Skip to main content
SpringerLink
Log in

Gendiagnostik bei kardiovaskulären Erkrankungen

Positionspapier der Deutschen Gesellschaft für Kardiologie (DGK) und der Deutschen Gesellschaft für Pädiatrische Kardiologie (DGPK)

Molecular diagnostics of cardiovascular diseases

Expert consensus statement by the German Cardiac Society (DGK) and the German Society of Pediatric Cardiology (DGPK)

  • Positionspapier
  • Published:
Der Kardiologe Aims and scope

Zusammenfassung

Eine Vielzahl von kardiovaskulären Erkrankungen hat eine genetische Ursache und ist damit familiär. Die meisten dieser Erkrankungen werden den sog. Seltenen (Herz-)Erkrankungen (Prävalenz < 1:2000) zugerechnet; lediglich die hypertrophe Kardiomyopathie und die familiäre Hypercholesterinämie sind häufiger. Oft bestehen eine genetische Heterogenität und Komplexität (5 bis 15 Gene pro Erkrankung) und eine variable, phänotypische Manifestation einer spezifischen Mutation in einer Familie. Einer molekulargenetischen Untersuchung kommt je nach Erkrankung neben der diagnostischen mitunter auch eine therapeutische, präventive und damit auch prognostische Bedeutung zu. Sie kann bei der Früherkennung und innerhalb einer Familie hilfreich sein. Das vorliegende Positionspapier nimmt zur Bedeutung von molekulargenetischen Untersuchungen bei bestimmten Arrhythmieformen, Kardiomyopathien, Herz- und Gefäßfehlern, seltenen Syndromen als auch der familiären Hypercholesterinämie und molekularen Autopsie (SIDS, SUDS) Stellung und soll hierbei hilfreich sein.

Abstract

Many cardiovascular disorders have a genetic background and occur in a familial setting. The majority belong to the group of rare diseases as their prevalence is low (< 1:2000); only hypertrophic cardiomyopathy and familial hypercholesterolemia are more frequent. There is often a widespread genetic heterogeneity and complexity (5–15 specific genes causing the disease) and a private (family-specific) mutation associated with a variable phenotypic manifestation. Molecular diagnostics and genetic testing are helpful in cardiovascular diseases and may be useful for therapeutic and preventive decisions in addition to the diagnostic value. In particular, they allow early detection of disease development and better family counselling. This expert consensus statement provides useful information and recommendations on the importance of genetic testing in cardiac arrhythmia, cardiomyopathy, congenital heart and vessel diseases, rare cardiac syndromes as well as in familial hypercholesterolemia and for molecular autopsies, e.g. for sudden infant death syndrome (SIDS) and sudden unexpected death syndrome (SUDS).

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Abb. 1
Abb. 2
Abb. 3
Abb. 4
Abb. 5
Abb. 6
Abb. 7
Abb. 8
Abb. 9
Abb. 10
Abb. 11
Abb. 12
Abb. 13
Abb. 14

Literatur

  1. Andreasen C, Nielsen JB, Refsgaard L et al (2013) New population-based exome data are questioning the pathogenicity of previously cardiomyopathy-associated genetic variants. Eur J Hum Genet 21(9):918–928

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Antzelevitch C, Brugada P, Borggrefe M et al (2005) Brugada syndrome: report of the second consensus conference. Heart Rhythm 2:429–440

    Article  PubMed  Google Scholar 

  3. Bagnall RD, Das KJ, Duflou J, Semsarian C (2014) Exome analysis-based molecular autopsy in cases of sudden unexplained death in the young. Heart Rhythm 11:655–662

    Article  PubMed  Google Scholar 

  4. Basso C, Burke M, Fornes P et al (2010) Guidelines for autopsy investigation of sudden cardiac death. Pathologica 102:391–404

    CAS  PubMed  Google Scholar 

  5. Basso C, Carturan E, Pilichou K et al (2010) Sudden cardiac death with normal heart: molecular autopsy. Cardiovasc Pathol 19:321–325

    Article  PubMed  Google Scholar 

  6. Bauce B, Nava A, Beffagna G et al (2010) Multiple mutations in desmosomal proteins encoding genes in arrhythmogenic right ventricular cardiomyopathy/dysplasia. Heart Rhythm 7:22–29

    Article  PubMed  Google Scholar 

  7. Bayes de LA, Brugada J, Baranchuk A et al (2012) Current electrocardiographic criteria for diagnosis of Brugada pattern: a consensus report. J Electrocardiol 45:433–442

