Skip to main content
SpringerLink
Log in

Gendiagnostik bei kardiovaskulären Erkrankungen

Konsensuspapier der Deutschen Gesellschaft für Kardiologie (DGK), der Gesellschaft für Humangenetik (GfH) und der Deutschen Gesellschaft für Pädiatrische Kardiologie (DGPK)

Gene diagnostics for cardiovascular diseases

Consensus statement of the German Cardiac Society (DGK), the Society for Human Genetics (GfH) and the German Society for Pediatric Cardiology (DGPK)

  • Konsensuspapiere
  • Published:
Die Kardiologie Aims and scope

Zusammenfassung

Dieses Konsensuspapier beschreibt die Bedeutung, Vorgehensweise und die gesetzlichen Regelungen der molekulargenetischen Diagnostik bei kardiovaskulären Erkrankungen. Inhaltlich werden konkrete diagnostische Empfehlungen zu hereditären Arrhythmien, Kardiomyopathien, Herz- und Gefäßfehlern, seltenen Syndromen, familiärer Hypercholesterinämie, molekularer Autopsie (plötzlicher Herztod) und Pharmakogenetik gegeben. Das vorherige Positionspapier der DGK/DGPK von 2015 wurde aktualisiert und nun mit der GfH als weitere Fachgesellschaft abgestimmt. Die interdisziplinäre Autorengruppe aus Kardiologen, Kinderkardiologen und Humangenetikern mit Expertise in der Behandlung von kardiovaskulären Erkrankungen von Erwachsenen, Kindern und Jugendlichen trägt mit dieser Aktualisierung dem großen Zuwachs des kardiogenetischen Wissens nach aktuellem Stand Rechnung. Die Hochdurchsatzsequenzierung (Next Generation Sequencing [NGS]) wurde zwischenzeitlich für die klinische Gendiagnostik als Leistung der gesetzlichen Krankenkasse eingeführt, was zu einer deutlich höheren Rate an positiven Befunden geführt hat. Die genetische Diagnostik sollte mit einer humangenetischen Beratung vor und nach der molekulargenetischen Untersuchung einhergehen. Mit der genetischen Diagnose der Erkrankung sind häufig bessere Behandlungsmöglichkeiten und Interventionen verbunden, die die Lebensqualität und Prognose der Patienten verbessern können. Die systematische Untersuchung der Patienten erfordert eine genaue Familienanamnese und die detaillierte Phänotypisierung des Indexpatienten. Weitere Familienmitglieder sollten molekulargenetisch untersucht werden, wenn sich daraus eine diagnostische, therapeutische und/oder prognostische Konsequenz ergibt. Eine molekulargenetische Untersuchung von Kindern und Jugendlichen im Rahmen eines familiären Kaskadenscreenings kann durchgeführt werden, wenn aus dem genetischen Befund unmittelbare, therapeutische Konsequenzen folgen. Insbesondere bei syndromalen Erkrankungen ergibt sich die Notwendigkeit einer interdisziplinären Betreuung. Eine genetische Untersuchung kann über die Beurteilung des Analyseergebnisses (bioinformatische Sequenzauswertung) molekulargenetische Zusatzbefunde generieren. Die genetische Heterogenität und variable Penetranz und die fortschreitenden Erkenntnisse im Bereich der kardiovaskulären Erkrankungen stellen weiterhin eine Herausforderung bei der Betreuung der betroffenen Patienten dar und bedingen eine begleitende Behandlung in spezialisierten Einrichtungen.

Abstract

This expert consensus paper describes the relevance, practical approach and national legal regulations in molecular genetic diagnostics with the focus on cardiovascular diseases. Diagnostic recommendations are given for hereditary arrhythmia syndromes, cardiomyopathies, cardiovascular defects, rare cardiac syndromes, familial hypercholesterolemia, molecular autopsy (sudden cardiac death) and pharmacogenetics. The previous position paper of the DGK/DGPK from 2015 was now updated and agreed with the GfH as an additional partcipating society. With this update, the interdisciplinary working group of authors consisting of cardiologists, pediatric cardiologists and human geneticists with expertise in the treatment of cardiovascular diseases in adults, children and adolescents, takes into account the current state of the increasing growth of cardiogenetic knowledge. High-throughput next generation sequencing (NGS) was meanwhile introduced for clinical gene diagnostics as a service of the statutory health insurance, which led to a much higher rate of positive results. The genetic diagnostics should be accompanied by genetic counselling before and after genetic testing. A genetic diagnosis of a disease frequently leads to better treatment options and medical interventions, which can improve the quality of life and prognosis of patients. The systematic investigation of patients necessitates an exact family history and a detailed phenotyping assessment of the index patient. Other family members should undergo molecular genetic testing when this directly leads to a diagnostic, therapeutic and/or prognostic consequences. A molecular genetic testing of children and adolescents can be carried out as part of the family cascade screening when the genetic finding leads to direct therapeutic consequences. There is a necessity for interdisciplinary patient care, particularly for syndromic cardiac disorders. During the analytical assessment of a genetic test (bioinformatic sequence evaluation) also additional molecular genetic findings (incidental findings) may come up. The large genetic heterogeneity and variable penetrance of cardiovascular diseases und their increasing knowledge still represent a major challenge in the care of affected patients and emphasis additional patient monitoring in specialized care units.

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

Notes

  1. http://www.gesetze-im-internet.de/gendg/index.html.

Abbreviations

ACMG:

American College of Medical Genetics and Genomics

AHF:

Angeborener Herzfehler

ARVC:

Arrhythmogene, rechtsventrikuläre Kardiomyopathie

ASD:

Vorhofseptumdefekt

ASS:

Atrial stand still

ATS:

Andersen-Tawil-Syndrom

A(U)CM:

Arrhythmogene (unklassifizierte) Kardiomyopathie

AVB:

Atrioventrikulärer Block

AVSD:

Vorhof-Kammer-Septumdefekt

BÄK:

Bundesärztekammer

BAV:

Bikuspide Aortenklappe

Bp:

Basenpaare

BRU, BRGDA:

Brugada-Syndrom

BVDH:

Berufsverband Deutscher Humangenetiker e. V.

CCD:

Cardiac conduction disease

CFC:

Kardiofaziokutanes Syndrom

CGH:

Comparative genome hybridization

ClinGen:

Clinical Genome Resource; https://www.clinicalgenome.org/

CNV:

Copy number variation

CoA:

Coarctatio aortaeCPVT

CPVT:

Stressinduzierte, polymorphe ventrikuläre Kammertachykardie

CYP:

Cytochrom P

DCM:

Dilatative Kardiomyopathie

diLQTS:

Medikamenteninduzierte QT-Intervall-Verlängerung

EDS:

Ehlers-Danlos-Syndrom

EFE:

Endokardfibroelastose

EKG:

Elektrokardiogramm

ERS:

Frühes Repolarisationssyndrom

FH:

Familiäre Hypercholesterinämie

FISH:

Fluoreszenz-in-situ-Hybridisierung

GEKO:

Gendiagnostik-Kommission

GenDG:

Gendiagnostik-Gesetz

GfH:

Deutsche Gesellschaft für Humangenetik e. V.

GRS:

Genetischer Risiko-Score

GWAS:

Genomweite Assoziationsstudie

H(O)CM:

Hypertrophe (obstruktive) Kardiomyopathie

HOS:

Holt-Oram-Syndrom

HTAD:

Hereditäre Aortenerkrankungen

HTXS:

Heterotaxiesyndrom

IAA:

Interrupted aortic arch

ICD:

Implantierbarer Kardioverter-Defibrillator

ID:

Identifier

IVF:

Idiopathisches Kammerflimmern

JLNS:

Jervell und Lange-Nielsen-Syndrom

kbp:

Kilo-Basenpaare

KHK:

Koronare Herzkrankheit

LDL:

Lipoprotein niedriger Dichte

LDS:

Loeys-Dietz-Syndrom

LJ:

Lebensjahr

Lp(a):

Lipoprotein(a)

LQTS:

Langes QT-Syndrom

LVH:

Linksventrikuläre Hypertrophie

LVNC:

Non-compaction-Kardiomyopathie

LVOTO:

Linksventrikuläre Ausflusstraktobstruktion

M.:

Morbus

Mbp:

Mega-Basenpaare

MFS:

Marfan-Syndrom

MGPS:

Multi-Gen-Panelsequenzierung

MLPA:

Multiplexe ligationsabhängige Sondenamplifikation

MMVP:

Myxomatöser Mitralklappenprolaps

MonDO:

Monarch Disease Ontology

MRT:

Magnetresonanztomographie

MVP:

Mitralklappenprolaps

MVPS:

Mitralklappenprolapssyndrom

NCBI:

National Center for Biotechnology Information

NCCM:

Non-compaction-Kardiomyopathie

NGS:

Next-Generation-Sequenzierung

NS:

Noonan-Syndrom

ns:

nicht-synonym

OMIM:

Online Mendelian Inheritance of Man

PA:

Pulmonalatresie

PCCD:

Progressive cardiac conduction disease

PPCM:

Peripartum-Kardiomyopathie (Schwangerschaftskardiomyopathie)

QMS:

Qualitätsmanagementsystem

RCM:

Restriktive Kardiomyopathie

RR:

Relatives Risiko

SADS:

Sudden arrhythmic death syndrome

SCA:

Überlebter plötzlicher Herztod, „sudden cardiac arrest“

SCD:

Plötzlicher Herztod, „sudden cardiac death“

SIDS:

Plötzlicher Kindstod, „sudden infant death syndrome“

SNP:

Single nucleotide polymorphism

SNV:

Single nucleotide variation

SQTS:

Kurzes QT-Syndrom

SUDS:

Plötzlicher unerwarteter Herztod, „sudden unexpected death syndrome“

SUNDS:

Plötzlicher unerwarteter nächtlicher Herztod, „sudden unexpected nocturnal death syndrome“

TAAD:

Thorakales Aortenaneurysma und Dissektion

TES:

Targeted-exome-Sequenzierung

TOF:

Fallot-Tetralogie

TS:

Timothy-Syndrom

TTE:

Transthorakale Echokardiographie

VCFS:

Velokardiofaziales Syndrom

vEDS:

Vaskuläres Ehlers-Danlos-Syndrom

VSD:

Ventrikelseptumdefekt

VUS:

Variante unklarer Signifikanz

WBS:

Williams-Beuren-Syndrom

WES:

Whole-exome-Sequenzierung

WGS:

Whole-genome-Sequenzierung

WPW:

Wolff-Parkinson-White-Syndrom

Literatur

  1. Aalberts JJ, Thio CH, Schuurman AG et al (2012) Diagnostic yield in adults screened at the Marfan outpatient clinic using the 1996 and 2010 Ghent nosologies. Am J Med Genet A 158A:982–988

