[Skip to Content]
[Skip to Content Landing]

Role of Genetic Testing in Inherited Cardiovascular DiseaseA Review

Educational Objective
To review important concepts for clinical genetic testing of cardiovascular diseases.
1 Credit CME
Abstract

Importance  Genetic testing is a valuable tool for managing inherited cardiovascular disease in patients and families, including hypertrophic, dilated, and arrhythmogenic cardiomyopathies and inherited arrhythmias. By identifying the molecular etiology of disease, genetic testing can improve diagnostic accuracy and refine family management. However, unique features associated with genetic testing affect the interpretation and application of results and differentiate it from traditional laboratory-based diagnostics. Clinicians and patients must have accurate and realistic expectations about the yield of genetic testing and its role in management. Familiarity with the rationale, implications, benefits, and limitations of genetic testing is essential to achieve the best possible outcomes.

Observations  Successfully incorporating genetic testing into clinical practice requires (1) recognizing when inherited cardiovascular disease may be present, (2) identifying appropriate individuals in the family for testing, (3) selecting the appropriate genetic test, (4) understanding the complexities of result interpretation, and (5) effectively communicating the results and implications to the patient and family. Obtaining a detailed family history is critical to identify families who will benefit from genetic testing, determine the best strategy, and interpret results. Instead of focusing on an individual patient, genetic testing requires consideration of the family as a unit. Consolidation of care in centers with a high level of expertise is recommended. Clinicians without expertise in genetic testing will benefit from establishing referral or consultative networks with experienced clinicans in specialized multidisciplinary clinics.

Conclusions and Relevance  Genetic testing provides a foundation for transitioning to more precise and individualized management. By distinguishing phenotypic subgroups, identifying disease mechanisms, and focusing family care, gene-based diagnosis can improve management. Successful integration of genetic testing into clinical practice requires understanding of the complexities of testing and effective communication of the implications to patients and families.

Sign in to take quiz and track your certificates

Buy This Activity
Article Information

Corresponding Author: Carolyn Y. Ho, MD, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115 (cho@partners.org).

Accepted for Publication: May 25, 2017.

Published Online: August 9, 2017. doi:10.1001/jamacardio.2017.2352

Author Contributions: Ms Cirino and Dr Ho had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Cirino, Harris, Lakdawala, Michels, Olivotto, Day, Abrams, Caleshu, Semsarian, Ingles, Rakowski, Ho.

Acquisition, analysis, or interpretation of data: Lakdawala, Charron, Judge.

Drafting of the manuscript: Cirino, Harris, Charron, Caleshu, Semsarian, Ho.

Critical revision of the manuscript for important intellectual content: Cirino, Harris, Lakdawala, Michels, Olivotto, Day, Abrams, Caleshu, Semsarian, Ingles, Rakowski, Judge, Ho.

Administrative, technical, or material support: Michels, Ingles, Ho.

Study supervision: Olivotto, Abrams, Charron, Ho.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Charron reports receiving funding from an 11CVD01 network grant from the Leducq Foundation, funding from the FP7 UE Best Ageing network, and consultancies, honoraria, and speakers’ fees from Amicus, Boehringer, Genzyme, MyoKardia Inc, Novartis, Sanofi, Servier, and Shire. Ms Caleshu reports serving as a consultant and advisor for Recombine and an advisor for Invitae and Phosphorous. Dr Semsarian reports receiving practitioner fellowship 1059156 from the National Health and Medical Research Council, Australia. Dr Judge reports serving as a scientific advisor for Invitae Corp, MyoKardia Inc, Alnylam Pharmaceuticals, GlaxoSmithKline, and Pfizer. Dr Ho reports serving as a scientific advisor for MyoKardia Inc. No other disclosures were reported.

Funding/Support: This work was supported in part by grants 1P20HL101408 and 1P50HL112349 from the National Heart, Lung, and Blood Institute at the National Institutes of Health (Dr Ho).

Role of the Funder/Sponsor: The sponsor had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

