State of the Molecular Autopsy
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1 State of the Molecular Autopsy Michael J. Ackerman, MD, PhD Windland Smith Rice Cardiovascular Genomics Research Professor Professor of Medicine, Pediatrics, and Pharmacology Director, Long QT Syndrome/Genetic Heart Rhythm Clinic and the Mayo Clinic Windland Smith Rice Sudden Death Genomics Laboratory President, Sudden Arrhythmia Death Syndromes (SADS) Foundation 10 th Annual International SADS Foundation Conference Toronto, Canada 09/22/2017
2 Learning Objectives to Disclose: To DETAIL the state of postmortem genetic testing (AKA, the molecular autopsy ) for autopsy positive and autopsy negative sudden cardiac death (SCD) in the young To EXAMINE the three Achilles heels that threaten to derail the molecular autopsy WINDLAND Smith Rice Sudden Death Genomics Laboratory Conflicts of Interest to Disclose: Consultant Audentes Therapeutics, Boston Scientific, Gilead Sciences, Invitae, Medtronic, MyoKardia, and St. Jude Medical Royalties AliveCor, Blue Ox Health Corp, and StemoniX
3 Sudden Death in the Young (SDY) Nature Medicine 2013
4 Sudden Death in the Young (SDY) Nature Medicine 2013
5
6 CLOSURE & CLARITY!
7 Autopsy Negative Sudden Unexplained Death Syndrome In Autopsy Negative SUD, How Often Would a Molecular Autopsy Be Positive? 1. Don t know what a molecular autopsy is % % % 5. > 50% Nature Medicine 2013
8 State of Postmortem Genetic Testing N = 173 cases of SUD (106 males) Average age = years (1-69 yrs) Personal or FHx of Cardiac Events = 70 (40%) Autopsy Negative Sudden Unexplained Death ~ 25-30% Tester Ackerman. Mayo Clin Proc 79: , 2004 Tester Ackerman. JACC 49: , 2007 Tester Ackerman. Mayo Clin Proc 87: , 2012
9 60 Age- and Sex-Specific Effect on the Yield of a Cardiac Channel Molecular Autopsy Tester Ackerman. Mayo Clin Proc 87: , 2012 Percent Yield (%) % 26 p< % 19 32% 6 21% 5 48% 12 18% 9 40% 4 24% 4 38% 3 13% 1 25% 1 0 F M All Ages (n=173) 0% 0% 0% F M F M F M F M F M 4 5 F M ys (n=43) 11-20ys (n=75) 21-30ys (n=27) 31-40ys (n=16) 41-50ys (n=9) > 50ys (n=3)
10 LQTS Mutations - Pathogenic Basis for ~10% of SIDS or SUID Ackerman et al. JAMA 286: , 2001 Tester Ackerman. Cardiovasc Res 67:388-96, 2005 Arnestad Schwartz. Circulation 115:361-67, 2007
11 SUDS/SIDS Molecular Autopsy 1. In the setting of autopsy negative SUDS, comprehensive or targeted (RYR2, KCNQ1, KCNH2, and SCN5A) ion channel genetic testing may be considered in an attempt to establish probable cause and manner of death and to facilitate the identification of potentially at-risk relatives and is recommended if circumstantial evidence points towards a clinical diagnosis of LQTS or CPVT specifically (such as emotional stress, acoustic trigger, drowning as the trigger of death). Ackerman, Priori, et al. Heart Rhythm 8: , 2011 (HRS/EHRA)
12 Next Generation Whole Exome Sequencing Whole exome sequencing (WES) allows for simultaneous mutational analysis of a patient s entire library of genes! 10% 29 consecutive sudden death cases (21 males, years) collected at the Office of the Gene specific Medical Examiner, Cook County, Illinois from targeted analysis January 2012 to December 2013 were referred to Mayo Clinic for molecular autopsy. Will Ackerman. HRS 2015
13 The Whole Exome Molecular Autopsy (WEMA) Whole exome sequencing (WES) allows for simultaneous mutational analysis of a patient s entire library of genes! 44% 32 (20 males) consecutive, medical examinerreferred cases of autopsy negative, exertional sudden death in the young (SDY) cases ( years, 2 19 year range). Gene specific targeted analysis Anderson Ackerman. Circulation: CV Genetics 2016
14 Molecular Autopsy s 3 Achilles Heels 1. Cost Insurance companies do NOT like to pay for things when you have died! 2. Medical Examiner s SOP Paraffin-embedded tissue is NOT DNA friendly! 3. Interpreting the Molecular Autopsy X does NOT always mark the spot!