    Article  PubMed  Google Scholar 

  2. Abdullah-Koolmees H, van Keulen AM, Nijenhuis M et al (2020) Pharmacogenetics guidelines: overview and comparison of the DPWG, CPIC, CPNDS, and RNPGx guidelines. Front Pharmacol 11:595219

    Article  CAS  PubMed  Google Scholar 

  3. Ackerman MJ, Priori SG, Willems S et al (2011) 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). Heart Rhythm 8:1308–1339

    Article  PubMed  Google Scholar 

  4. Adler A, Novelli V, Amin AS et al (2020) An international, multicentered, evidence-based reappraisal of genes reported to cause congenital long QT syndrome. Circulation 141:418–428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ahamed H, Balegadde AV, Menon S et al (2020) Phenotypic expression and clinical outcomes in a South Asian PRKAG2 cardiomyopathy cohort. Sci Rep 10:20610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ahmad F, Mcnally EM, Ackerman MJ et al (2019) Establishment of specialized clinical cardiovascular genetics programs: recognizing the need and meeting standards: a scientific statement from the American heart association. Circ Genom Precis Med 12:e54

    Article  PubMed  Google Scholar 

  7. Al-Azaam B, Darbar D (2021) Atrial fibrillation in inherited channelopathies. Card Electrophysiol Clin 13:155–163

    Article  PubMed  PubMed Central  Google Scholar 

  8. Al-Khatib SM, Stevenson WG, Ackerman MJ et al (2018) 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American college of cardiology/American heart association task force on clinical practice guidelines and the heart rhythm society. J Am Coll Cardiol 72:e91–e220

    Article  PubMed  Google Scholar 

  9. Alankarage D, Ip E, Szot JO et al (2019) Identification of clinically actionable variants from genome sequencing of families with congenital heart disease. Genet Med 21:1111–1120

    Article  PubMed  Google Scholar 

  10. Albornoz G, Coady MA, Roberts M et al (2006) Familial thoracic aortic aneurysms and dissections—incidence, modes of inheritance, and phenotypic patterns. Ann Thorac Surg 82:1400–1405

    Article  PubMed  Google Scholar 

  11. Anderson RH, Jensen B, Mohun TJ et al (2017) Key questions relating to left ventricular noncompaction cardiomyopathy: is the emperor still wearing any clothes? Can J Cardiol 33:747–757

    Article  PubMed  Google Scholar 

  12. Robert Koch-Institut (2017) Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 60:472–475

    Article  Google Scholar 

  13. Anonymous (2022) Richtlinie der Gendiagnostik-Kommission (GEKO) für die Anforderungen an die Inhalte der Aufklärung bei genetischen Untersuchungen zu medizinischen Zwecken gemäß § 23 Abs. 2 Nr. 3 GenDG. Bundesgesundheitsbl 65:963–968

    Google Scholar 

  14. Anonymous (2017) Richtlinie der Gendiagnostik-Kommission (GEKO) für die Anforderungen an die Inhalte der Aufklärung bei genetischen Untersuchungen zu medizinischen Zwecken gemäß § 23 Abs. 2 Nr. 3 GenDG. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 60:923–927

    Article  Google Scholar 

  15. Anonymous (2018) S1 Leitlinie: Molekulargenetische Diagnostik mit Hochdurchsatz-Verfahren der Keimbahn, beispielsweise mit Next-Generation Sequencing. medgen 30:278–292

    Article  Google Scholar 

  16. Anonymous (2019) S2k-Leitlinie Humangenetische Diagnostik und Genetische Beratung. medgen 30:469–522

    Google Scholar 

  17. Antzelevitch C, Yan GX, Ackerman MJ et al (2016) J‑wave syndromes expert consensus conference report: emerging concepts and gaps in knowledge. J Arrhythm 32:315–339

    Article  PubMed  PubMed Central  Google Scholar 

  18. Arbustini E, Behr ER, Carrier L et al (2022) Interpretation and actionability of genetic variants in cardiomyopathies: a position statement from the European society of cardiology council on cardiovascular genomics. Eur Heart J 43:1901–1916

    Article  CAS  PubMed  Google Scholar 

  19. Arbustini E, Favalli V, Narula N et al (2016) Left ventricular noncompaction: a distinct genetic cardiomyopathy? J Am Coll Cardiol 68:949–966

    Article  PubMed  Google Scholar 

  20. Arking DE, Pulit SL, Crotti L et al (2014) Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization. Nat Genet 46:826–836

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Arnaud P, Hanna N, Benarroch L et al (2019) Genetic diversity and pathogenic variants as possible predictors of severity in a French sample of nonsyndromic heritable thoracic aortic aneurysms and dissections (nshTAAD). Genet Med 21:2015–2024

    Article  PubMed  Google Scholar 

  22. Asiimwe IG, Zhang EJ, Osanlou R et al (2021) Warfarin dosing algorithms: a systematic review. Br J Clin Pharmacol 87:1717–1729

    Article  CAS  PubMed  Google Scholar 

  23. Aung N, Doimo S, Ricci F et al (2020) Prognostic significance of left ventricular noncompaction: systematic review and meta-analysis of observational studies. Circ Cardiovasc Imaging 13:e9712

    Article  PubMed  PubMed Central  Google Scholar 

  24. Baggio C, Gagno G, Porcari A et al (2021) Myocarditis: which role for genetics? Curr Cardiol Rep 23:58

    Article  PubMed  PubMed Central  Google Scholar 

  25. Balaji S, Dilorenzo MP, Fish FA et al (2019) Risk factors for lethal arrhythmic events in children and adolescents with hypertrophic cardiomyopathy and an implantable defibrillator: an international multicenter study. Heart Rhythm 16:1462–1467

    Article  PubMed  Google Scholar 

  26. Barc J, Tadros R, Glinge C et al (2022) Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility. Nat Genet 54:232–239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Baumgartner H, De Backer J, Babu-Narayan SV et al (2021) 2020 ESC guidelines for the management of adult congenital heart disease. Eur Heart J 42:563–645

    Article  CAS  PubMed  Google Scholar 

  28. Belbachir N, Portero V, Al Sayed ZR et al (2019) RRAD mutation causes electrical and cytoskeletal defects in cardiomyocytes derived from a familial case of Brugada syndrome. Eur Heart J 40:3081–3094

    Article  PubMed  PubMed Central  Google Scholar 

  29. Benrashid E, Ohman JW (2020) Current management of the vascular subtype of Ehlers–Danlos syndrome. Curr Opin Cardiol 35:603–609

    Article  PubMed  Google Scholar 

  30. Bermúdez-Jiménez FJ, Carriel V, Brodehl A et al (2018) Novel Desmin mutation p.Glu401asp impairs filament formation, disrupts cell membrane integrity, and causes severe arrhythmogenic left ventricular cardiomyopathy/dysplasia. Circulation 137:1595–1610

    Article  PubMed  Google Scholar 

  31. Boodhwani M, Andelfinger G, Leipsic J et al (2014) Canadian cardiovascular society position statement on the management of thoracic aortic disease. Can J Cardiol 30:577–589

    Article  PubMed  Google Scholar 

  32. Bos JM, Theis JL, Tajik AJ et al (2008) Relationship between sex, shape, and substrate in hypertrophic cardiomyopathy. Am Heart J 155:1128–1134

    Article  PubMed  PubMed Central  Google Scholar 

  33. Bosman LP, Sammani A, James CA et al (2018) Predicting arrhythmic risk in arrhythmogenic right ventricular cardiomyopathy: a systematic review and meta-analysis. Heart Rhythm 15:1097–1107

    Article  PubMed  Google Scholar 

  34. Bourfiss M, van Vugt M, Alasiri AI et al (2022) Prevalence and disease expression of pathogenic and likely pathogenic variants associated with inherited cardiomyopathies in the general population. Circ Genom Precis Med 15:e3704

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Braenne I, Kleinecke M, Reiz B et al (2016) Systematic analysis of variants related to familial hypercholesterolemia in families with premature myocardial infarction. Eur J Hum Genet 24:191–197

    Article  CAS  PubMed  Google Scholar 

  36. Brodehl A, Ferrier RA, Hamilton SJ et al (2016) Mutations in FLNC are associated with familial restrictive cardiomyopathy. Hum Mutat 37:269–279

    Article  CAS  PubMed  Google Scholar 

  37. Brodehl A, Gaertner-Rommel A, Klauke B et al (2017) The novel αB-crystallin (CRYAB) mutation p.D109G causes restrictive cardiomyopathy. Hum Mutat 38:947–952

    Article  CAS  PubMed  Google Scholar 

  38. Brodehl A, Gerull B (2022) Genetic insights into primary restrictive cardiomyopathy. J Clin Med 11(8):2094. https://doi.org/10.3390/jcm11082094

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Brown EE, Sturm AC, Cuchel M et al (2020) Genetic testing in dyslipidemia: a scientific statement from the national lipid association. J Clin Lipidol 14:398–413

    Article  PubMed  Google Scholar 

  40. Burke MA, Cook SA, Seidman JG et al (2016) Clinical and mechanistic insights into the genetics of cardiomyopathy. J Am Coll Cardiol 68:2871–2886

    Article  PubMed  PubMed Central  Google Scholar 

  41. Byers PH, Belmont J, Black J et al (2017) Diagnosis, natural history, and management in vascular Ehlers-Danlos syndrome. Am J Med Genet C Semin Med Genet 175:40–47

    Article  PubMed  Google Scholar 

  42. Cadrin-Tourigny J, Bosman LP, Wang W et al (2021) Sudden cardiac death prediction in arrhythmogenic right ventricular cardiomyopathy: a multinational collaboration. Circ Arrhythm Electrophysiol 14:e8509

    Article  CAS  PubMed  Google Scholar 

  43. Calloe K, Broendberg AK, Christensen AH et al (2018) Multifocal atrial and ventricular premature contractions with an increased risk of dilated cardiomyopathy caused by a Nav1.5 gain-of-function mutation (G213D). Int J Cardiol 257:160–167

    Article  PubMed  Google Scholar 

  44. Campuzano O, Fernandez-Falgueras A, Lemus X et al (2019) Short QT syndrome: a comprehensive genetic interpretation and clinical translation of rare variants. J Clin Med 8(7):1035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Campuzano O, Sanchez-Molero O, Fernandez A et al (2017) Sudden arrhythmic death during exercise: a post-mortem genetic analysis. Sports Med 47:2101–2115

    Article  PubMed  Google Scholar 

  46. Carter A, Brackley SM, Gao J et al (2019) The global prevalence and genetic spectrum of lysosomal acid lipase deficiency: a rare condition that mimics NAFLD. J Hepatol 70:142–150

