Post-mortem genetic testing in sudden cardiac death and genetic screening of relatives at risk: lessons learned from a Czech pilot multidisciplinary study

. 2023 Nov ; 137 (6) : 1787-1801. [epub] 20230513

Jazyk angličtina Země Německo Médium print-electronic

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/pmid37178278

Grantová podpora
NV18-02-00237 Ministry of Health, Czech Republic
NV15-27682A Ministry of Health, Czech Republic
CZ.2.16/3.1.00/24022 European Regional Development Fund
NF-CZ11-PDP-3-003-2014 Norway Grants

Odkazy

PubMed 37178278
PubMed Central PMC10567875
DOI 10.1007/s00414-023-03007-z
PII: 10.1007/s00414-023-03007-z
Knihovny.cz E-zdroje

Sudden cardiac death (SCD) might have an inherited cardiac condition background. Genetic testing supports post-mortem diagnosis and screening of relatives at risk. Our aim is to determine the feasibility of a Czech national collaboration group and to establish the clinical importance of molecular autopsy and family screening. From 2016 to 2021, we have evaluated 100 unrelated SCD cases (71.0% males, age: 33.3 (12.8) years). Genetic testing was performed by next-generation sequencing utilizing a panel of 100 genes related to inherited cardiac/aortic conditions and/or whole exome sequencing. According to autopsy, cases were divided into cardiomyopathies, sudden arrhythmic death syndrome, sudden unexplained death syndrome, and sudden aortic death. We identified pathogenic/likely pathogenic variants following ACMG/AMP recommendations in 22/100 (22.0%) of cases. Since poor DNA quality, we have performed indirect DNA testing in affected relatives or in healthy parents reaching a diagnostic genetic yield of 11/24 (45.8%) and 1/10 (10.0%), respectively. Cardiological and genetic screening disclose 83/301 (27.6%) relatives at risk of SCD. Genetic testing in affected relatives as starting material leads to a high diagnostic yield offering a valuable alternative when suitable material is not available. This is the first multidisciplinary/multicenter molecular autopsy study in the Czech Republic which supports the establishment of this type of diagnostic tests. A central coordinator and proper communication among centers are crucial for the success of a collaboration at a national level.

1st Department of Internal Medicine Cardiology and Laboratory of Cardiogenomics University Hospital Olomouc and Palacky University Olomouc Czech Republic

Department of Biology and Medical Genetics 2nd Faculty of Medicine Charles University and Motol University Hospital 5 Úvalu 84 150 06 Prague 5 Czech Republic

Department of Biology and Medical Genetics University Hospital Ostrava Ostrava Czech Republic

Department of Cardiology Center for Inherited Cardiovascular Diseases IKEM Vídeňská 1958 9 140 21 Prague 4 Czech Republic

Department of Forensic Medicine and Toxicology Liberec Regional Hospital Liberec Czech Republic

Department of Forensic Medicine Faculty of Medicine in Hradec Králové Charles University and University Hospital Hradec Králové Prague Czech Republic

Department of Forensic Medicine Faculty of Medicine University Hospital Bulovka Charles University 2nd Prague Czech Republic

Department of Medical Genetics University Hospital Pilsen Pilsen Czech Republic

Faculty of Medicine Children's Heart Centre Charles University and Motol University Hospital 2nd Prague Czech Republic

Forensic Department Hospital České Budějovice České Budějovice Czech Republic

Forensic Department of Military University Hospital Prague Czech Republic

Institute for Forensic Medicine 3rd Faculty of Medicine Charles University Prague Czech Republic

Institute of Forensic Medicine and Toxicology 1st Faculty of Medicine Charles University Prague Czech Republic

Institute of Forensic Medicine Faculty of Medicine in Pilsen Charles University Prague Czech Republic

Institute of Forensic Science and Medical Law University Hospital Olomouc and Palacký University Olomouc Czech Republic

Institute of Medical Genetics University Hospital Olomouc and Palacky University Olomouc Czech Republic

Institute of Pathological Physiology University Hospital Olomouc and Palacky University Olomouc Czech Republic

Paediatric Department 3rd Faculty of Medicine Charles University Prague Czech Republic

Zobrazit více v PubMed

Goldstein S. The necessity of a uniform definition of sudden coronary death: witnessed death within 1 hour of the onset of acute symptoms. Am Heart J. 1982;103(1):156–159. doi: 10.1016/0002-8703(82)90552-X. PubMed DOI

Stiles MK, Wilde AAM, Abrams DJ, et al. 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. 2021;18(1):e1–e50. doi: 10.1016/J.HRTHM.2020.10.010. PubMed DOI PMC

Wong CX, Brown A, Lau DH, et al. Epidemiology of sudden cardiac death: global and regional perspectives. Heart Lung Circ. 2019;28(1):6–14. doi: 10.1016/J.HLC.2018.08.026. PubMed DOI

