Genetic Variants and Genetic Testing in CPVT Michael J. Ackerman, MD, PhD, FACC Windland Smith Rice Cardiovascular Genomics Research Professor Professor of Medicine, Pediatrics, and Pharmacology Director, Long QT Syndrome Clinic and the Mayo Clinic Windland Smith Rice Sudden Death Genomics Laboratory President, Sudden Arrhythmia Death Syndromes (SADS) Foundation 2015 SADS Foundation International Meeting New York City, NY May 29, 2015
Learning Objectives to Disclose: • To ASSESS clinical genetic testing for CPVT and EVALUATE its role and yield • To EXPOSE the “dark side” (aka, Genetic Purgatory) of the CPVT genetic test www.StopSADS.org 1-800-Stop SAD WINDLAND Smith Rice Sudden Death Genomics Laboratory Conflicts of Interest to Disclose: • Consultant – Boston Scientific, Gilead Sciences, Medtronic, St. Jude Medical, and Transgenomic/FAMILION • Royalties – Transgenomic/FAMILION
Learning Objectives to Disclose: • To ASSESS clinical genetic testing for CPVT and EVALUATE its role and yield • To EXPOSE the “dark side” (aka, Genetic Purgatory) of the CPVT genetic test www.StopSADS.org 1-800-Stop SAD WINDLAND Smith Rice Sudden Death Genomics Laboratory Conflicts of Interest to Disclose: • Consultant – Boston Scientific, Gilead Sciences, Medtronic, St. Jude Medical, and Transgenomic/FAMILION • Royalties – Transgenomic/FAMILION
FAF SIDS SUDS TS SSS DCM DI-TdP LQTS CPVT Cardiac Channelopathies - RWS - JLNS SQTS August 2011 HRS/EHRA Consensus Statement on the FAVCB ATS State of Genetic Testing for the Channelopathies and Cardiomyopathies IVF BrS Ackerman, Priori, et al. Heart Rhythm 8:1308-1339, 2011 IER
Decoding a CPVT Genetic Test Result - What is my index of suspicion? - What is the test’s DIAGNOSTIC, PROGNOSTIC, and THERAPEUTIC impact? - What is the test’s YIELD? - What is the test’s Achilles’ heel (its “NOISE”)?
Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) Exertion Induced Syncope or Sudden Cardiac Death Clinical No Structural Heart Defect Phenotypically Mimics Long QT Syndrome Hallmark Arrhythmia Bi-Directional Ventricular Tachycardia Priori et al. J Clin Invest 115:2033-2038, 2005
Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) Exertion Induced Syncope or Sudden Cardiac Death Clinical No Structural Heart Defect Phenotypically Mimics Long QT Syndrome Exercise-induced PVCs in bigeminy initiating at heart Hallmark Arrhythmia rates > 120 beats per minute – Bi-Directional Ventricular suspicious for CPVT! Tachycardia Horner … Ackerman. Heart Rhythm 2008 Priori et al. J Clin Invest 115:2033-2038, 2005
Decoding a CPVT Genetic Test Result - What is my index of suspicion? - What is the test’s DIAGNOSTIC, PROGNOSTIC, and THERAPEUTIC impact? - What is the test’s YIELD? - What is the test’s Achilles’ heel (its “NOISE”)?
Decoding a CPVT Genetic Test Result Disease Diagnostic Prognostic Therapeutic +++ +++ ++ LQTS +++ + - CPVT + + - BrS + + + CCD +/- - - SQTS - - - AF +++ ++ + HCM + +/- - ARVC +/- - - DCM + - - LVNC + + + RCM Ackerman, Priori, et al. Heart Rhythm 8:1308-1339, 2011
“CPVT genetic testing is recommended for any patient in whom a cardiologist has established a clinical index of suspicion for CPVT…[and] is recommended for family members and appropriate relatives” “…genotype influences the management and treatment of a patient with genetically confirmed CPVT“
Decoding a CPVT Genetic Test Result - “Positive” Test Result Mutation-specific genetic testing is recommended for family members and other appropriate relatives subsequently following the identification of the disease-causative mutation in an index case. Ackerman, Priori, et al. Heart Rhythm 8:1308-1339, 2011
Decoding a CPVT Genetic Test Result - “Negative” Test Result - What was my index of suspicion? - What exons were included/excluded? - Was it a clinical or research test result?
Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) Cell membrane Cellular RyR2 – Sarcoplasmic CASQ2 Molecular reticulum Calcium Induced Calcium Release (CICR) 105 1 8 14 15 44 45 46 47 49 83 88 100 101 102 103 90 93 97 RyR2 (CPVT1, Ch 1q42.1-q43) 105 Exons 11 Exons 4967 amino 339 amino 1 2 3 4 5 6 7 8 9 10 11 acids acids CASQ2 (CPVT2, Ch 1p13.1)
RyR2 Targeted Screening Mutations seem to be distributed across three canonical structure-function domains 0 1000 2000 3000 4000 4967 77-466 2246-2534 3778-4959 I II III Yano et. al, Nat Clin Prac Card 3:43-52 , 2006 George et al. J Mol Cardiol; 42:34-50, 2007
The Cardiac Ryanodine Receptor (RyR2) Central Domain Channel Region N-terminal Domain RYR2 “Hot Spot Domains” 2246-2534 3778-4959 77-466 Exons 1 – 28 Exons 37 – 50 Exon 75 Exons 83 – 105 Targeted Genetic Test Region 1-1141 1638-2578 3564-3575 3776-4967 Exons 3, 8, 10, 12- Exons 83, 86-91, 93- Regions of Exons 38, 40-50 Exon 75 15, 17, 19, 21, 26-28 97, 99-105 Higher Pathogenicity Targeted Genetic Test 66/105 exons tested, covering 66% of the protein Exon 1 Exon 105 RyR2 1 4967 Yano et. al, Nat Clin Prac Card 3:43-52 , 2006 George et al. J Mol Cardiol; 42:34-50, 2007 Medeiros-Domingo et al. JACC 54:2065-74, 2009
Decoding a CPVT Genetic Test Result - What is my index of suspicion? - What is the test’s DIAGNOSTIC, PROGNOSTIC, and THERAPEUTIC impact? - What is the test’s YIELD? - What is the test’s Achilles’ heel (its “NOISE”)?
