Genetic testing in Cardiomyopathies

Transcription

1 Genetic testing in Cardiomyopathies Silvia Giuliana Priori Cardiovascular Genetics, Langone Medical Center, New York University School of Medicine, New York, USA and Molecular Cardiology, IRCCS Fondazione Maugeri Dept of Cardiology, University of Pavia. Italy

2 HRS/EHRA Expert Consensus Statement on the State of Genetic Testing for the Channelopathies and Cardiomyopathies

3 Michael J. Ackerman, MD, PhD, Silvia G Priori, MD, PhD, Stephen Willems, MD, PhD, Co-Chairs Charles Berul,MD Ramon Brugada, MD, PhD Hugh Calkins, MD Eric Schulze-Bahr, MD, PhD, John A Camm, MD Chris Semsarian, MBBS, PhD Patrick Ellinor, MD PhD Jeffrey Towbin, MD Michael Gollob, MD Hugh Watkins, MD, PhD Robert Hamilton, MD Arthur Wilde, MD, PhD Ray Hershberger,MD Christian Wolpert, MD Dan Judge, MD Douglas Zipes, MD Hervè Le Marec, MD

4 Long QT syndrome / Timothy /Andersen/Jervell and Lange Nielsen Brugada syndrome Catecholaminergic Polymorphic Ventricular Tachycardia Short QT syndrome Progressive conduction defect Hypertrophic Cardiomyopathy Dilated Cardiomyopathy Arrhythmogenic right ventricular cardiomyopathy SIDS/SUDS, Channellopathies and Cardiomyopaties

5 Clinical value of genetic testing A key objective of the document is to clarify that genetic testing at present time does not have the same indication in all inherited arrhythmias. In some conditions genetic testing is indicated to allow more accurate screening of family members & to identify carriers of disease-causing mutations In other conditions results of genetic testing bears implications for risk stratification and management In some diseases genetic testing is not yet ready for clinical use. As knowledge increases guidelines will have to be updated

6 Which is the probability that the test will serve your needs

7 Yield of genetic testing (1) Disease Yield of Genetic Test LQTS 75% (80%) CPVT 60% (70%) BrS 20% (30%) CCD SQTS AF Unknown Unknown Unknown

8 Yield of genetic testing (2) Disease Yield of Genetic Test HCM 60% (70%) ARVC 60% DCM 30% DCM+ CCD Unknown LVNC 17-41% RCM Unknown

9 What the impact of VUS (Variants of Unknown Significance)?

10 VARIANTS OF UNKNOWN SIGNIFICANCE (1) Disease Yield of Genetic Test LQTS 75% (80%) % of Controls with a Rare VUS 4% (LQT1,2,3) CPVT 60% (70%) 3% BrS 20% (30%) 2% (SCN5A) CCD Unknown Unknown SQTS Unknown 3% AF Unknown Unknown

11 VARIANTS OF UNKNOWN SIGNIFICANCE (2) Disease Yield of Genetic Test % of Controls with a Rare VUS HCM 60% (70%) 5% ARVC 60% 16% DCM 30% Unknown DCM+CCD Unknown 4% (SCN5A & LMNA) LVNC 17-41% Unknown RCM Unknown Unknown

12 Why you request the test (Diagnostic? Prognostic? FM?...)

13 Role of Genetics in LQTS Diagnosis in family members (non penetrant carriers) Diagnosis in borderline index cases Risk stratification Therapy management Family counseling Reproductive risk

14 Event-free survival in LQTS according to genotype Cumulative Survival (%) P=0.007 Genotype LQT1: LQT2: LQT3: Priori et al NEJM Age (years) LQT LQT LQT

15 Cardiac event free survival Event-free survival on Beta-blockers LQT1 LQT2 LQT Follow up (years) Priori et al. JAMA 2004

16 Clinical impact of genetic testing (1) Disease Diagnostic Prognostic Therapeutic LQTS CPVT BrS CCD SQTS +/- - - AF - - -

17 Clinical impact of genetic testing (2) Disease Diagnostic Prognostic Therapeutic HCM ARVC + +/- - DCM +/- - - DCM + CCD LVNC + RCM + + +

18 GENES THAT ACCOUNT FOR MORE THAN 5% OF GENOTYPE POSITIVE PATIENTS

19 LONG QT SYNDROME GENES

20 The KEY LQTS genes Gene Locus Protein % of Disease Long QT Syndrome (LQTS) KCNQ1 (LQT1) 11p15.5 KCNH2 (LQT2) SCN5A (LQT3) 7q35-q36 3p21 I Ks potassium channel alpha subunit (Kv7.1) 30-35% I Kr potassium channel alpha subunit (Kv11.1 or herg) 25-40% Cardiac sodium channel alpha subunit (NaV1.5) 5-10%

21 CPVT genes AUTOSOMAL DOMINANT Ryanodine Receptor (RyR2) AUTOSOMAL RECESSIVE Calsequestrin (CASQ2)

22 The KEY CPVT genes Gene Locus Protein % of Disease Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) Ryanodine RYR2 (CPVT1) 1q42.1-q43 Receptor 2 60%