Rücklová K, Dobiáš M, Bílek M, et al. Burden of sudden cardiac death in persons aged 1–40 years in the Czech Republic. Cent Eur J Public Health. 2022;30(1):58–64. doi: 10.21101/CEJPH.A6793. PubMed DOI

Charron P, Arad M, Arbustini E, et al. Genetic counselling and testing in cardiomyopathies: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J. 2010;31(22):2715–2728. doi: 10.1093/EURHEARTJ/EHQ271. PubMed DOI

Zeppenfeld K, Tfelt-Hansen J, de Riva M et al (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. 10.1093/eurheartj/ehac262 PubMed

Basso C, Burke M, Fornes P, et al. Guidelines for autopsy investigation of sudden cardiac death. Virchows Arch. 2008;452(1):11–18. doi: 10.1007/s00428-007-0505-5. PubMed DOI

Basso C, Aguilera B, Banner J, et al. Guidelines for autopsy investigation of sudden cardiac death: 2017 update from the Association for European Cardiovascular Pathology. Virchows Arch. 2017;471(6):691–705. doi: 10.1007/s00428-017-2221-0. PubMed DOI PMC

Verhagen JMA, Kempers M, Cozijnsen L, et al. Expert consensus recommendations on the cardiogenetic care for patients with thoracic aortic disease and their first-degree relatives. Int J Cardiol. 2018;258:243–248. doi: 10.1016/j.ijcard.2018.01.145. PubMed DOI

Harris SL, Lubitz SA. Clinical and genetic evaluation after sudden cardiac arrest. J Cardiovasc Electrophysiol. 2020;31(2):570–578. doi: 10.1111/jce.14333. PubMed DOI PMC

Coll M, Oliva A, Grassi S, Brugada R, Campuzano O (2019) Update on the genetic basis of sudden unexpected death in epilepsy. Int J Mol Sci 20(8):1979. 10.3390/ijms20081979 PubMed PMC

Semsarian C, Ingles J, Wilde AAM. Sudden cardiac death in the young: the molecular autopsy and a practical approach to surviving relatives. Eur Heart J. 2015;36(21):1290–1296. doi: 10.1093/eurheartj/ehv063. PubMed DOI

Fellmann F, van El CG, Charron P, et al. European recommendations integrating genetic testing into multidisciplinary management of sudden cardiac death. Eur J Hum Genet. 2019;27(12):1763–1773. doi: 10.1038/S41431-019-0445-Y. PubMed DOI PMC

Whiffin N, Minikel E, Walsh R, et al. Using high-resolution variant frequencies to empower clinical genome interpretation. Genet Med. 2017;19(10):1151–1158. doi: 10.1038/GIM.2017.26. PubMed DOI PMC

Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405–424. doi: 10.1038/gim.2015.30. PubMed DOI PMC

Butters A, Arnott C, Sweeting J, Winkel BG, Semsarian C, Ingles J (2021) Sex disparities in sudden cardiac death. Circ Arrhythm Electrophysiol 14(8):e009834. 10.1161/CIRCEP.121.009834 PubMed

Kim SK, Bennett R, Ingles J, Kumar S, Zaman S. Arrhythmia in cardiomyopathy: sex and gender differences. Curr Heart Fail Rep. 2021;18(5):274–283. doi: 10.1007/S11897-021-00531-0. PubMed DOI

Kong MH, Fonarow GC, Peterson ED, et al. Systematic review of the incidence of sudden cardiac death in the United States. J Am Coll Cardiol. 2011;57(7):794–801. doi: 10.1016/j.jacc.2010.09.064. PubMed DOI PMC

Larsen MK, Christiansen SL, Hertz CL, et al. Targeted molecular genetic testing in young sudden cardiac death victims from Western Denmark. Int J Legal Med. 2020;134(1):111–121. doi: 10.1007/S00414-019-02179-X. PubMed DOI

Thakur RK, Hoffmann RG, Olson DW, et al. Circadian variation in sudden cardiac death: effects of age, sex, and initial cardiac rhythm. Ann Emerg Med. 1996;27(1):29–34. doi: 10.1016/S0196-0644(96)70292-5. PubMed DOI

Lahrouchi N, Raju H, Lodder EM, et al. Utility of post-mortem genetic testing in cases of sudden arrhythmic death syndrome. J Am Coll Cardiol. 2017;69(17):2134–2145. doi: 10.1016/j.jacc.2017.02.046. PubMed DOI PMC

Lahrouchi N, Raju H, Lodder EM, et al. The yield of postmortem genetic testing in sudden death cases with structural findings at autopsy. Eur J Hum Genet. 2020;28(1):17–22. doi: 10.1038/S41431-019-0500-8. PubMed DOI PMC

Raju H, Parsons S, Thompson TN, et al. Insights into sudden cardiac death: exploring the potential relevance of non-diagnostic autopsy findings. Eur Heart J. 2019;40(10):831–838. doi: 10.1093/EURHEARTJ/EHY654. PubMed DOI