References
1.
Seidman  JG, Seidman  C.  The genetic basis for cardiomyopathy: from mutation identification to mechanistic paradigms.  Cell. 2001;104(4):557-567.PubMedGoogle ScholarCrossref
2.
McKoy  G, Protonotarios  N, Crosby  A,  et al.  Identification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma and woolly hair (Naxos disease).  Lancet. 2000;355(9221):2119-2124.PubMedGoogle ScholarCrossref
3.
Curran  ME, Splawski  I, Timothy  KW, Vincent  GM, Green  ED, Keating  MT.  A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome.  Cell. 1995;80(5):795-803.PubMedGoogle ScholarCrossref
4.
Dietz  HC, Cutting  GR, Pyeritz  RE,  et al.  Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene.  Nature. 1991;352(6333):337-339.PubMedGoogle ScholarCrossref
5.
Gersh  BJ, Maron  BJ, Bonow  RO,  et al; American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines; American Association for Thoracic Surgery; American Society of Echocardiography; American Society of Nuclear Cardiology; Heart Failure Society of America; Heart Rhythm Society; Society for Cardiovascular Angiography and Interventions; Society of Thoracic Surgeons.  2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.  Circulation. 2011;124(24):e783-e831.PubMedGoogle ScholarCrossref
6.
Ackerman  MJ, Priori  SG, Willems  S,  et al; Heart Rhythm Society (HRS); European Heart Rhythm Association (EHRA).  HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies: this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA) [published correction appears in Europace. 2012;14(2):277].  Europace. 2011;13(8):1077-1109.PubMedGoogle ScholarCrossref
7.
Elliott  PM, Anastasakis  A, Borger  MA,  et al; Authors/Task Force members.  2014 ESC guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC).  Eur Heart J. 2014;35(39):2733-2779.PubMedGoogle ScholarCrossref
8.
Hershberger  RE, Lindenfeld  J, Mestroni  L, Seidman  CE, Taylor  MR, Towbin  JA; Heart Failure Society of America.  Genetic evaluation of cardiomyopathy—a Heart Failure Society of America practice guideline.  J Card Fail. 2009;15(2):83-97.PubMedGoogle ScholarCrossref
9.
Hiratzka  LF, Bakris  GL, Beckman  JA,  et al; American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines; American Association for Thoracic Surgery; American College of Radiology; American Stroke Association; Society of Cardiovascular Anesthesiologists; Society for Cardiovascular Angiography and Interventions; Society of Interventional Radiology; Society of Thoracic Surgeons; Society for Vascular Medicine.  2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with thoracic aortic disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons,and Society for Vascular Medicine.  J Am Coll Cardiol. 2010;55(14):e27-e129.PubMedGoogle ScholarCrossref
10.
Priori  SG, Wilde  AA, Horie  M,  et al.  HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013.  Heart Rhythm. 2013;10(12):1932-1963.PubMedGoogle ScholarCrossref
11.
Charron  P, Arad  M, Arbustini  E,  et al; European Society of Cardiology Working Group on Myocardial and Pericardial Diseases.  Genetic counselling and testing in cardiomyopathies: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases.  Eur Heart J. 2010;31(22):2715-2726.PubMedGoogle ScholarCrossref
12.
Bonter  K, Desjardins  C, Currier  N, Pun  J, Ashbury  FD.  Personalised medicine in Canada: a survey of adoption and practice in oncology, cardiology and family medicine.  BMJ Open. 2011;1(1):e000110.PubMedGoogle ScholarCrossref
13.
Mainous  AG  III, Johnson  SP, Chirina  S, Baker  R.  Academic family physicians’ perception of genetic testing and integration into practice: a CERA study.  Fam Med. 2013;45(4):257-262.PubMedGoogle Scholar
14.
Mital  S, Musunuru  K, Garg  V,  et al; American Heart Association Council on Functional Genomics and Translational Biology; Council on Cardiovascular Disease in the Young; Council on Cardiovascular and Stroke Nursing; Stroke Council; Council on Lifestyle and Cardiometabolic Health; Council on Quality of Care and Outcomes Research.  Enhancing literacy in cardiovascular genetics: a scientific statement from the American Heart Association.  Circ Cardiovasc Genet. 2016;9(5):448-467.PubMedGoogle ScholarCrossref
15.
Quarta  G, Muir  A, Pantazis  A,  et al.  Familial evaluation in arrhythmogenic right ventricular cardiomyopathy: impact of genetics and revised task force criteria.  Circulation. 2011;123(23):2701-2709.PubMedGoogle ScholarCrossref
16.
Probst  V, Wilde  AA, Barc  J,  et al.  SCN5A mutations and the role of genetic background in the pathophysiology of Brugada syndrome.  Circ Cardiovasc Genet. 2009;2(6):552-557.PubMedGoogle ScholarCrossref
17.
Borry  P, Evers-Kiebooms  G, Cornel  MC, Clarke  A, Dierickx  K; Public and Professional Policy Committee (PPPC) of the European Society of Human Genetics (ESHG).  Genetic testing in asymptomatic minors: background considerations towards ESHG recommendations.  Eur J Hum Genet. 2009;17(6):711-719.PubMedGoogle ScholarCrossref
18.
Ingles  J, Sarina  T, Yeates  L,  et al.  Clinical predictors of genetic testing outcomes in hypertrophic cardiomyopathy.  Genet Med. 2013;15(12):972-977.PubMedGoogle ScholarCrossref
19.
