmias Changes Clinical Management, JACC: Clinical Electrophysiology, 10.1016/j.jacep.2020.11.006, 7:3, (410-412), Online publication date: 1-Mar-2021. Shoemaker M, Shah R, Roden D and Perez M (2020) How Will Genetics Inform the Clinical Care of Atrial Fibrillation?, Circulation Research, 127:1, (111-127), Online publication date: 19-Jun-2020. November 2019Vol 12, Issue 11 Advertisement Article InformationMetrics © 2019 American Heart Association, Inc.https://doi.org/10.1161/CIRCGEN.119.002713PMID: 31638414 Originally publishedOctober 22, 2019 Keywordscomorbiditygenetic testingcardiomyopathiesatrial fibrillationheart failurePDF download Advertisement SubjectsAtrial FibrillationGeneticsOmicsPrecision Medicine