    Article  CAS  PubMed  Google Scholar 

  47. Casas G, Limeres J, Oristrell G et al (2021) Clinical risk prediction in patients with left ventricular myocardial noncompaction. J Am Coll Cardiol 78:643–662

    Article  PubMed  Google Scholar 

  48. Cascorbi I (2012) Drug interactions—principles, examples and clinical consequences. Dtsch Ärztebl Int 109:546–555 (quiz 556)

    PubMed  PubMed Central  Google Scholar 

  49. Castaño A, Drachman BM, Judge D et al (2015) Natural history and therapy of TTR-cardiac amyloidosis: emerging disease-modifying therapies from organ transplantation to stabilizer and silencer drugs. Heart Fail Rev 20:163–178

    Article  PubMed  PubMed Central  Google Scholar 

  50. Castiglione A, Odening K (2020) QT interval and its prolongation—what does it mean? Dtsch Med Wochenschr 145:536–542

    PubMed  Google Scholar 

  51. Chan RH, Maron BJ, Olivotto I et al (2014) Prognostic value of quantitative contrast-enhanced cardiovascular magnetic resonance for the evaluation of sudden death risk in patients with hypertrophic cardiomyopathy. Circulation 130:484–495

    Article  PubMed  Google Scholar 

  52. Chen L, Song J, Chen X et al (2019) A novel genotype-based clinicopathology classification of arrhythmogenic cardiomyopathy provides novel insights into disease progression. Eur Heart J 40:1690–1703

    Article  CAS  PubMed  Google Scholar 

  53. Chen X, Barajas-Martinez H, Xia H et al (2021) Clinical and functional genetic characterization of the role of cardiac calcium channel variants in the early repolarization syndrome. Front Cardiovasc Med 8:680819

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Cheng A, Owens D (2015) Marfan syndrome, inherited aortopathies and exercise: what is the right answer? Heart 101:752–757

    Article  PubMed  Google Scholar 

  55. Chin TK, Perloff JK, Williams RG et al (1990) Isolated noncompaction of left ventricular myocardium. A study of eight cases. Circulation 82:507–513

    Article  CAS  PubMed  Google Scholar 

  56. Chintanaphol M, Orgil BO, Alberson NR et al (2022) Restrictive cardiomyopathy: from genetics and clinical overview to animal modeling. Rev Cardiovasc Med 23:108

    Article  PubMed  Google Scholar 

  57. Chou C, Chin MT (2021) Pathogenic mechanisms of hypertrophic cardiomyopathy beyond sarcomere dysfunction. Int J Mol Sci 22:8933

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Clemens DJ, Tester DJ, Giudicessi JR et al (2019) International triadin knockout syndrome registry. Circ Genom Precis Med 12:e2419

    Article  PubMed  Google Scholar 

  59. Corrado D, Perazzolo Marra M, Zorzi A et al (2020) Diagnosis of arrhythmogenic cardiomyopathy: the Padua criteria. Int J Cardiol 319:106–114

    Article  PubMed  Google Scholar 

  60. Crotti L, Spazzolini C, Tester DJ et al (2019) Calmodulin mutations and life-threatening cardiac arrhythmias: insights from the international calmodulinopathy registry. Eur Heart J 40:2964–2975

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Cuchel M, Bruckert E, Ginsberg HN et al (2014) Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the consensus panel on familial hypercholesterolaemia of the European atherosclerosis society. Eur Heart J 35:2146–2157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Daniels MJ, Fusi L, Semsarian C et al (2021) Myosin modulation in hypertrophic cardiomyopathy and systolic heart failure: getting inside the engine. Circulation 144:759–762

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Das KJ, Ingles J, Bagnall RD et al (2014) Determining pathogenicity of genetic variants in hypertrophic cardiomyopathy: importance of periodic reassessment. Genet Med 16:286–293

    Article  Google Scholar 

  64. Demartino RR, Sen I, Huang Y et al (2018) Population-based assessment of the incidence of aortic dissection, intramural hematoma, and penetrating ulcer, and its associated mortality from 1995 to 2015. Circ Cardiovasc Qual Outcomes 11:e4689

    Article  PubMed  PubMed Central  Google Scholar 

  65. Diab NS, Barish S, Dong W et al (2021) Molecular genetics and complex inheritance of congenital heart disease. Genes (Basel) 12(7):1020. https://doi.org/10.3390/genes12071020

    Article  CAS  PubMed  Google Scholar 

  66. Dietz HC, Cutting CR, Pyeritz RE et al (1991) Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature 352:337–339

    Article  CAS  PubMed  Google Scholar 

  67. Doesch C, Tulumen E, Akin I et al (2017) Incremental benefit of late gadolinium cardiac magnetic resonance imaging for risk stratification in patients with hypertrophic cardiomyopathy. Sci Rep 7:6336

    Article  PubMed  PubMed Central  Google Scholar 

  68. Doisne N, Waldmann V, Redheuil A et al (2020) A novel gain-of-function mutation in SCN5A responsible for multifocal ectopic Purkinje-related premature contractions. Hum Mutat 41:850–859

    Article  CAS  PubMed  Google Scholar 

  69. Dungu JN, Langley SG, Hardy-Wallace A et al (2021) Dilated cardiomyopathy: the role of genetics, highlighted in a family with Filamin C (FLNC) variant. Heart. https://doi.org/10.1136/heartjnl-2021-319682

    Article  PubMed  Google Scholar 

  70. El-Battrawy I, Besler J, Liebe V et al (2018) Long-term follow-up of patients with short QT syndrome: clinical profile and outcome. J Am Heart Assoc 7:e10073

    Article  PubMed  PubMed Central  Google Scholar 

  71. Ellesoe SG, Workman CT, Bouvagnet P et al (2018) Familial co-occurrence of congenital heart defects follows distinct patterns. Eur Heart J 39:1015–1022

    Article  PubMed  Google Scholar 

  72. Elliott P, Andersson B, Arbustini E et al (2008) Classification of the cardiomyopathies: a position statement from the European society of cardiology working group on myocardial and pericardial diseases. Eur Heart J 29:270–276

    Article  PubMed  Google Scholar 

  73. Elliott PM, Anastasakis A, Asimaki A et al (2019) Definition and treatment of arrhythmogenic cardiomyopathy: an updated expert panel report. Eur J Heart Fail 21:955–964

    Article  PubMed  Google Scholar 

  74. Elliott PM, Anastasakis A, Borger MA et al (2014) 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 35:2733–2779

    Article  PubMed  Google Scholar 

  75. Erbel R, Aboyans V, Boileau C et al (2014) 2014 ESC guidelines on the diagnosis and treatment of aortic diseases. Eur Heart J 35:2873–2926

    Article  PubMed  Google Scholar 

  76. Fellmann F, van El CG, Charron P et al (2019) European recommendations integrating genetic testing into multidisciplinary management of sudden cardiac death. Eur J Hum Genet 27:1763–1773

    Article  PubMed  PubMed Central  Google Scholar 

  77. Finocchiaro G, Merlo M, Sheikh N et al (2020) The electrocardiogram in the diagnosis and management of patients with dilated cardiomyopathy. Eur J Heart Fail 22:1097–1107

    Article  PubMed  Google Scholar 

  78. Flynn CD, Tian DH, Wilson-Smith A et al (2017) Systematic review and meta-analysis of surgical outcomes in Marfan patients undergoing aortic root surgery by composite-valve graft or valve sparing root replacement. Ann Cardiothorac Surg 6:570–581

    Article  PubMed  PubMed Central  Google Scholar 

  79. Fujii Y, Itoh H, Ohno S et al (2017) A type 2 ryanodine receptor variant associated with reduced Ca(2+) release and short-coupled torsades de pointes ventricular arrhythmia. Heart Rhythm 14:98–107

    Article  PubMed  Google Scholar 

  80. Gallego-Delgado M, Delgado JF, Brossa-Loidi V et al (2016) Idiopathic restrictive cardiomyopathy is primarily a genetic disease. J Am Coll Cardiol 67:3021–3023

    Article  PubMed  Google Scholar 

  81. Gao X, Ye D, Zhou W et al (2022) A novel functional variant residing outside the SCN5A-encoded Nav1.5 voltage-sensing domain causes multifocal ectopic Purkinje-related premature contractions. HeartRhythm Case Rep 8:54–59

    Article  PubMed  Google Scholar 

  82. Gati S, Chandra N, Bennett RL et al (2013) Increased left ventricular trabeculation in highly trained athletes: do we need more stringent criteria for the diagnosis of left ventricular non-compaction in athletes? Heart 99:401–408

    Article  CAS  PubMed  Google Scholar 

  83. Gati S, Papadakis M, Papamichael ND et al (2014) Reversible de novo left ventricular trabeculations in pregnant women: implications for the diagnosis of left ventricular noncompaction in low-risk populations. Circulation 130:475–483

    Article  PubMed  Google Scholar 

  84. Gelb BD (2016) Genetic discovery for congenital heart defects. In: Nakanishi T, Markwald RR, Baldwin HS, Keller BB, Srivastava D, Yamagishi H (Hrsg) Etiology and morphogenesis of congenital heart disease: from gene function and cellular interaction to morphology. Springer, Tokyo, S 355–360

    Chapter  Google Scholar 

  85. Gelb BD, Cave H, Dillon MW et al (2018) ClinGen’s RASopathy expert panel consensus methods for variant interpretation. Genet Med 20:1334–1345

    Article  PubMed  PubMed Central  Google Scholar 

  86. Gersh BJ, Maron BJ, Bonow RO et al (2011) 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: executive summary: a report of the American college of cardiology foundation/American heart association task force on practice guidelines. Circulation 124:2761–2796

    Article  PubMed  Google Scholar 

  87. Gerull B, Heuser A, Wichter T et al (2004) Mutations in the desmosomal protein plakophilin‑2 are common in arrhythmogenic right ventricular cardiomyopathy. Nat Genet 36:1162–1164

    Article  CAS  PubMed  Google Scholar 

  88. Gigli M, Merlo M, Graw SL et al (2019) Genetic risk of arrhythmic phenotypes in patients with dilated cardiomyopathy. J Am Coll Cardiol 74:1480–1490

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Giudicessi JR, Lieve KVV, Rohatgi RK et al (2019) Assessment and validation of a phenotype-enhanced variant classification framework to promote or demote RYR2 missense variants of uncertain significance. Circ Genom Precis Med 12:e2510

    Article  CAS  PubMed  Google Scholar 

  90. Giustetto C, Scrocco C, Schimpf R et al (2015) Usefulness of exercise test in the diagnosis of short QT syndrome. Europace 17:628–634

    Article  PubMed  Google Scholar 

  91. Gollob MH, Redpath CJ, Roberts JD (2011) The short QT syndrome: proposed diagnostic criteria. J Am Coll Cardiol 57:802–812