    Article  Google Scholar 

  8. Behr ER, January C, Schulze-Bahr E et al (2013) The International Serious Adverse Events Consortium (iSAEC) phenotype standardization project for drug-induced torsades de pointes. Eur Heart J 34:1958–1963

    Article  PubMed Central  PubMed  Google Scholar 

  9. Boczek NJ, Best JM, Tester DJ et al (2013) Exome sequencing and systems biology converge to identify novel mutations in the L-type calcium channel, CACNA1C, linked to autosomal dominant long QT syndrome. Circ Cardiovasc Genet 6:279–289

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Crotti L, Tester DJ, White WM et al (2013) Long QT syndrome-associated mutations in intrauterine fetal death. JAMA 309:1473–1482

    Article  CAS  PubMed  Google Scholar 

  11. Dichgans M, Malik R, Konig IR et al (2014) Shared genetic susceptibility to ischemic stroke and coronary artery disease: a genome-wide analysis of common variants. Stroke 45:24–36

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Erdmann J, Stark K, Esslinger UB et al (2013) Dysfunctional nitric oxide signalling increases risk of myocardial infarction. Nature 504:432–436

    Article  CAS  PubMed  Google Scholar 

  13. Fahed AC, Gelb BD, Seidman JG, Seidman CE (2013) Genetics of congenital heart disease: the glass half empty. Circ Res 112:707–720

    Article  CAS  PubMed  Google Scholar 

  14. Futema M, Whittall RA, Kiley A et al (2013) Analysis of the frequency and spectrum of mutations recognised to cause familial hypercholesterolaemia in routine clinical practice in a UK specialist hospital lipid clinic. Atherosclerosis 229:161–168

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Giudicessi JR, Ackerman MJ (2013) Genetic testing in heritable cardiac arrhythmia syndromes: differentiating pathogenic mutations from background genetic noise. Curr Opin Cardiol 28:63–71

    Article  PubMed Central  PubMed  Google Scholar 

  16. Golbus JR, Puckelwartz MJ, Fahrenbach JP et al (2012) Population-Based Variation in Cardiomyopathy Genes. Circ Cardiovasc Genet 5(4):391–399

    Article  PubMed Central  PubMed  Google Scholar 

  17. Hershberger RE, Cowan J, Morales A, Siegfried JD (2009) Progress with genetic cardiomyopathies: screening, counseling, and testing in dilated, hypertrophic, and arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circ Heart Fail 2:253–261

    Article  PubMed Central  PubMed  Google Scholar 

  18. Hershberger RE, Lindenfeld J, Mestroni L et al (2009) Genetic evaluation of cardiomyopathy – a Heart Failure Society of America practice guideline. J Card Fail 15:83–97

    Article  PubMed  Google Scholar 

  19. Hershberger RE, Siegfried JD (2011) Update 2011: clinical and genetic issues in familial dilated cardiomyopathy. J Am Coll Cardiol 57:1641–1649

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Hoedemaekers YM, Caliskan K, Michels M et al (2010) The importance of genetic counseling, DNA diagnostics, and cardiologic family screening in left ventricular noncompaction cardiomyopathy. Circ Cardiovasc Genet 3:232–239

    Article  PubMed  Google Scholar 

  21. Hughes MF, Saarela O, Stritzke J et al (2012) Genetic markers enhance coronary risk prediction in men: the MORGAM prospective cohorts. PLoS One 7:e40922

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Jabbari J, Jabbari R, Nielsen MW et al (2013) New exome data question the pathogenicity of genetic variants Previously associated with catecholaminergic polymorphic ventricular tachycardia. Circ Cardiovasc Genet 6(5):481–499

    Article  PubMed  Google Scholar 

  23. Kapplinger JD, Landstrom AP, Salisbury BA et al (2011) Distinguishing arrhythmogenic right ventricular cardiomyopathy/dysplasia-associated mutations from background genetic noise. J Am Coll Cardiol 57:2317–2327

    Article  CAS  PubMed  Google Scholar 

  24. Klaassen S, Probst S, Oechslin E et al (2008) Mutations in sarcomere protein genes in left ventricular noncompaction. Circulation 117:2893–2901

    Article  CAS  PubMed  Google Scholar 

  25. Lindinger A, Schwedler G, Hense HW (2010) Prevalence of congenital heart defects in newborns in Germany: results of the first registration year of the PAN Study (July 2006 to June 2007). Klin Padiatr 222:321–326