Catecholaminergic Polymorphic Yield of Genetic Testing Ventricular Tachycardia (CPVT) Cell membrane Cellular RyR2 – Sarcoplasmic CASQ2 Molecular reticulum Calcium Induced Calcium Release (CICR) 105 1 8 14 15 44 45 46 47 49 83 88 100 101 102 103 90 93 97 RyR2 (CPVT1, Ch 1q42.1-q43) 105 Exons 11 Exons 4967 amino 339 amino 1 2 3 4 5 6 7 8 9 10 11 Medeiros-Domingo…Ackerman. JACC 54:2064-2075, 2009 acids acids Medeiros-Domingo…Ackerman. JACC 54:2064-2075, 2009 CASQ2 (CPVT2, Ch 1p13.1)
Catecholaminergic Polymorphic Yield of Genetic Testing Ventricular Tachycardia (CPVT) Cell membrane CPVT Strong – 60% Cellular CPVT Possible – 30% RyR2 – Real World (N = 1200) – 18% Sarcoplasmic CASQ2 Molecular reticulum Autopsy Negative SUDS – 10% Calcium Induced Calcium Release (CICR) 105 1 8 14 15 44 45 46 47 49 83 88 100 101 102 103 90 93 97 RyR2 (CPVT1, Ch 1q42.1-q43) 105 Exons 11 Exons 4967 amino 339 amino 1 2 3 4 5 6 7 8 9 10 11 Medeiros-Domingo…Ackerman. JACC 54:2064-2075, 2009 acids acids Medeiros-Domingo…Ackerman. JACC 54:2064-2075, 2009 CASQ2 (CPVT2, Ch 1p13.1)
CPVT Genetic Testing in Real World Total Cases 1200 Avg Age (years) 31 ± 19 % Female 46% Caucasian 78% African 9% Hispanic 7% Asian 3% Other 3% Test Exons on Version Panel Exons Sample Count 1 38 3, 8-15, 37, 41, 44-50, 83, 87-105 291 2 66 1-28, 37-50, 75, and 83-105 656 3 105 1-105 253
Kapplinger … Ackerman. 2015 (submitted)
Decoding a CPVT Genetic Test Result - What is my index of suspicion? - What is the test’s DIAGNOSTIC, PROGNOSTIC, and THERAPEUTIC impact? - What is the test’s YIELD? - What is the test’s Achilles’ heel (its “NOISE”)?
Genetic Testing’s Achilles’ Heel Non-Synonymous Single Nucleotide Polymorphism Is the “X” that marks the spot truly • Common/rare SNP w/o functional/clinical significance • Common/rare SNP w/ functional/clinical significance THE disease-causing mutation? • Pathogenic (“disease-causing”) mutation “With great power comes great responsibility” Spider Man’s Uncle
Background Noise Issue 2003
RESULTS N 1 RyR2 (n = 221) 40 250 Control Variants Yield of CPVT Genetic Test in Controls 507 328 1 > 8000 “controls” 377 754 1136 2.0% 1013 2% 1810 FKBP12.6 1.5% Binding 2284 2156 2435 Domain 2094 2812 1.4% Yield 1.0% 3510 3152 C 4967 3973 0.5% 11 0.6% Cytosol 4281 4573 0.0% All Targeted Outside Region Targeted Region SR lumen 4344 4653 Kapplinger … Ackerman. 2015 (submitted)
Background Rate Issue in CPVT • 3% background rate of rare variants identified in 200 ostensibly healthy controls • 15/142 (10.5%) of the previously published CPVT variants were found in controls (Medeiros-Domingo…Ackerman JACC 2009) • Reconfirmed – 11% (Jabbari…Olesen Circ. Cardiovasc. Genet. 2013)
Reported Variants Represented in Controls* Mutation Reference (PMID) Count (Out of 8075) 13 (0.16%) R1013Q PMID: 21964171 10 (0.12%) R4307C PMID: 19926015 7 (0.09%) V2113M PMID: 19926015 5 (0.06%) T1107M PMID: 19926015 3 (0.04%) V919M Kellen et al., HRS 2012 3 (0.04%) V377M PMID: 19926015 2 (0.02%) P466A PMID: 19926015 2 (0.02%) V4010M PMID: 19926015 2 (0.02%) A4556T PMID: 19926015 *Variants found only once in controls were omitted
Decoding a CPVT Genetic Test Result - “Maybe” Test Result ? “Possible Deleterious” “Variant of Uncertain Significance (VUS)” “Genetic Purgatory” “Genetic Purgatory is a - What was my index of suspicion? Real Place and its - Have I done my homework? Scary!”
MAF < 1:10000 MAF > 1:10000 Case 1053 non-synonymous variants with a MAF < 1/10,000 alleles Background rate of 3.2% 68 non-synonymous variants with a MAF > 1/10,000 alleles Kapplinger … Ackerman. 2015 (submitted)
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