    Article  PubMed  Google Scholar 

  92. Gouveia E Melo R, Silva Duarte G, Lopes A et al (2021) Incidence and prevalence of thoracic aortic aneurysms: a systematic review and meta-analysis of population-based studies. Semin Thorac Cardiovasc Surg 34(1):1–16

    Article  PubMed  Google Scholar 

  93. Gregg AR, Skotko BG, Benkendorf JL et al (2016) Noninvasive prenatal screening for fetal aneuploidy, 2016 update: a position statement of the American college of medical genetics and genomics. Genet Med 18:1056–1065

    Article  CAS  PubMed  Google Scholar 

  94. Groeneweg JA, Bhonsale A, James CA et al (2015) Clinical presentation, long-term follow-up, and outcomes of 1001 arrhythmogenic right ventricular dysplasia/cardiomyopathy patients and family members. Circ Cardiovasc Genet 8:437–446

    Article  CAS  PubMed  Google Scholar 

  95. Groenink M, den Hartog AW, Franken R et al (2013) Losartan reduces aortic dilatation rate in adults with Marfan syndrome: a randomized controlled trial. Eur Heart J 34:3491–3500

    Article  CAS  PubMed  Google Scholar 

  96. Groth KA, Hove H, Kyhl K et al (2015) Prevalence, incidence, and age at diagnosis in Marfan syndrome. Orphanet J Rare Dis 10:153

    Article  PubMed  PubMed Central  Google Scholar 

  97. Guerri G, Krasi G, Precone V et al (2019) Cardiac conduction defects. Acta Biomed 90:20–29

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Gussak I, Brugada P, Brugada J et al (2000) Idiopathic short QT interval: a new clinical syndrome? Cardiology 94:99–102

    Article  CAS  PubMed  Google Scholar 

  99. Haas J, Frese KS, Peil B et al (2015) Atlas of the clinical genetics of human dilated cardiomyopathy. Eur Heart J 36:1123–1135a

    Article  CAS  PubMed  Google Scholar 

  100. Harper AR, Goel A, Grace C et al (2021) Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity. Nat Genet 53:135–142

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Harrell DT, Ashihara T, Ishikawa T et al (2015) Genotype-dependent differences in age of manifestation and arrhythmia complications in short QT syndrome. Int J Cardiol 190:393–402

    Article  PubMed  Google Scholar 

  102. Hartung B, Tank A, Dittmann S et al (2021) A rare cause of sudden unexpected death syndrome (SUDS) in the first year of life: endomyocardial fibroelastosis (EFE) due to two compound heterozygous MYBPC3 mutations. BMC Cardiovasc Disord 21:174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Haywood AF, Merner ND, Hodgkinson KA et al (2013) Recurrent missense mutations in TMEM43 (ARVD5) due to founder effects cause arrhythmogenic cardiomyopathies in the UK and Canada. Eur Heart J 34:1002–1011

    Article  CAS  PubMed  Google Scholar 

  104. Hegele RA, Boren J, Ginsberg HN et al (2020) Rare dyslipidaemias, from phenotype to genotype to management: a European atherosclerosis society task force consensus statement. Lancet Diabetes Endocrinol 8:50–67

    Article  CAS  PubMed  Google Scholar 

  105. Heidbuchel H, Arbelo E, D’ascenzi F et al (2021) Recommendations for participation in leisure-time physical activity and competitive sports of patients with arrhythmias and potentially arrhythmogenic conditions. Part 2: ventricular arrhythmias, channelopathies, and implantable defibrillators. Europace 23:147–148

    Article  PubMed  Google Scholar 

  106. Hershberger RE, Givertz MM, Ho CY et al (2018) Genetic evaluation of cardiomyopathy—a heart failure society of america practice guideline. J Card Fail 24:281–302

    Article  PubMed  PubMed Central  Google Scholar 

  107. Hershberger RE, Givertz MM, Ho CY et al (2018) Genetic evaluation of cardiomyopathy: a clinical practice resource of the American college of medical genetics and genomics (ACMG). Genet Med 20:899–909

    Article  PubMed  Google Scholar 

  108. Hershberger RE, Hedges DJ, Morales A (2013) Dilated cardiomyopathy: the complexity of a diverse genetic architecture. Nat Rev Cardiol 10:531–547

    Article  CAS  PubMed  Google Scholar 

  109. Hirose S, Murayama T, Tetsuo N et al (2022) Loss-of-function mutations in cardiac ryanodine receptor channel cause various types of arrhythmias including long QT syndrome. Europace 24(3):497–510. https://doi.org/10.1093/europace/euab250

    Article  PubMed  Google Scholar 

  110. Ho CY, Day SM, Ashley EA et al (2018) Genotype and lifetime burden of disease in hypertrophic cardiomyopathy: insights from the sarcomeric human cardiomyopathy registry (SHaRe). Circulation 138:1387–1398

    Article  PubMed  PubMed Central  Google Scholar 

  111. Homsy J, Zaidi S, Shen Y et al (2015) De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies. Science 350:1262–1266

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Honarbakhsh S, Providencia R, Garcia-Hernandez J et al (2021) A primary prevention clinical risk score model for patients with Brugada syndrome (BRUGADA-RISK). JACC Clin Electrophysiol 7:210–222

    Article  PubMed  Google Scholar 

  113. Hosseini SM, Kim R, Udupa S et al (2018) Reappraisal of reported genes for sudden arrhythmic death: evidence-based evaluation of gene validity for Brugada syndrome. Circulation 138:1195–1205

    Article  PubMed  PubMed Central  Google Scholar 

  114. Hu D, Li Y, Zhang J et al (2017) The phenotypic spectrum of a mutation hotspot responsible for the short QT syndrome. JACC Clin Electrophysiol 3:727–743

    Article  PubMed  Google Scholar 

  115. Huang L, Wu KH, Zhang L et al (2018) Critical roles of Xirp proteins in cardiac conduction and their rare variants identified in sudden unexplained nocturnal death syndrome and Brugada syndrome in Chinese Han population. J Am Heart Assoc 7(1):e6320. https://doi.org/10.1161/JAHA.117.006320

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Huang PS, Hsieh CS, Chang SN et al (2020) Prevalence of sudden arrhythmic death syndrome-related genetic mutations in an Asian cohort of whole genome sequence. Europace 22:1287–1297

    Article  PubMed  Google Scholar 

  117. https://www.pharmgkb.org (Stand: Herbst 2022)

  118. https://drug-interactions.medicine.iu.edu/MainTable.aspx (Stand: Herbst 2022)

  119. http://flockharttable.org/ (Stand: Herbst 2022)

  120. https://www.gelbe-liste.de/arzneimitteltherapiesicherheit/cyp-interaktionen (Stand: Herbst 2022)

  121. Ingles J, Goldstein J, Thaxton C et al (2019) Evaluating the clinical validity of hypertrophic cardiomyopathy genes. Circ Genom Precis Med 12:e2460

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Isselbacher EM, Preventza O, Hamilton Black J 3rd et al (2022) 2022 ACC/AHA guideline for the diagnosis and management of aortic disease: a report of the American heart association/American college of cardiology joint committee on clinical practice guidelines. J Am Coll Cardiol 80:e223–e393

    Article  PubMed  Google Scholar 

  123. Itoh H, Crotti L, Aiba T et al (2016) The genetics underlying acquired long QT syndrome: impact for genetic screening. Eur Heart J 37:1456–1464

    Article  PubMed  Google Scholar 

  124. James CA, Jongbloed JDH, Hershberger RE et al (2021) International evidence based reappraisal of genes associated with arrhythmogenic right ventricular cardiomyopathy using the clinical genome resource framework. Circ Genom Precis Med 14:e3273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Januzzi JL, Marayati F, Mehta RH et al (2004) Comparison of aortic dissection in patients with and without Marfan’s syndrome (results from the international registry of aortic dissection). Am J Cardiol 94:400–402

    Article  PubMed  Google Scholar 

  126. Jenni R, Oechslin E, Schneider J et al (2001) Echocardiographic and pathoanatomical characteristics of isolated left ventricular non-compaction: a step towards classification as a distinct cardiomyopathy. Heart 86:666–671

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Jimmy Juang JM, Liu YB, Julius Chen CY et al (2020) Validation and disease risk assessment of previously reported genome-wide genetic variants associated with Brugada syndrome: SADS-TW brS registry. Circ Genom Precis Med 13:e2797

    Article  PubMed  PubMed Central  Google Scholar 

  128. Jin SC, Homsy J, Zaidi S et al (2017) Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands. Nat Genet 49:1593–1601

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Jondeau G, Ropers J, Regalado E et al (2016) International registry of patients carrying TGFBR1 or TGFBR2 mutations: results of the MAC (Montalcino aortic consortium). Circ Cardiovasc Genet 9:548–558

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Jordan E, Peterson L, Ai T et al (2021) Evidence-based assessment of genes in dilated cardiomyopathy. Circulation 144:7–19

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Juang JJ, Binda A, Lee SJ et al (2020) GSTM3 variant is a novel genetic modifier in Brugada syndrome, a disease with risk of sudden cardiac death. EBioMedicine 57:102843

    Article  PubMed  PubMed Central  Google Scholar 

  132. Kahlert A‑K, Hoff K, Hitz M‑P (2017) Genetik der angeborenen Herzfehler. medgen 29:248–256

    Article  CAS  Google Scholar 

  133. Kajiyama T, Miyazawa K, Kondo Y et al (2020) SCN5A mutation and a short coupled variant of Torsades de Pointes originating from the right ventricle: a case report. J Cardiol Cases 21:104–105

    Article  PubMed  Google Scholar 

  134. Kalia SS, Adelman K, Bale SJ et al (2017) 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 (vol 19, pg 249, 2016). Genet Med 19:484–485

    Article  Google Scholar 

  135. Kamp NJ, Chery G, Kosinski AS et al (2021) Risk stratification using late gadolinium enhancement on cardiac magnetic resonance imaging in patients with hypertrophic cardiomyopathy: a systematic review and meta-analysis. Prog Cardiovasc Dis 66:10–16

    Article  PubMed  Google Scholar 

  136. Kannankeril PJ, Moore JP, Cerrone M et al (2017) Efficacy of flecainide in the treatment of catecholaminergic polymorphic ventricular tachycardia: a randomized clinical trial. JAMA Cardiol 2:759–766

    Article  PubMed  PubMed Central  Google Scholar 

  137. Kapplinger JD, Pundi KN, Larson NB et al (2018) Yield of the RYR2 genetic test in suspected catecholaminergic polymorphic ventricular tachycardia and implications for test interpretation. Circ Genom Precis Med 11:e1424

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Kaski JP, Syrris P, Burch M et al (2008) Idiopathic restrictive cardiomyopathy in children is caused by mutations in cardiac sarcomere protein genes. Heart 94:1478–1484