    Article  CAS  PubMed  Google Scholar 

  26. Loeys B, De PA (2008) New insights in the pathogenesis of aortic aneurysms. Verh K Acad Geneeskd Belg 70:69–84

    CAS  PubMed  Google Scholar 

  27. Loeys BL, Dietz HC, Braverman AC et al (2010) The revised Ghent nosology for the Marfan syndrome. J Med Genet 47:476–485

    Article  CAS  PubMed  Google Scholar 

  28. Lopes LR, Zekavati A, Syrris P et al (2013) Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing. J Med Genet 50:228–239

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Marcus FI, McKenna WJ, Sherrill D et al (2010) Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the Task Force Criteria. Eur Heart J 31:806–814

    Article  PubMed Central  PubMed  Google Scholar 

  30. Marian AJ, Belmont J (2011) Strategic approaches to unraveling genetic causes of cardiovascular diseases. Circ Res 108:1252–1269

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. McKenna WJ, Spirito P, Desnos M et al (1997) Experience from clinical genetics in hypertrophic cardiomyopathy: proposal for new diagnostic criteria in adult members of affected families. Heart 77:130–132

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Mestroni L, Maisch B, McKenna WJ et al (1999) Guidelines for the study of familial dilated cardiomyopathies. Collaborative Research Group of the European Human and Capital Mobility Project on Familial Dilated Cardiomyopathy. Eur Heart J 20:93–102

    Article  CAS  PubMed  Google Scholar 

  33. Metzker ML (2010) Sequencing technologies – the next generation. Nat Rev Genet 11:31–46

    Article  CAS  PubMed  Google Scholar 

  34. Ng D, Johnston JJ, Teer JK (2013) Interpreting secondary cardiac disease variants in an exome cohort. Circ Cardiovasc Genet 6:337–346

    Article  PubMed  Google Scholar 

  35. Norton N, Li D, Hershberger RE (2012) Next-generation sequencing to identify genetic causes of cardiomyopathies. Curr Opin Cardiol 27:214–220

    Article  PubMed  Google Scholar 

  36. Norton N, Li D, Rampersaud E et al (2013) Exome sequencing and genome-wide linkage analysis in 17 families illustrate the complex contribution of TTN truncating variants to dilated cardiomyopathy. Circ Cardiovasc Genet 6:144–153

    Article  CAS  PubMed  Google Scholar 

  37. Oechslin E, Jenni R (2011) Left ventricular non-compaction revisited: a distinct phenotype with genetic heterogeneity? Eur Heart J 32:1446–1456

    Article  PubMed  Google Scholar 

  38. Oyen N, Poulsen G, Wohlfahrt J et al (2010) Recurrence of discordant congenital heart defects in families. Circ Cardiovasc Genet 3:122–128

    Article  PubMed  Google Scholar 

  39. Petretta M, Pirozzi F, Sasso L et al (2011) Review and metaanalysis of the frequency of familial dilated cardiomyopathy. Am J Cardiol 108:1171–1176

    Article  PubMed  Google Scholar 

  40. Qureshi N, Armstrong S, Saukko P et al (2009) Realising the potential of the family history in risk assessment and primary prevention of coronary heart disease in primary care: ADDFAM study protocol. BMC Health Serv Res 9:184

    Article  PubMed Central  PubMed  Google Scholar 

  41. Refsgaard L, Holst AG, Sadjadieh G et al (2012) High prevalence of genetic variants previously associated with LQT syndrome in new exome data. Eur J Hum Genet 20(8):905–908

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Semsarian C, Hamilton RM (2012) Key role of the molecular autopsy in sudden unexpected death. Heart Rhythm 9:145–150

    Article  PubMed  Google Scholar 

  43. Sen-Chowdhry S, Morgan RD, Chambers JC, McKenna WJ (2010) Arrhythmogenic cardiomyopathy: etiology, diagnosis, and treatment. Annu Rev Med 61:233–253

    Article  CAS  PubMed  Google Scholar 

  44. Spin JM (2011) Gene mutations and familial thoracic aortic aneurysms: a walk on the mild side. Circ Cardiovasc Genet 4:4–6

    Article  CAS  PubMed  Google Scholar 

  45. Tester DJ, Medeiros-Domingo A, Will ML et al (2012) Cardiac channel molecular autopsy: insights from 173 consecutive cases of autopsy-negative sudden unexplained death referred for postmortem genetic testing. Mayo Clin Proc 87:524–539

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Bom T van der, Bouma BJ, Meijboom FJ et al (2012) The prevalence of adult congenital heart disease, results from a systematic review and evidence based calculation. Am Heart J 164:568–575

