Strength and weakness of genetic testing in clinical routine. Silvia G Priori MD PhD Molecular Cardiology, IRCCS Fondazione Maugeri Pavia, Italy AND Leon Charney Division of Cardiology, Cardiovascular Genetics Program, Langone Medical Center, New York University School of Medicine, New York, USA DISCLOSURES: Member of the advisory board of Transgenomics and GeneDX
Clinical value of molecular diagnosis in inherited arrhythmogenic diseases Define the specific genetic defect Confirm diagnosis in borderline cases/neonates Risk stratification Gene-specific therapy Identification of true sporadic cases Asymptomatic gene-carriers (penetrance) Strength and weaknesses are specific for each disease!
The clinical applicability of genetic testing in inherited disorders is disease-specific. Variables to be considered before counseling on the usefulness of genetic screening: Technical Success rate Size of genomic region to screen (number of genes) Clinical Relevance of pre-symptomatic diagnosis Relevance of identification of silent carriers Results influence risk stratification Results influence therapy/lifestyle Prenatal diagnosis is clinically justified Priori SG, Napolitano C - Circulation 2006
Strength and Weaknesses of genetic testing in LQTS
Multiple genes and mechanisms for similar phenotypes LQTS
What to expect from genetic testing in LQTS Disease Yield of Genetic Test LQTS 75% (80%) % of Controls with a Rare VUS 4% (LQT1,2,3) HRS / EHRA Expert Consensus Statement on the State of Genetic Testing for the Channelopathies and Cardiomyopathies in press 2011
Gene Locus Protein % of Disease Long QT Syndrome (LQTS) KCNQ1 (LQT1) 11p15.5 KCNH2 (LQT2) SCN5A (LQT3) KEY GENES IN LQTS 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% HRS / EHRA Expert Consensus Statement on the State of Genetic Testing for the Channelopathies and Cardiomyopathies in press 2011
Survival according to genotype in 580 genotyped patients Cumulative Survival (%) 100 90 80 P=0.007 70 60 50 40 Genotype 30 20 10 LQT1: LQT2: LQT3: 0 0 10 20 Age (years) 30 40 Priori et al NEJM 2003
Cardiac event free survival Event-free survival on Beta-blockers 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 LQT1 LQT2 LQT3 0.1 0.0 0 5 10 Follow up (years) 15 20 Priori et al. JAMA 2004
Clinical impact of genetic testing Disease Diagnostic Prognostic Therapeutic LQTS +++ +++ ++ HRS / EHRA Expert Consensus Statement on the State of Genetic Testing for the Channelopathies and Cardiomyopathies in press 2011
Recommendations for genetic testing in LQTS Diseas e Confirmed Diagnosis/ Symptomatic Asymptomatic Family members LQTS RECOMMENDED KCNQ1, KCNH2, and SCN5A RECOMMENDED QT>500(480 Ped) Otherwise MAY BE indicated RECOMMEDED HRS / EHRA Expert Consensus Statement on the State of Genetic Testing for the Channelopathies and Cardiomyopathies in press 2011
Strength and Weaknesses of genetic testing in Brugada Syndrome
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%? BrS9 KCNE5 Transient outward (Kv4.3) beta subunnit Increased Ito 1%?
Only ONE KEY gene Gene Locus Protein Brugada Syndrome SCN5A 3p21 % of Disease Cardiac sodium channel alpha subunit (NaV1.5) 20-30% HRS / EHRA Expert Consensus Statement on the State of Genetic Testing for the Channelopathies and Cardiomyopathies in press 2011
Clinical impact of genetic testing Disease Diagnostic Prognostic Therapeutic BrS + + - HRS / EHRA Expert Consensus Statement on the State of Genetic Testing for the Channelopathies and Cardiomyopathies in press 2011
Recommendations for genetic testing in Brugada Syndrome Diseas e Confirmed Diagnosis/ Symptomatic Asymptomatic BrS CAN BE USEFUL Not indicated if type 2 or 3 Family members RECOMMENDED HRS / EHRA Expert Consensus Statement on the State of Genetic Testing for the Channelopathies and Cardiomyopathies in press 2011
Strength and Weaknesses of genetic testing in Catecholaminergic Ventricular Tachycardia
CPVT genes AUTOSOMAL DOMINANT Ryanodine Receptor (RyR2) AUTOSOMAL RECESSIVE Calsequestrin (CASQ2)
The KEY CPVT genes Gene Locus Protein % of Disease Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) Ryanodine RYR2 (CPVT1) 1q42.1-q43 Receptor 2 60% HRS / EHRA Expert Consensus Statement on the State of Genetic Testing for the Channelopathies and Cardiomyopathies in press 2011
VARIANTS OF UNKNOWN SIGNIFICANCE IN RyR2 Disease Yield of Genetic Test % of Controls with a Rare VUS CPVT 60% (70%) 3% HRS / EHRA Expert Consensus Statement on the State of Genetic Testing for the Channelopathies and Cardiomyopathies in press 2011
Clinical impact of genetic testing in CPVT Disease Diagnostic Prognostic Therapeutic CPVT +++ + - HRS / EHRA Expert Consensus Statement on the State of Genetic Testing for the Channelopathies and Cardiomyopathies in press 2011
Clinical value of genetic testing 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 the impact of genetic testing will increase
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 HRS / EHRA Expert Consensus Statement on the State of Genetic Testing for the Channelopathies and Cardiomyopathies in press 2011