    Article  CAS  PubMed  Google Scholar 

  139. Kayvanpour E, Sammani A, Sedaghat-Hamedani F et al (2021) A novel risk model for predicting potentially life-threatening arrhythmias in non-ischemic dilated cardiomyopathy (DCM-SVA risk). Int J Cardiol 339:75–82

    Article  PubMed  Google Scholar 

  140. Kayvanpour E, Sedaghat-Hamedani F, Amr A et al (2017) Genotype-phenotype associations in dilated cardiomyopathy: meta-analysis on more than 8000 individuals. Clin Res Cardiol 106:127–139

    Article  CAS  PubMed  Google Scholar 

  141. Kelly MA, Caleshu C, Morales A et al (2018) Adaptation and validation of the ACMG/AMP variant classification framework for MYH7-associated inherited cardiomyopathies: recommendations by ClinGen’s inherited cardiomyopathy expert panel. Genet Med 20:351–359

    Article  PubMed  PubMed Central  Google Scholar 

  142. Khera AV, Won HH, Peloso GM et al (2016) Diagnostic yield and clinical utility of sequencing familial hypercholesterolemia genes in patients with severe hypercholesterolemia. J Am Coll Cardiol 67:2578–2589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Kim JA, Chelu MG, Li N (2021) Genetics of atrial fibrillation. Curr Opin Cardiol 36:281–287

    Article  PubMed  PubMed Central  Google Scholar 

  144. Kimura M, Fujisawa T, Aizawa Y et al (2017) An RyR2 mutation found in a family with a short-coupled variant of torsade de pointes. Int J Cardiol 227:367–369

    Article  PubMed  Google Scholar 

  145. Klaassen S, Kühnisch J, Schultze-Berndt A et al (2022) Left ventricular noncompaction in children: the role of genetics, morphology, and function for outcome. J Cardiovasc Dev Dis 9(7):206

    CAS  PubMed  PubMed Central  Google Scholar 

  146. 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 

  147. Kohli SK, Pantazis AA, Shah JS et al (2008) Diagnosis of left-ventricular non-compaction in patients with left-ventricular systolic dysfunction: time for a reappraisal of diagnostic criteria? Eur Heart J 29:89–95

    Article  PubMed  Google Scholar 

  148. Kusumoto FM, Schoenfeld MH, Barrett C et al (2019) 2018 ACC/AHA/HRS guideline on the evaluation and management of patients with bradycardia and cardiac conduction delay: a report of the American college of cardiology/American heart association task force on clinical practice guidelines and the heart rhythm society. Circulation 140:e382–e482

    PubMed  Google Scholar 

  149. Lahrouchi N, Tadros R, Crotti L et al (2020) Transethnic genome-wide association study provides insights in the genetic architecture and heritability of long QT syndrome. Circulation 142:324–338

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Landstrom AP, Kim JJ, Gelb BD et al (2021) Genetic testing for heritable cardiovascular diseases in pediatric patients: a scientific statement from the American heart association. Circ Genomic Precis Med 14:e86

    Article  Google Scholar 

  151. Laurent G, Saal S, Amarouch MY et al (2012) Multifocal ectopic Purkinje-related premature contractions: a new SCN5A-related cardiac channelopathy. J Am Coll Cardiol 60:144–156

    Article  PubMed  Google Scholar 

  152. Lee YK, Sala L, Mura M et al (2021) MTMR4 SNVs modulate ion channel degradation and clinical severity in congenital long QT syndrome: insights in the mechanism of action of protective modifier genes. Cardiovasc Res 117:767–779

    Article  CAS  PubMed  Google Scholar 

  153. Lek M, Karczewski KJ, Minikel EV et al (2016) Analysis of protein-coding genetic variation in 60,706 humans. Nature 536:285–291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Liebrechts-Akkerman G, Liu F, van Marion R et al (2020) Explaining sudden infant death with cardiac arrhythmias: complete exon sequencing of nine cardiac arrhythmia genes in Dutch SIDS cases highlights new and known DNA variants. Forensic Sci Int Genet 46:102266

    Article  CAS  PubMed  Google Scholar 

  155. Linschoten M, Teske AJ, Baas AF et al (2017) Truncating titin (TTN) variants in chemotherapy-induced cardiomyopathy. J Card Fail 23:476–479

    Article  CAS  PubMed  Google Scholar 

  156. Loeys B, De Backer J, Van Acker P et al (2004) Comprehensive molecular screening of the FBN1 gene favors locus homogeneity of classical Marfan syndrome. Hum Mutat 24:140–146

    Article  CAS  PubMed  Google Scholar 

  157. Loeys BL, Chen J, Neptune ER et al (2005) A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet 37:275–281

    Article  CAS  PubMed  Google Scholar 

  158. 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 

  159. Loeys BL, Schwarze U, Holm T et al (2006) Aneurysm syndromes caused by mutations in the TGF-beta receptor. N Engl J Med 355:788–798

    Article  CAS  PubMed  Google Scholar 

  160. Lord J, Mcmullan DJ, Eberhardt RY et al (2019) Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): a cohort study. Lancet 393:747–757

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Luirink IK, Wiegman A, Kusters DM et al (2019) 20-year follow-up of statins in children with familial hypercholesterolemia. N Engl J Med 381:1547–1556

    Article  CAS  PubMed  Google Scholar 

  162. Maccarrick G, Black JH 3rd, Bowdin S et al (2014) Loeys-Dietz syndrome: a primer for diagnosis and management. Genet Med 16:576–587

    Article  PubMed  PubMed Central  Google Scholar 

  163. Mach F, Baigent C, Catapano AL et al (2020) 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 41:111–188

    Article  PubMed  Google Scholar 

  164. Mak CM, Mok NS, Shum HC et al (2019) Sudden arrhythmia death syndrome in young victims: a five-year retrospective review and two-year prospective molecular autopsy study by next-generation sequencing and clinical evaluation of their first-degree relatives. Hong Kong Med J 25:21–29

    CAS  PubMed  Google Scholar 

  165. Malfait F, Francomano C, Byers P et al (2017) The 2017 international classification of the Ehlers-Danlos syndromes. Am J Med Genet C Semin Med Genet 175:8–26

    Article  PubMed  Google Scholar 

  166. 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  PubMed Central  Google Scholar 

  167. Maron BJ (2002) Hypertrophic cardiomyopathy: a systematic review. JAMA 287:1308–1320

    Article  PubMed  Google Scholar 

  168. Maron BJ, Desai MY, Nishimura RA et al (2022) Diagnosis and evaluation of hypertrophic cardiomyopathy: JACC state-of-the-art review. J Am Coll Cardiol 79:372–389

    Article  PubMed  Google Scholar 

  169. Maron BJ, Towbin JA, Thiene G et al (2006) Contemporary definitions and classification of the cardiomyopathies: an American heart association scientific statement from the council on clinical cardiology, heart failure and transplantation committee; quality of care and outcomes research and functional genomics and translational biology interdisciplinary working groups; and council on epidemiology and prevention. Circulation 113:1807–1816

    Article  PubMed  Google Scholar 

  170. Marston NA, Han L, Olivotto I et al (2021) Clinical characteristics and outcomes in childhood-onset hypertrophic cardiomyopathy. Eur Heart J 42:1988–1996

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Marstrand P, Picard K, Lakdawala NK (2020) Second hits in dilated cardiomyopathy. Curr Cardiol Rep 22:8

    Article  PubMed  Google Scholar 

  172. Matthijs G, Souche E, Alders M et al (2016) Guidelines for diagnostic next-generation sequencing. Eur J Hum Genet 24:2–5

    Article  CAS  PubMed  Google Scholar 

  173. Mazzanti A, Maragna R, Vacanti G et al (2017) Hydroquinidine prevents life-threatening arrhythmic events in patients with short QT syndrome. J Am Coll Cardiol 70:3010–3015

    Article  CAS  PubMed  Google Scholar 

  174. Mazzanti A, Maragna R, Vacanti G et al (2018) Interplay between genetic substrate, QTc duration, and arrhythmia risk in patients with long QT syndrome. J Am Coll Cardiol 71:1663–1671

    Article  PubMed  Google Scholar 

  175. Mazzarotto F, Girolami F, Boschi B et al (2019) Defining the diagnostic effectiveness of genes for inclusion in panels: the experience of two decades of genetic testing for hypertrophic cardiomyopathy at a single center. Genet Med 21:284–292

    Article  CAS  PubMed  Google Scholar 

  176. Mazzarotto F, Hawley MH, Beltrami M et al (2021) Systematic large-scale assessment of the genetic architecture of left ventricular noncompaction reveals diverse etiologies. Genet Med 23(5):856–864. https://doi.org/10.1038/s41436-020-01049-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Mcdonagh TA, Metra M, Adamo M et al (2021) 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 42:3599–3726

    Article  CAS  PubMed  Google Scholar 

  178. Mckenna WJ, Maron BJ, Thiene G (2017) Classification, epidemiology, and global burden of cardiomyopathies. Circ Res 121:722–730

    Article  CAS  PubMed  Google Scholar 

  179. Mcnally EM, Mestroni L (2017) Dilated cardiomyopathy: genetic determinants and mechanisms. Circ Res 121:731–748

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Meester JAN, Verstraeten A, Schepers D et al (2017) Differences in manifestations of Marfan syndrome, Ehlers-Danlos syndrome, and Loeys-Dietz syndrome. Ann Cardiothorac Surg 6:582–594

    Article  PubMed  PubMed Central  Google Scholar 

  181. Mehta A, Ramachandra CJA, Singh P et al (2018) Identification of a targeted and testable antiarrhythmic therapy for long-QT syndrome type 2 using a patient-specific cellular model. Eur Heart J 39:1446–1455

    Article  CAS  PubMed  Google Scholar 

  182. Mellor GJ, Blom LJ, Groeneveld SA et al (2021) Familial evaluation in idiopathic ventricular fibrillation: diagnostic yield and significance of J wave syndromes. Circ Arrhythm Electrophysiol 14:e9089

    Article  CAS  PubMed  Google Scholar 

  183. Milewicz DM, Østergaard JR, Ala-Kokko LM et al (2010) De novo ACTA2 mutation causes a novel syndrome of multisystemic smooth muscle dysfunction. Am J Med Genet A 152A:2437–2443

    Article  PubMed  PubMed Central  Google Scholar 

  184. Milewicz DM, Regalado E (2017) Heritable thoracic aortic disease overview

    Google Scholar 

  185. Miller DT, Lee K, Gordon AS et al (2021) Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2021 update: a policy statement of the American college of medical genetics and genomics (ACMG). Genet Med 23:1391–1398

    Article  PubMed  Google Scholar 

  186. Milman A, Andorin A, Gourraud JB et al (2018) Profile of patients with Brugada syndrome presenting with their first documented arrhythmic event: data from the survey on arrhythmic events in BRUgada syndrome (SABRUS). Heart Rhythm 15:716–724