    Article  PubMed  Google Scholar 

  47. Rijsingen IA van, Arbustini E, Elliott PM et al (2012) Risk factors for malignant ventricular arrhythmias in lamin a/c mutation carriers a European cohort study. J Am Coll Cardiol 59:493–500

    Article  PubMed  Google Scholar 

  48. Venetucci L, Denegri M, Napolitano C, Priori SG (2012) Inherited calcium channelopathies in the pathophysiology of arrhythmias. Nat Rev Cardiol 9:561–575

    Article  CAS  PubMed  Google Scholar 

  49. Waldmuller S, Erdmann J, Binner P et al (2011) Novel correlations between the genotype and the phenotype of hypertrophic and dilated cardiomyopathy: results from the German Competence Network Heart Failure. Eur J Heart Fail 13:1185–1192

    Article  PubMed  Google Scholar 

  50. Ware SM, Jefferies JL (2012) New genetic insights into congenital heart disease. J Clin Exp Cardiolog S8:pii:003

  51. Weeke P, Mosley JD, Hanna D et al (2014) Exome sequencing implicates an increased burden of rare potassium channel variants in the risk of drug induced long QT syndrome. J Am Coll Cardiol 63(14):1430–1437

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  52. Xu T, Yang Z, Vatta M et al (2010) Compound and digenic heterozygosity contributes to arrhythmogenic right ventricular cardiomyopathy. J Am Coll Cardiol 55:587–597

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  53. Zaidi S, Choi M, Wakimoto H et al (2013) De novo mutations in histone-modifying genes in congenital heart disease. Nature 498:220–223

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  54. Zenker M (2011) Clinical manifestations of mutations in RAS and related intracellular signal transduction factors. Curr Opin Pediatr 23:443–451

    Article  CAS  PubMed  Google Scholar 

  55. Zou Y, Wang J, Liu X et al (2013) Multiple gene mutations, not the type of mutation, are the modifier of left ventricle hypertrophy in patients with hypertrophic cardiomyopathy. Mol Biol Rep 40:3969–3976

    Article  CAS  PubMed  Google Scholar 

Download references

Interessenkonflikt

Den Interessenkonflikt der Autoren finden Sie online auf der DGK-Homepage unter http://leitlinien.dgk.org/bei der entsprechenden Publikation.

Author information

Authors and Affiliations

  1. Institut für Genetik von Herzerkrankungen (IfGH), Spezialambulanz für Patienten mit familiären Herzerkrankungen, Department für Kardiologie und Angiologie, Universitätsklinikum Münster (UKM), Albert-Schweitzer Campus 1 (Gebäude D3), 48149, Münster, Deutschland

    E. Schulze-Bahr

  2. Klinik für Pädiatrie mit Schwerpunkt Kardiologie und Experimental and Clinical Research Center (ECRC), Charité – Universitätsmedizin Berlin, Berlin, Deutschland

    S. Klaassen

  3. Klinik für Kinderkardiologie, Universitätsklinikum des Saarlandes, Homburg/Saar, Deutschland

    H. Abdul-Khaliq

  4. Kompetenznetz Angeborene Herzfehler e. V., Berlin, Deutschland

    S. Klaassen & H. Abdul-Khaliq

  5. Klinik für Herz- und Kreislauferkrankungen, Deutsches Herzzentrum und Technische Universität München, Deutsches Zentrum für Herz- und Kreislaufforschung (DZHK), Munich Heart Alliance, München, Deutschland

    H. Schunkert

Authors
  1. E. Schulze-Bahr
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. Klaassen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H. Abdul-Khaliq
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. H. Schunkert
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E. Schulze-Bahr.

Additional information

Ein Glossar „Humangenetische Fachausdrücke“ findet sich z. B. unter http://klinikum.uni-muenster.de/index.php?id=4640.

___ ___

H. Schunkert für die Kommission für Klinische Kardiologie der DGK.

Zusatzmaterial online

Positionspapier_Gendiagnostik-Anhang

Empfehlungen E1-E8 (PDF 0,2MB)

Tabellen 6-8 (PDF 0,9MB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Schulze-Bahr, E., Klaassen, S., Abdul-Khaliq, H. et al. Gendiagnostik bei kardiovaskulären Erkrankungen. Kardiologe 9, 213–243 (2015). https://doi.org/10.1007/s12181-014-0636-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12181-014-0636-2

Schlüsselwörter

Keywords

Search

Navigation