Gruner  C, Ivanov  J, Care  M,  et al.  Toronto hypertrophic cardiomyopathy genotype score for prediction of a positive genotype in hypertrophic cardiomyopathy.  Circ Cardiovasc Genet. 2013;6(1):19-26.PubMedGoogle ScholarCrossref
20.
Bai  R, Napolitano  C, Bloise  R, Monteforte  N, Priori  SG.  Yield of genetic screening in inherited cardiac channelopathies: how to prioritize access to genetic testing.  Circ Arrhythm Electrophysiol. 2009;2(1):6-15.PubMedGoogle ScholarCrossref
21.
Ackerman  JP, Bartos  DC, Kapplinger  JD, Tester  DJ, Delisle  BP, Ackerman  MJ.  The promise and peril of precision medicine: phenotyping still matters most.  Mayo Clin Proc. 2016;S0025-6196(16)30463-3.PubMedGoogle Scholar
22.
Waddell-Smith  KE, Donoghue  T, Oates  S,  et al.  Inpatient detection of cardiac-inherited disease: the impact of improving family history taking [published online October 8, 2016].  Open Heart. doi:10.1016/j.mayocp.2016.08.008 PubMedGoogle Scholar
23.
Alfares  AA, Kelly  MA, McDermott  G,  et al.  Results of clinical genetic testing of 2912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity.  Genet Med. 2015;17(11):880-888.PubMedGoogle ScholarCrossref
24.
Walsh  R, Thomson  KL, Ware  JS,  et al.  Reassessment of mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples.  Genet Med. 2017;19(2):192-203.PubMedGoogle Scholar
25.
Mogensen  J, van Tintelen  JP, Fokstuen  S,  et al.  The current role of next-generation DNA sequencing in routine care of patients with hereditary cardiovascular conditions: a viewpoint paper of the European Society of Cardiology working group on myocardial and pericardial diseases and members of the European Society of Human Genetics.  Eur Heart J. 2015;36(22):1367-1370.PubMedGoogle ScholarCrossref
26.
Ingles  J, Semsarian  C.  Conveying a probabilistic genetic test result to families with an inherited heart disease.  Heart Rhythm. 2014;11(6):1073-1078.PubMedGoogle ScholarCrossref
27.
Richards  S, Aziz  N, Bale  S,  et al; ACMG Laboratory Quality Assurance Committee.  Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.  Genet Med. 2015;17(5):405-424.PubMedGoogle ScholarCrossref
28.
Auton  A, Brooks  LD, Durbin  RM,  et al; 1000 Genomes Project Consortium.  A global reference for human genetic variation.  Nature. 2015;526(7571):68-74.PubMedGoogle ScholarCrossref
29.
National Heart, Lung, and Blood Institute. NHLBI Exome Sequencing Project (ESP): Exome Variant Server. http://evs.gs.washington.edu/EVS/. November 3, 2014. Accessed January 12, 2017.
30.
Lek  M, Karczewski  KJ, Minikel  EV,  et al; Exome Aggregation Consortium.  Analysis of protein-coding genetic variation in 60,706 humans.  Nature. 2016;536(7616):285-291.PubMedGoogle ScholarCrossref
31.
Das K  J, Ingles  J, Bagnall  RD, Semsarian  C.  Determining pathogenicity of genetic variants in hypertrophic cardiomyopathy: importance of periodic reassessment.  Genet Med. 2014;16(4):286-293.PubMedGoogle ScholarCrossref
32.
Green  RC, Lautenbach  D, McGuire  AL.  GINA, genetic discrimination, and genomic medicine.  N Engl J Med. 2015;372(5):397-399.PubMedGoogle ScholarCrossref
33.
Clifton  JM, VanBeuge  SS, Mladenka  C, Wosnik  KK.  The Genetic Information Nondiscrimination Act 2008: what clinicians should understand.  J Am Acad Nurse Pract. 2010;22(5):246-249.PubMedGoogle ScholarCrossref
34.
Caleshu  C, Kasparian  NA, Edwards  KS,  et al.  Interdisciplinary psychosocial care for families with inherited cardiovascular diseases.  Trends Cardiovasc Med. 2016;26(7):647-653.PubMedGoogle ScholarCrossref
35.
Aatre  RD, Day  SM.  Psychological issues in genetic testing for inherited cardiovascular diseases.  Circ Cardiovasc Genet. 2011;4(1):81-90.PubMedGoogle ScholarCrossref
36.
Burns  C, McGaughran  J, Davis  A, Semsarian  C, Ingles  J.  Factors influencing uptake of familial long QT syndrome genetic testing.  Am J Med Genet A. 2016;170A(2):418-425.PubMedGoogle ScholarCrossref
37.
Forrest  LE, Delatycki  MB, Skene  L, Aitken  M.  Communicating genetic information in families—a review of guidelines and position papers.  Eur J Hum Genet. 2007;15(6):612-618.PubMedGoogle ScholarCrossref
38.
Green  RC, Berg  JS, Grody  WW,  et al; American College of Medical Genetics and Genomics.  ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.  Genet Med. 2013;15(7):565-574.PubMedGoogle ScholarCrossref
39.
Kalia  SS, Adelman  K, Bale  SJ,  et al.  Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics.  Genet Med. 2017;19(2):249-255.PubMedGoogle Scholar
40.
Biesecker  LG, Green  RC.  Diagnostic clinical genome and exome sequencing.  N Engl J Med. 2014;371(12):1170.PubMedGoogle ScholarCrossref
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_LoginSubscribe_Purchase
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_LoginSubscribe_Purchase
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right

Name Your Search

Save Search
With a personal account, you can:
  • Track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
jn-learning_Modal_SaveSearch_NoAccess_Purchase

Lookup An Activity

or

My Saved Searches

You currently have no searches saved.

With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Topics
State Requirements