    Article  PubMed  Google Scholar 

  187. Miron A, Lafreniere-Roula M, Steve Fan CP et al (2020) A validated model for sudden cardiac death risk prediction in pediatric hypertrophic cardiomyopathy. Circulation 142:217–229

    Article  PubMed  PubMed Central  Google Scholar 

  188. Mital S, Musunuru K, Garg V et al (2016) Enhancing literacy in cardiovascular genetics: a scientific statement from the American heart association. Circ Cardiovasc Genet 9:448–467

    Article  CAS  PubMed  Google Scholar 

  189. Muchtar E, Blauwet LA, Gertz MA (2017) Restrictive cardiomyopathy: genetics, pathogenesis, clinical manifestations, diagnosis, and therapy. Circ Res 121:819–837

    Article  CAS  PubMed  Google Scholar 

  190. Mühlstädt K, De Backer J, von Kodolitsch Y et al (2019) Case-matched comparison of cardiovascular outcome in Loeys-Dietz syndrome versus Marfan syndrome. J Clin Med 8:E2079

    Article  Google Scholar 

  191. Mulder BJM, van de Laar IMBH, De Backer J (2020) Heritable thoracic aortic diseases: syndromal and isolated (F)TAAD. In: Baars HF, Doevendans PAFM, Houweling AC, van Tintelen JP (Hrsg) Clinical cardiogenetics. Springer, Cham, S 309–343

    Chapter  Google Scholar 

  192. Musunuru K, Hershberger RE, Day SM et al (2020) Genetic testing for inherited cardiovascular diseases: a scientific statement from the American heart association. Circ Genom Precis Med 13:e67

    Article  PubMed  Google Scholar 

  193. Musunuru K, Hickey KT, Al-Khatib SM et al (2015) Basic concepts and potential applications of genetics and genomics for cardiovascular and stroke clinicians: a scientific statement from the American heart association. Circ Cardiovasc Genet 8:216–242

    Article  PubMed  PubMed Central  Google Scholar 

  194. Nafissi NA, Abdulrahim JW, Kwee LC et al (2022) Prevalence and phenotypic burden of monogenic arrhythmias using integration of electronic health records with genetics. Circ Genom Precis Med 15:e3675

    Article  CAS  PubMed  Google Scholar 

  195. Naraen A, Mckay V, Shaw M et al (2020) Clinical predictors of informative genetic testing in hypertrophic cardiomyopathy. Eur J Prev Cardiol 27:777–779

    Article  PubMed  Google Scholar 

  196. Neves R, Tester DJ, Simpson MA et al (2022) Exome sequencing highlights a potential role for concealed cardiomyopathies in youthful sudden cardiac death. Circ Genom Precis Med 15:e3497

    Article  CAS  PubMed  Google Scholar 

  197. Nordestgaard BG, Chapman MJ, Humphries SE et al (2013) Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European atherosclerosis society. Eur Heart J 34:3478–3490a

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Norrish G, Ding T, Field E et al (2019) Development of a novel risk prediction model for sudden cardiac death in childhood hypertrophic cardiomyopathy (HCM risk-kids). JAMA Cardiol 4:918–927

    Article  PubMed  PubMed Central  Google Scholar 

  199. Norrish G, Kolt G, Cervi E et al (2021) Clinical presentation and long-term outcomes of infantile hypertrophic cardiomyopathy: a European multicentre study. ESC Heart Fail 8:5057–5067

    Article  PubMed  PubMed Central  Google Scholar 

  200. O’mahony C, Jichi F, Pavlou M et al (2014) A novel clinical risk prediction model for sudden cardiac death in hypertrophic cardiomyopathy (HCM risk-SCD). Eur Heart J 35:2010–2020

    Article  PubMed  Google Scholar 

  201. O’sullivan JW, Raghavan S, Marquez-Luna C et al (2022) Polygenic risk scores for cardiovascular disease: a scientific statement from the. Am Heart Assoc Circ 146:e93–e118

    Google Scholar 

  202. Oechslin E, Jenni R, Klaassen S (2021) Left ventricular noncompaction is a myocardial phenotype: cardiomyopathy-yes or no? Can J Cardiol 37:366–369

    Article  PubMed  Google Scholar 

  203. Oechslin EN, Attenhofer Jost CH, Rojas JR et al (2000) Long-term follow-up of 34 adults with isolated left ventricular noncompaction: a distinct cardiomyopathy with poor prognosis. J Am Coll Cardiol 36:493–500

    Article  CAS  PubMed  Google Scholar 

  204. Offerhaus JA, Bezzina CR, Wilde AAM (2020) Epidemiology of inherited arrhythmias. Nat Rev Cardiol 17:205–215

    Article  PubMed  Google Scholar 

  205. Olivotto I, Oreziak A, Barriales-Villa R et al (2020) Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 396:759–769

    Article  CAS  PubMed  Google Scholar 

  206. Ommen SR, Mital S, Burke MA et al (2020) 2020 AHA/ACC guideline for the diagnosis and treatment of patients with hypertrophic cardiomyopathy: a report of the American college of cardiology/American heart association joint committee on clinical practice guidelines. J Am Coll Cardiol 76:e159–e240

    Article  PubMed  Google Scholar 

  207. Overwater E, Marsili L, Baars MJH et al (2018) Results of next-generation sequencing gene panel diagnostics including copy-number variation analysis in 810 patients suspected of heritable thoracic aortic disorders. Hum Mutat 39:1173–1192

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Papadakis M, Papatheodorou E, Mellor G et al (2018) The diagnostic yield of Brugada syndrome after sudden death with normal autopsy. J Am Coll Cardiol 71:1204–1214

    Article  PubMed  Google Scholar 

  209. Peled Y, Gramlich M, Yoskovitz G et al (2014) Titin mutation in familial restrictive cardiomyopathy. Int J Cardiol 171:24–30

    Article  PubMed  Google Scholar 

  210. Peltenburg PJ, Kallas D, Bos JM et al (2022) An international multicenter cohort study on β‑blockers for the treatment of symptomatic children with catecholaminergic polymorphic ventricular tachycardia. Circulation 145:333–344

    Article  CAS  PubMed  Google Scholar 

  211. Pereira NL, Grogan M, Dec GW (2018) Spectrum of restrictive and infiltrative cardiomyopathies: part 1 of a 2-part series. J Am Coll Cardiol 71:1130–1148

    Article  PubMed  Google Scholar 

  212. Pereira NL, Grogan M, Dec GW (2018) Spectrum of restrictive and infiltrative cardiomyopathies: part 2 of a 2-part series. J Am Coll Cardiol 71:1149–1166

    Article  PubMed  Google Scholar 

  213. Pierpont ME, Brueckner M, Chung WK et al (2018) Genetic basis for congenital heart disease: revisited: a scientific statement from the American heart association. Circulation 138:e653–e711

    Article  PubMed  PubMed Central  Google Scholar 

  214. Pinto YM, Elliott PM, Arbustini E et al (2016) Proposal for a revised definition of dilated cardiomyopathy, hypokinetic non-dilated cardiomyopathy, and its implications for clinical practice: a position statement of the ESC working group on myocardial and pericardial diseases. Eur Heart J 37:1850–1858

    Article  PubMed  Google Scholar 

  215. Plon SE, Eccles DM, Easton D et al (2008) Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results. Hum Mutat 29:1282–1291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Ponikowski P, Voors AA, Anker SD et al (2016) 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the European society of cardiology (ESC) developed with the special contribution of the heart failure association (HFA) of the ESC. Eur Heart J 37:2129–2200

    Article  PubMed  Google Scholar 

  217. Porta-Sanchez A, Priori SG (2021) Genetic abnormalities of the sinoatrial node and atrioventricular conduction. Card Electrophysiol Clin 13:625–639

    Article  PubMed  Google Scholar 

  218. Priori SG, Blomstrom-Lundqvist C (2015) 2015 European society of cardiology guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death summarized by co-chairs. Eur Heart J 36:2757–2759

    Article  PubMed  Google Scholar 

  219. Priori SG, Napolitano C, Schwartz PJ (1999) Low penetrance in the long-QT syndrome: clinical impact. Circulation 99:529–533

    Article  CAS  PubMed  Google Scholar 

  220. Priori SG, Wilde AA, Horie M et al (2013) 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 10:1932–1963

    Article  PubMed  Google Scholar 

  221. Probst V, Goronflot T, Anys S et al (2021) Robustness and relevance of predictive score in sudden cardiac death for patients with Brugada syndrome. Eur Heart J 42:1687–1695

    Article  PubMed  Google Scholar 

  222. Protonotarios N, Tsatsopoulou A (2004) Naxos disease and Carvajal syndrome: cardiocutaneous disorders that highlight the pathogenesis and broaden the spectrum of arrhythmogenic right ventricular cardiomyopathy. Cardiovasc Pathol 13:185–194

    Article  CAS  PubMed  Google Scholar 

  223. Pruszczyk P, Kostera-Pruszczyk A, Shatunov A et al (2007) Restrictive cardiomyopathy with atrioventricular conduction block resulting from a desmin mutation. Int J Cardiol 117:244–253

    Article  PubMed  Google Scholar 

  224. Purevjav E, Arimura T, Augustin S et al (2012) Molecular basis for clinical heterogeneity in inherited cardiomyopathies due to myopalladin mutations. Hum Mol Genet 21:2039–2053

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Pyeritz R, Jondeau G, Moran R et al (2014) Loeys-Dietz syndrome is a specific phenotype and not a concomitant of any mutation in a gene involved in TGF-beta signaling. Genet Med 16:641–642

    Article  CAS  PubMed  Google Scholar 

  226. Quarta G, Muir A, Pantazis A et al (2011) Familial evaluation in arrhythmogenic right ventricular cardiomyopathy: impact of genetics and revised task force criteria. Circulation 123:2701–2709

    Article  PubMed  Google Scholar 

  227. Raschwitz LS, El-Battrawy I, Schlentrich K et al (2019) Differences in short QT syndrome subtypes: a systematic literature review and pooled analysis. Front Genet 10:1312

    Article  CAS  PubMed  Google Scholar 

  228. Rehm HL, Bale SJ, Bayrak-Toydemir P et al (2013) ACMG clinical laboratory standards for next-generation sequencing. Genet Med 15:733–747

    Article  PubMed  PubMed Central  Google Scholar 

  229. Rehm HL, Berg JS, Brooks LD et al (2015) ClinGen—the clinical genome resource. N Engl J Med 372:2235–2242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Renard M, Francis C, Ghosh R et al (2018) Clinical validity of genes for heritable thoracic aortic aneurysm and dissection. J Am Coll Cardiol 72:605–615