Wilde AA, Semsarian C, Márquez MF, et al. European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) expert consensus statement on the state of genetic testing for cardiac diseases. Heart Rhythm Published online. 2022 doi: 10.1016/j.hrthm.2022.03.1225. PubMed DOI

Marschall C, Moscu-Gregor A, Klein HG (2019) Variant panorama in 1,385 index patients and sensitivity of expanded next-generation sequencing panels in arrhythmogenic disorders. Cardiovasc Diagn Ther 9(Suppl 2):S292–S298. 10.21037/CDT.2019.06.06 PubMed PMC

Akhtar M, Elliott PM. (2019) Risk stratification for sudden cardiac death in non-ischaemic dilated cardiomyopathy. 10.1007/s11886-019-1236-3 PubMed PMC

Mazzarotto F, Tayal U, Buchan RJ, et al. Reevaluating the genetic contribution of monogenic dilated cardiomyopathy. Circulation. 2020;141(5):387–398. doi: 10.1161/CIRCULATIONAHA.119.037661. PubMed DOI PMC

Kellermayer D, Smith JE, Granzier H. Titin mutations and muscle disease. Pflugers Arch - Eur J Physiol. 2019;471(5):673–682. doi: 10.1007/s00424-019-02272-5. PubMed DOI PMC

Begay RL, Graw SL, Sinagra G, et al. Filamin C Truncation mutations are associated with arrhythmogenic dilated cardiomyopathy and changes in the cell–cell adhesion structures. JACC Clin Electrophysiol. 2018;4(4):504–514. doi: 10.1016/J.JACEP.2017.12.003. PubMed DOI PMC

Isbister JC, Nowak N, Butters A, et al. “Concealed cardiomyopathy” as a cause of previously unexplained sudden cardiac arrest. Int J Cardiol. 2021;324:96–101. doi: 10.1016/J.IJCARD.2020.09.031. PubMed DOI

Verdonschot JAJ, Vanhoutte EK, Claes GRF, et al. A mutation update for the FLNC gene in myopathies and cardiomyopathies. Hum Mutat. 2020;41(6):1091–1111. doi: 10.1002/humu.24004. PubMed DOI PMC

Ortiz-Genga MF, Cuenca S, Dal Ferro M, et al. Truncating FLNC mutations are associated with high-risk dilated and arrhythmogenic cardiomyopathies. J Am Coll Cardiol. 2016;68(22):2440–2451. doi: 10.1016/J.JACC.2016.09.927. PubMed DOI

Ader F, de Groote P, Réant P, et al. FLNC pathogenic variants in patients with cardiomyopathies: prevalence and genotype-phenotype correlations. Clin Genet. 2019;96(4):317–329. doi: 10.1111/cge.13594. PubMed DOI

Garmany R, Giudicessi JR, Ye D, Zhou W, Tester DJ, Ackerman MJ. Clinical and functional reappraisal of alleged type 5 long QT syndrome: causative genetic variants in the KCNE1-encoded minK β-subunit. Heart Rhythm. 2020;17(6):937–944. doi: 10.1016/J.HRTHM.2020.02.003. PubMed DOI

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(6):429–439. 10.1161/CIRCULATIONAHA.119.043114 PubMed PMC

Lane CM, Giudicessi JR, Ye D, et al. Long QT syndrome type 5-Lite: Defining the clinical phenotype associated with the potentially proarrhythmic p.Asp85Asn-KCNE1 common genetic variant. Heart Rhythm. 2018;15(8):1223–1230. doi: 10.1016/j.hrthm.2018.03.038. PubMed DOI PMC

Wilde AAM, Amin AS, Postema PG. Diagnosis, management and therapeutic strategies for congenital long QT syndrome. Heart. 2022;108(5):332–338. doi: 10.1136/HEARTJNL-2020-318259. PubMed DOI PMC

Grassi S, Campuzano O, Coll M, et al. Genetic variants of uncertain significance: how to match scientific rigour and standard of proof in sudden cardiac death? Leg Med (Tokyo) 2020;45:101712. doi: 10.1016/j.legalmed.2020.101712. PubMed DOI

Campuzano O, Sarquella-Brugada G, Fernandez-Falgueras A et al (2020) Reanalysis and reclassification of rare genetic variants associated with inherited arrhythmogenic syndromes. BioMedicine 54:102732. 10.1016/j.ebiom.2020.102732 PubMed PMC

Gandjbakhch E, Redheuil A, Pousset F, Charron P, Frank R. Clinical diagnosis, imaging, and genetics of arrhythmogenic right ventricular cardiomyopathy/dysplasia: JACC state-of-the-art review. J Am Coll Cardiol. 2018;72(7):784–804. doi: 10.1016/J.JACC.2018.05.065. PubMed DOI

Najít záznam

Citační ukazatele

Nahrávání dat ...

Možnosti archivace

Nahrávání dat ...