15 Genetic Testing s Achilles Heel Mutation-specific genetic testing is recommended for family What s members the Background and other appropriate Noise Rate? relatives subsequently What s the following Signal-to-Noise the identification Ratio? of the disease-causative mutation in an index case. Ackerman, Priori, et al. Heart Rhythm 8: , 2011 (HRS/EHRA)
16 Genetic Testing s Achilles Heel Is the X that marks the spot truly THE disease-causative mutation? What s the Background Noise Rate? What s the Signal-to-Noise Ratio?
17 Background Noise Issue
18 Genetic Testing for LQTS Patients LQT1 LQT2 LQTS C 1159 LQT3 Mayo Clinic 541 Series of LQTS referrals Tester Ackerman. Heart Rhythm 2: , 2005
19 LQT1 LQTS Variants in Health LQT2 LQTS C 1159 LQT3 LQTS Variants in Health Ackerman et al. Mayo Clin Proc 78: , 2003 Ackerman et al. Heart Rhythm 1: , 2004
20 Genetic Testing for LQTS Patients LQT1 LQT2 LQTS 4% Background Rate in Healthy Caucasians 6-8% Background Rate in Healthy Non-Caucasians C 1159 Exercise Extreme Caution When Calling Mutations LQT3 Mayo Clinic 541 Series of LQTS referrals Tester Ackerman. Heart Rhythm 2: , 2005
21 Background Noise Issue KCNQ1, KCNH2, SCN5A, RYR2 = ~5%
22 Sudden Cardiac Death in the Young Autopsy Negative SUD is NOT a Good Phenotype! Autopsy Negative LQTS 15% CPVT 10% BrS 3% Autopsy Positive KCNQ1, KCNH2, SCN5A, RYR2 Tester and Ackerman. Pediatric Cardiology 33: , 2012
23 Postmortem Genetic Testing - Maybe Test Result? Possible Deleterious Variant of Uncertain Significance (VUS) Genetic Purgatory is a Real Place and its Scary!
24 Mayo Clinic Proceedings 2016 Slide courtesy of Arthur Wilde Heart Centre
25 Sudden Death in the Young Pedigree 13-year-old Hispanic Male Sudden death during sleep Autopsy Findings: Heart weight of 430 g LVWT 17 mm Mild fiber disarray in LV Medical examiner deemed inconclusive autopsy 13 years SUD Clinical Genetic Testing for LQTS Living Brother s ECG
26 Genetic Testing Results and Cascade Family Screening Pathogenic Variant LQT1-Causative Negative for c.397g>a, p.v133i -? + +? V133I KCNQ1 Positive
27 V133I-KCNQ1 has a Normal Electrophysiological Phenotype
28 WES-Based Familial Genomic Triangulation Sporadic p.r454w-desmin Mutation ACMG Pathogenic Described previously as a sporadic mutation in a 15 year old with exercise intolerance and HCM and in a autosomal dominant pedigree of HCM and SCD. In vivo and in vitro studies show a dramatic effect on filament formation.
29
30 Sudden Cardiac Death in the Young The only thing worse than telling a family I don t know why your child died is to tell them we have found the answer and be wrong! Nature Medicine 2013
31 State of the Molecular Autopsy 1. ~25% of autopsy negative SUD and 10% of SIDS - Channelopathic! 2. Genotype-phenotype correlations still matter after death. Autopsy negative SUD is NOT that informative! 3. Formalin-fixed paraffin embedded tissue is the enemy of a molecular autopsy. 4. X does NOT always mark the spot! Genetic purgatory exists! Believe in it!
32 October 6-7, 2017 Charleston, SC
33 WINDLAND Smith Rice Sudden Death Genomics Laboratory Dr. Scholl Foundation, CJ Foundation for SIDS Hannah Wernke Memorial Foundation Sheikh Zayed Saif Mohammed Al Nahyan Fund Tsai Family Fund for HCM, National Institutes of Health
34 WINDLAND Smith Rice Sudden Death Genomics Laboratory To heal the sick and advance the science Dr. Charles W. Mayo
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