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. Richards S, Aziz N, Bale S et al (2015) 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 17:405–424

    Article  PubMed  PubMed Central  Google Scholar 

  232. Richmond CM, James PA, Pantaleo SJ et al (2021) Clinical and laboratory reporting impact of ACMG-AMP and modified ClinGen variant classification frameworks in MYH7-related cardiomyopathy. Genet Med 23:1108–1115

    Article  CAS  PubMed  Google Scholar 

  233. Riggs ER, Andersen EF, Cherry AM et al (2020) Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American college of medical genetics and genomics (ACMG) and the clinical genome resource (ClinGen). Genet Med 22:245–257

    Article  PubMed  Google Scholar 

  234. Roberts JD, Asaki SY, Mazzanti A et al (2020) An international multicenter evaluation of type 5 long QT syndrome: a low penetrant primary arrhythmic condition. Circulation 141:429–439

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  235. Rojanasopondist P, Nesheiwat L, Piombo S et al (2022) Genetic basis of left ventricular noncompaction. Circ Genom Precis Med 15:e3517

    Article  CAS  PubMed  Google Scholar 

  236. Roston TM, Wei J, Guo W et al (2022) Clinical and functional characterization of ryanodine receptor 2 variants implicated in calcium-release deficiency syndrome. JAMA Cardiol 7:84–92

    Article  PubMed  Google Scholar 

  237. Rowin EJ, Maron BJ, Haas TS et al (2017) Hypertrophic cardiomyopathy with left ventricular apical aneurysm: implications for risk stratification and management. J Am Coll Cardiol 69:761–773

    Article  PubMed  Google Scholar 

  238. Rucinski C, Winbo A, Marcondes L et al (2020) A population-based registry of patients with inherited cardiac conditions and resuscitated cardiac arrest. J Am Coll Cardiol 75:2698–2707

    Article  CAS  PubMed  Google Scholar 

  239. Rüping U et al (2022) Ärztliche Aufklärungspflichten über die Möglichkeit von Nebenbefunden in der genomischen Medizin. MedR 40:663–667

    Article  Google Scholar 

  240. Rybczynski M, Bernhardt AMJ, Rehder U et al (2008) The spectrum of syndromes and manifestations in individuals screened for suspected Marfan syndrome. Am J Med Genet A 146A:3157–3166

    Article  PubMed  Google Scholar 

  241. Sammani A, Kayvanpour E, Bosman LP et al (2020) Predicting sustained ventricular arrhythmias in dilated cardiomyopathy: a meta-analysis and systematic review. ESC Heart Fail 7:1430–1441

    Article  PubMed  PubMed Central  Google Scholar 

  242. Schmidtke J et al (2022) Nebenbefunde in der Genommedizin: Rechtliche Sprengkraft. Dtsch Arztebl Int 119:29–30

    Google Scholar 

  243. Schultheiss HP, Fairweather D, Caforio ALP et al (2019) Dilated cardiomyopathy. Nat Rev Dis Primers 5:32

    Article  PubMed  PubMed Central  Google Scholar 

  244. Schultze-Berndt A, Kuhnisch J, Herbst C et al (2021) Reduced systolic function and not genetic variants determine outcome in pediatric and adult left ventricular noncompaction cardiomyopathy. Front Pediatr 9:722926

    Article  PubMed  PubMed Central  Google Scholar 

  245. Schulze-Bahr E, Dettmeyer RB, Klingel K et al (2021) Postmortale molekulargenetische Untersuchungen (molekulare Autopsie) bei kardiovaskulären und bei ungeklärten Todesfällen. Kardiologe 15:176–193

    Article  Google Scholar 

  246. Schulze-Bahr E, Klaassen S, Abdul-Khaliq H et al (2015) Gendiagnostik bei kardiovaskulären Erkrankungen. Kardiologe 9:213–243

    Article  CAS  Google Scholar 

  247. Schulze-Bahr E, Klaassen S, Abdul-Khaliq H et al (2015) Molecular diagnosis for cardiovascular diseases. Dtsch Med Wochenschr 140:1538

    PubMed  Google Scholar 

  248. Schwartz PJ, Ackerman MJ, Antzelevitch C et al (2020) Inherited cardiac arrhythmias. Nat Rev Dis Primers 6:58

    Article  PubMed  PubMed Central  Google Scholar 

  249. Schwartz PJ, Crotti L (2011) QTc behavior during exercise and genetic testing for the long-QT syndrome. Circulation 124:2181–2184

    Article  PubMed  Google Scholar 

  250. Schwartz PJ, Gnecchi M, Dagradi F et al (2019) From patient-specific induced pluripotent stem cells to clinical translation in long QT syndrome type 2. Eur Heart J 40:1832–1836

    Article  CAS  PubMed  Google Scholar 

  251. Schwartz PJ, Priori SG, Spazzolini C et al (2001) Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias. Circulation 103:89–95

    Article  CAS  PubMed  Google Scholar 

  252. Schwartz PJ, Stramba-Badiale M, Crotti L et al (2009) Prevalence of the congenital long-QT syndrome. Circulation 120:1761–1767

    Article  PubMed  PubMed Central  Google Scholar 

  253. Schwartz PJ, Woosley RL (2016) Predicting the unpredictable: drug-induced QT prolongation and Torsades de pointes. J Am Coll Cardiol 67:1639–1650

    Article  PubMed  Google Scholar 

  254. Sedaghat-Hamedani F, Haas J, Zhu F et al (2017) Clinical genetics and outcome of left ventricular non-compaction cardiomyopathy. Eur Heart J 38:3449–3460

    Article  CAS  PubMed  Google Scholar 

  255. Sedaghat-Hamedani F, Kayvanpour E, Tugrul OF et al (2018) Clinical outcomes associated with sarcomere mutations in hypertrophic cardiomyopathy: a meta-analysis on 7675 individuals. Clin Res Cardiol 107:30–41

    Article  PubMed  Google Scholar 

  256. Shalhub S, Byers PH, Hicks KL et al (2020) A multi-institutional experience in vascular Ehlers-Danlos syndrome diagnosis. J Vasc Surg 71:149–157

    Article  PubMed  Google Scholar 

  257. Sheikhzadeh S, Kusch ML, Rybczynski M et al (2012) A simple clinical model to estimate the probability of Marfan syndrome. QJM 105:527–535

    Article  CAS  PubMed  Google Scholar 

  258. Shimizu A, Zankov DP, Sato A et al (2020) Identification of transmembrane protein 168 mutation in familial Brugada syndrome. Faseb J 34:6399–6417

    Article  CAS  PubMed  Google Scholar 

  259. Sifrim A, Hitz MP, Wilsdon A et al (2016) Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing. Nat Genet 48:1060–1065

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  260. Sinagra G, Elliott PM, Merlo M (2020) Dilated cardiomyopathy: so many cardiomyopathies! Eur Heart J 41:3784–3786

    Article  CAS  PubMed  Google Scholar 

  261. Smith ED, Lakdawala NK, Papoutsidakis N et al (2020) Desmoplakin cardiomyopathy, a fibrotic and inflammatory form of cardiomyopathy distinct from typical dilated or arrhythmogenic right ventricular cardiomyopathy. Circulation 141:1872–1884

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  262. Smogavec M, Neesen J, Laccone F (2019) Genetische Diagnostik. Wien Klin Wochenschr Educ 14:29–47

    Article  Google Scholar 

  263. Sonoda K, Ohno S, Shimizu Y et al (2020) SCN5A mutation identified in a patient with short-coupled variant of torsades de pointes. Pacing Clin Electrophysiol 43:456–461

    Article  PubMed  Google Scholar 

  264. Spertus JA, Fine JT, Elliott P et al (2021) Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): health status analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 397:2467–2475

    Article  CAS  PubMed  Google Scholar 

  265. Sreenivasan S, Monaghan M, Baranchuk A (2018) Multifactorial Brugada phenocopy. JAMA Intern Med 178:872–873

    Article  PubMed  Google Scholar 

  266. Stiles MK, Wilde AAM, Abrams DJ et al (2021) 2020 APHRS/HRS expert consensus statement on the investigation of decedents with sudden unexplained death and patients with sudden cardiac arrest, and of their families. Heart Rhythm 18:e1–e50

    Article  PubMed  Google Scholar 

  267. Strauss DG, Vicente J, Johannesen L et al (2017) Common genetic variant risk score is associated with drug-induced QT prolongation and Torsade de pointes risk: a pilot study. Circulation 135:1300–1310

    Article  PubMed  PubMed Central  Google Scholar 

  268. Sturm AC, Knowles JW, Gidding SS et al (2018) Clinical genetic testing for familial hypercholesterolemia: JACC scientific expert panel. J Am Coll Cardiol 72:662–680

    Article  PubMed  Google Scholar 

  269. Sun B, Yao J, Ni M et al (2021) Cardiac ryanodine receptor calcium release deficiency syndrome. Sci Transl Med 13(579):eaba7287. https://doi.org/10.1126/scitranslmed.aba7287

    Article  CAS  PubMed  Google Scholar 

  270. Tada H, Nomura A, Ogura M et al (2021) Diagnosis and management of sitosterolemia 2021. J Atheroscler Thromb 28:791–801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  271. Tadros R, Francis C, Xu X et al (2021) Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect. Nat Genet 53:128–134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  272. Tadros R, Nannenberg EA, Lieve KV et al (2017) Yield and pitfalls of ajmaline testing in the evaluation of unexplained cardiac arrest and sudden unexplained death: single-center experience with 482 families. JACC Clin Electrophysiol 3:1400–1408

    Article  PubMed  Google Scholar 

  273. Takagi H, Umemoto T (2016) Simple renal cyst and abdominal aortic aneurysm. J Vasc Surg 63:254–259.e1

    Article  PubMed  Google Scholar 

  274. Talmud PJ, Shah S, Whittall R et al (2013) Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study. Lancet 381:1293–1301

    Article  CAS  PubMed  Google Scholar 

  275. Tan HL, Hofman N, van Langen IM et al (2005) Sudden unexplained death: heritability and diagnostic yield of cardiological and genetic examination in surviving relatives. Circulation 112:207–213

    Article  PubMed  Google Scholar 

  276. Taylor MR, Fain PR, Sinagra G et al (2003) Natural history of dilated cardiomyopathy due to lamin A/C gene mutations. J Am Coll Cardiol 41:771–780

    Article  CAS  PubMed  Google Scholar 

  277. Towbin JA, Mckenna WJ, Abrams DJ et al (2019) 2019 HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy. Heart Rhythm 16:e301–e372

    Article  PubMed  Google Scholar 

  278. Watkins WS, Hernandez EJ, Wesolowski S et al (2019). De novo and recessive forms of congenital heart disease have distinct genetic and phenotypic landscapes. Nat Commun 10:4722