23 Brugada syndrome genes Locus Gene Function Functional effect of mutants Relative prevalence BrS1 SCN5A Cardiac sodium channel alpha sub-unit (Nav1.5) BrS2 GPD1-L Glycerol-6-phosphatedehydrogenase BrS3 CACNA1c L-type calcium channel alpha subunit (Cav1.2) BrS4 CACNB2 L-type calcium channel beta subunit BrS5 SCN1B Cardiac sodium channel beta1 subunit BrS6 KCNE3 Transient outward current beta subunit BrS7 SCN3B Cardiac sodium channel beta3 subunit Loss of function-reduced Na + current 15-20% Loss of function-reduced Na + current 1-2% Loss of function-reduced Ca 2+ current 7-10% Loss of function-reduced Ca 2+ current Loss of function-reduced Na + current 1% Gain of function-increased K + Ito current Loss of function-reduced Na + current? 1%? BrS8 MOG1 Nav1.5 trafficking control Loss of function-reduced Na + current <1%? BrS8 KCNE5 Transient outward (Kv4.3) beta subunnit Increased Ito 1%?

24 Only ONE KEY gene Gene Locus Protein Brugada Syndrome SCN5A 3p21 % of Disease Cardiac sodium channel alpha subunit (NaV1.5) 20-30%

25 The KEY genes Gene Locus Protein Cardiac Conduction Disease (CCD) SCN5A 3p21 % of Disease Cardiac sodium channel alpha subunit (NaV1.5) 5%

26 SQTS genetic variants Variant Gene Chromosome Protein Current Effect SQTS1 KCNH2 7q35-36 HERG IKr Gain of function SQTS2 KCNQ1 11p15.5 KCNQ1 IKs Gain of function SQTS3 KCNJ2 17q23 Kir2.1 IK1 Gain of function

27 The missing KEY genes Gene Locus Protein % of Disease Short QT Syndrome (SQTS) None of the 3 known disease associated genes have been shown to account for 5% of this disease

28 The MISSING genes Gene Locus Protein Atrial Fibrillation (AF) None of the known disease associated genes have been shown to account for 5% of this disease % of Disease

29 GENES OF HYPERTROPHIC CARDIOMYOPATHY

30 The KEY HCM genes Gene Locus Protein % of Disease MYBPC3 11p11.2 Cardiac myosin-binding prot C 20-45% MYH7 14q11.2-q12 Beta-myosin heavy chain 15-20% TNNT2 1q32 Cardiac troponin T type 2 1-7% TNNI3 19q13.4 Cardiac Troponin I type 3 1-7%

31 THE ARVC GENES

32 The KEY ARVC genes Gene Locus Protein % of Disease PKP2 12p11 Plakophilin % DSG2 18q12.1 Desmoglein % DSP 6p24 Desmoplakin 2-12% DSC2 18q12.1 Desmocollin 2 2-7%

33 THE DCMGENES Fukutin PSEN1/2 DTNA ACTN2 TPM1 LDB3 TNNC1/TNNI TMPO

34 The missing DCM genes Gene Locus Protein % of Disease None of the >25 disease-realted genes for DCM account for >5% DCM with Cardiac Conduction Defect (DCM+CCD) SCN5A 3p21 alpha subunit cardiac Na channel 5-10% LMNA 1q22 Lami A/C 5-10%

35 The KEY LVNC & RCM genes Gene Locus Protein Left Ventricular Non Compaction % of Disease LBD3 10q22.2q23.3 LIM binding domain 3 5% Restrictive Cardiomyopathy MYH7 14q11.2-q12 beta myosin heavy chain 5% TNNI3 19q13.4 Cardiac troponin I type 3 5%

36 RECOMMENDATIONS FOR GENETIC TESTING

37 Disease Confirmed Diagnosis/ Symptomatic Asymptomatic Family members LQTS RECOMMENDED KCNQ1, KCNH2, and SCN5A RECOMMENDED QT>500(480 Ped) Otherwise MAY BE indicated RECOMMEDED CPVT RECOMMENDED RECOMMENDED RECOMMENDED BrS CCD SQTS AF CAN BE USEFUL Not indicated if type 2 or 3 MAY BE CONSIDERED MAY BE CONSIDERED RECOMMENDED - RECOMMENDED - RECOMMENDED NOT INDICATED In the presence of strong familial AF evaluation at specialized center MAYBE INDICATED

38 Disease HCM Confirmed diagnosis Probands Possible diagnosis Family members RECOMMENDED NO RECOMMENDED ARVC CAN BE USEFUL MAY BE CONSIDERED (1 major or 2 minors criteria) RECOMMENDED DCM CAN BE USEFUL _ RECOMMENDED DCM+C CD RECOMMENDED _ RECOMMENDED LVNC CAN BE USEFUL _ RECOMMENDED RCM MAY BE RECOMMENDED _ RECOMMENDED

39 Genetic testing requires expert genetic counseling Before initiating genetic testing it is important that pros and cons of testing are discussed with patients and family members by a person expert in genetic counseling to address: Potential discrimination Psychological impact Handling of unclear results Meaning of negative results Chance of incomplete results Modification of interpretation over time

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