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  279. Vaidya VR, Lyle M, Miranda WR et al (2021) Long-term survival of patients with left ventricular noncompaction. J Am Heart Assoc 10:e15563

    Article  PubMed  PubMed Central  Google Scholar 

  280. van de Laar I, Arbustini E, Loeys B et al (2019) European reference network for rare vascular diseases (VASCERN) consensus statement for the screening and management of patients with pathogenic ACTA2 variants. Orphanet J Rare Dis 14:264

    Article  PubMed  PubMed Central  Google Scholar 

  281. van der Zwaag PA, van Rijsingen IA, Asimaki A et al (2012) Phospholamban R14del mutation in patients diagnosed with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy: evidence supporting the concept of arrhythmogenic cardiomyopathy. Eur J Heart Fail 14:1199–1207

    Article  PubMed  PubMed Central  Google Scholar 

  282. van Rijsingen IA, 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 

  283. van Waning JI, Caliskan K, Hoedemaekers YM et al (2018) Genetics, clinical features, and long-term outcome of noncompaction cardiomyopathy. J Am Coll Cardiol 71:711–722

    Article  PubMed  Google Scholar 

  284. Vardarli I, Weber M, Rischpler C et al (2021) Fabry cardiomyopathy: current treatment and future options. J Clin Med 10(14):3026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  285. Verstraelen TE, van Lint FHM, Bosman LP et al (2021) Prediction of ventricular arrhythmia in phospholamban p.Arg14del mutation carriers-reaching the frontiers of individual risk prediction. Eur Heart J 42:2842–2850

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  286. Vink AS, Neumann B, Lieve KVV et al (2018) Determination and interpretation of the QT interval. Circulation 138:2345–2358

    Article  PubMed  Google Scholar 

  287. Voigt N, Ort K, Sossalla S (2019) Drug-drug interactions you should know! Dtsch Med Wochenschr 144:264–275

    CAS  PubMed  Google Scholar 

  288. von Kodolitsch Y, De Backer J, Schüler H et al (2015) Perspectives on the revised Ghent criteria for the diagnosis of Marfan syndrome. Appl Clin Genet 8:137–155

    Article  Google Scholar 

  289. von Kodolitsch Y, Kutsche K (2017) Genetic diagnostics of inherited aortic diseases : medical strategy analysis. Herz 42:459–467

    Article  Google Scholar 

  290. von Kodolitsch Y, Rybczynski M, Vogler M et al (2016) The role of the multidisciplinary health care team in the management of patients with Marfan syndrome. J Multidiscip Healthc 9:587–614

    Article  Google Scholar 

  291. Walsh R, Adler A, Amin AS et al (2021) Evaluation of gene validity for CPVT and short QT syndrome in sudden arrhythmic death. Eur Heart J 43(15):1500–1510. https://doi.org/10.1093/eurheartj/ehab687

    Article  CAS  PubMed Central  Google Scholar 

  292. Walsh R, Lahrouchi N, Tadros R et al (2021) Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls. Genet Med 23:47–58

    Article  CAS  PubMed  Google Scholar 

  293. Walsh R, Offerhaus JA, Tadros R et al (2022) Minor hypertrophic cardiomyopathy genes, major insights into the genetics of cardiomyopathies. Nat Rev Cardiol 19:151–167

    Article  PubMed  Google Scholar 

  294. Walsh R, Thomson KL, Ware JS et al (2017) Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med 19:192–203

    Article  PubMed  Google Scholar 

  295. Ware JS, Amor-Salamanca A, Tayal U et al (2018) Genetic etiology for alcohol-induced cardiac toxicity. J Am Coll Cardiol 71:2293–2302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  296. Ware JS, Li J, Mazaika E et al (2016) Shared genetic predisposition in peripartum and dilated cardiomyopathies. N Engl J Med 374:233–241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  297. Watkins WS, Hernandez EJ, Wesolowski S et al (2019) De novo and recessive forms of congenital heart disease have distinct genetic and phenotypic landscapes. Nat Commun 10(1):4722. https://doi.org/10.1038/s41467-019-12582-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  298. Weerakkody R, Ross D, Parry DA et al (2018) Targeted genetic analysis in a large cohort of familial and sporadic cases of aneurysm or dissection of the thoracic aorta. Genet Med 20:1414–1422

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  299. Weinrich JM, Lenz A, Girdauskas E et al (2019) Current and emerging imaging techniques in patients with genetic aortic syndromes. RoFo 192(1):50–58. https://doi.org/10.1055/a-0914-3321

    Article  PubMed  Google Scholar 

  300. Weinsaft JW, Devereux RB, Preiss LR et al (2016) Aortic dissection in patients with genetically mediated aneurysms: incidence and predictors in the genTAC registry. J Am Coll Cardiol 67:2744–2754

    Article  PubMed  PubMed Central  Google Scholar 

  301. Wilcox JE, Hershberger RE (2018) Genetic cardiomyopathies. Curr Opin Cardiol 33:354–362

    Article  PubMed  Google Scholar 

  302. Wilde Aa M, Amin AS (2018) Clinical spectrum of SCN5A mutations: long QT syndrome, Brugada syndrome, and cardiomyopathy. JACC Clin Electrophysiol 4:569–579

    Article  PubMed  Google Scholar 

  303. Wilde AAM, Semsarian C, Marquez MF et al (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. Europace 24(8):1307–1367. https://doi.org/10.1093/europace/euac030

    Article  PubMed  PubMed Central  Google Scholar 

  304. Williams K, Carson J, Lo C (2019) Genetics of congenital heart disease. Biomolecules 9(12):879. https://doi.org/10.3390/biom9120879

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  305. Wilson KL, Czerwinski JL, Hoskovec JM et al (2013) NSGC practice guideline: prenatal screening and diagnostic testing options for chromosome aneuploidy. J Genet Counsel 22:4–15

    Article  CAS  Google Scholar 

  306. Wooderchak-Donahue W, Vansant-Webb C, Tvrdik T et al (2015) Clinical utility of a next generation sequencing panel assay for Marfan and Marfan-like syndromes featuring aortopathy. Am J Med Genet A 167a:1747–1757

    Article  PubMed  Google Scholar 

  307. Yamagata K, Horie M, Aiba T et al (2017) Genotype-phenotype correlation of SCN5A mutation for the clinical and electrocardiographic characteristics of probands with Brugada syndrome: a Japanese multicenter registry. Circulation 135:2255–2270

    Article  CAS  PubMed  Google Scholar 

  308. Yang A, Alankarage D, Cuny H et al (2022) CHDgene: a curated database for congenital heart disease genes. Circ Genom Precis Med 15:e3539

    Article  CAS  PubMed  Google Scholar 

  309. Yuan SM (2019) Fetal arrhythmias: genetic background and clinical implications. Pediatr Cardiol 40:247–256

    Article  PubMed  Google Scholar 

  310. 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  PubMed Central  Google Scholar 

  311. Zegkos T, Panagiotidis T, Parcharidou D et al (2021) Emerging concepts in arrhythmogenic dilated cardiomyopathy. Heart Fail Rev 26:1219–1229

    Article  PubMed  Google Scholar 

  312. Zeppenfeld K, Tfelt-Hansen J, de Riva M et al (2022) 2022 ESC guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur Heart J 43(40):3997–4126. https://doi.org/10.1093/eurheartj/ehac262

    Article  PubMed  Google Scholar 

  313. Zhang ZH, Barajas-Martinez H, Xia H et al (2021) Distinct features of probands with early repolarization and Brugada syndromes carrying SCN5A pathogenic variants. J Am Coll Cardiol 78:1603–1617

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  314. Ziganshin BA, Bailey AE, Coons C et al (2015) Routine genetic testing for thoracic aortic aneurysm and dissection in a clinical setting. Ann Thorac Surg 100:1604–1611

    Article  PubMed  Google Scholar 

  315. Ziganshin BA, Theodoropoulos P, Salloum MN et al (2016) Simple renal cysts as markers of thoracic aortic disease. J Am Heart Assoc 5:e2248

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

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

    E. Schulze-Bahr

  2. ERN Guard-HEART, Referenzzentrum für seltene Herzerkrankungen, Münster, Deutschland

    E. Schulze-Bahr

  3. Klinik für Angeborene Herzfehler – Kinderkardiologie, Deutsches Herzzentrum der Charité (DHZC) und Experimental and Clinical Research Center (ECRC), Charité – Universitätsmedizin Berlin und Max-Delbrück-Center, Berlin und DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Deutschland

    S. Klaassen

  4. Deutsches Zentrum für Herzinsuffizienz und Medizinische Klinik und Poliklinik I, Universitätsklinikum Würzburg, Würzburg, Deutschland

    B. Gerull

  5. Klinik und Poliklinik für Gefäßmedizin, Universitäres Herz- und Gefäßzentrum Hamburg (UHZ), Universitätsklinik Hamburg-Eppendorf (UKE), Hamburg, Deutschland

    Y. von Kodolitsch

  6. Deutsches Herzzentrum der Charité, Klinik für Kardiologie, Angiologie und Intensivmedizin, Berlin Institute of Health at Charité – Universitätsmedizin Berlin, DZHK (German Centre for Cardiovascular Research), partner site Berlin, Berlin, Deutschland

    U. Landmesser

  7. Institut für Medizinische Genetik und Angewandte Genomik, Universität Tübingen, Tübingen, Deutschland

    O. Rieß

  8. Kardiogenetikzentrum Heidelberg, Institut für Cardiomyopathien Heidelberg, Universitätsklinikum Heidelberg, Heidelberg, Deutschland

    B. Meder

  9. 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

  10. Kommission für Klinische Kardiovaskuläre Medizin, Deutsche Gesellschaft für Kardiologie, Düsseldorf, Deutschland

    U. Landmesser

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. B. Gerull
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Y. von Kodolitsch
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. U. Landmesser
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. O. Rieß
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. B. Meder
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. H. Schunkert
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E. Schulze-Bahr.

Ethics declarations

Interessenkonflikt

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

Additional information

Der Verlag veröffentlicht die Beiträge in der von den Autorinnen und Autoren gewählten Genderform. Bei der Verwendung des generischen Maskulinums als geschlechtsneutrale Form sind alle Geschlechter impliziert.

figure qr

QR-Code scannen & Beitrag online lesen

Anhang

Anhang

Tab. 23 Richtlinien und Empfehlungen
Full size table
Tab. 24 ClinGen-Gene mit „limited disease evidence“ (potenzielle Krankheitsgene) [229]
Full size table

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., Gerull, B. et al. Gendiagnostik bei kardiovaskulären Erkrankungen. Kardiologie 17, 300–349 (2023). https://doi.org/10.1007/s12181-023-00622-3

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12181-023-00622-3

Schlüsselwörter

Keywords

Search

Navigation