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How to evaluate the patient and family members for risk of sudden cardiac death: Role of genetic testing Robert L. Nussbaum, M.D. Chief, Division of Medical Genetics Outline • Describe how modern genetics views “mendelian” diseases and “multifactorial” diseases as sitting along a continuum rather than being distinctly different entities • Describe the characteristics of multifactorial disease. • Compare and contrast the terms polygenic, multifactorial and complex disorder. • Review the role of genetic counseling in arrhythmia cardiology Program in Cardiovascular Genetics Take Home Messages 1. 2. 3. 4. Taking a thorough family history is important and may give subtle clues to familial disease Genetic testing to identify the particular gene defect can help with individual prognosis but may require a sophisticated knowledge of molecular genetics Knowing the gene and mutation is critical for proper medical care of other family members Genetic counseling plays an important role in the care of patients with familial arrhythmias Program in Cardiovascular Genetics CASE 1: 33 yo woman with palpitations who is concerned about her children2 her husband is said to have HCM C P HCM 6 mo. Program in Cardiovascular Genetics Family History | Normal echo | C Normal echo No echo Normal echo Normal echo No echo Normal echo Program in Cardiovascular Genetics Upon referral to the UCSF Program in Cardiovascular Genetics: • Cardiology evaluation of the proband • Take a complete family history and prepare a pedigree to assess inheritance pattern and at risk relatives • Identify family members whose records need review and obtain records from the brother, sister, and nephew • After counseling, proceed to gene testing. Which genes? Program in Cardiovascular Genetics Genes Implicated in Various Cardiomyopathies HCM RCM DCM LV- C MYH7 (30%) MYH7 MYH7 (5-8%) MYH7 MYBPC3 (30%) (MYBPC3?) MYBPC3 (rare) TT2 (5%) TT2 TT2 (2-4%) TI3 (5%) TI3 TI3 (rare) TPM1 (< 5%) TPM1* TPM1 (rare) MYL3 (<5%) MYL3* TT2 MYL2 (<5%) ACTC (<5%) ACTC (<1-2%) ACTC LMA (7-8%) LMA (7-8%) LDB3/Cypher/ZASP LDB3/Cypher/ZASP TAZ/G4.5 TAZ/G4.5 DES (<1%) DTA (FKBP1A?) Hypertrophic cardiomyopathy Genetics: . • Autosomal dominant (usually) • Prevalence ~ 1/500 individuals • >15 genes associated with 1o HCM • Genetic testing: • Sequence 11-16 genes • 60-70% sensitive • Many “Private” mutations, no common mutations Program in Cardiovascular Genetics Test Results Program in Cardiovascular Genetics Variant of unknown significance (VUS) What is it? • genetic variant (most commonly missense mutation) • unknown whether it is benign or pathogenic • not previously reported in association with disease and often completely novel Should we just go ahead and test at-risk relatives? NOT RECOMMENDED! Program in Cardiovascular Genetics VUS detective work • • • • • Known single nucleotide polymorphism? Prevalence in ethnically matched controls? Conserved amino acid? Predictive software (ex. polyphen) Test affected family members - does it track with phenotype? • Functional studies (ACMG Standards and Guidelines for Clinical Genetics Laboratories, 2006 Edition) Program in Cardiovascular Genetics VUS detective work: PolyPhen V338M Program in Cardiovascular Genetics VUS testing | + Who needs to be tested? Normal echo + + | No echo + Normal echo Normal echo Normal echo + No echo Normal echo Program in Cardiovascular Genetics Case 2: Long QT Syndrome family • 43yo woman referred for genetic counseling because of concern for her children • Medical History: – Dizziness, pre-syncope – No hx of syncope – QTc on ECG: 480 @ HR=70; 537 @ HR=75 – Holter monitor: QTc 480-540 msec (@ HR=52107) (2004) • Therapy: – ICD placed in 2006 before genotype was known Family History • Sudden cardiac death in sister at 36 years of age, while at rest; history of multiple syncopal events – Did not lead to any family screening • Great-nephew had bradycardia in the newborn period, ECG revealed a prolonged QTc Pedigree Clinical History CANNOT Definitively Identify Asymptomatic Gene Mutation Carriers1 Lack of penetrance in LQT syndromes: • ~37% of individuals with LQT1: 37% • ~54% of individuals with LQT2: 545 • ~82% of individuals with LQT3: 82% are asymptomatic Standard ECG Diagnostic Methods CANNOT Definitively Identify Asymptomatic Gene Mutation Carriers1 Adapted from: Priori SG, Napolitano C, Schwartz PJ. Low penetrance in the long-QT syndrome: clinical impact. Circulation. 1999;99:529533. Reference: 1. Priori SG, Napolitano C, Schwartz PJ. Low penetrance in the long-QT syndrome: clinical impact. Circulation. 1999;99:529-533. Risk of an Initial Cardiac Event for Asymptomatic Parents of Probands Extends Into Adulthood1 Reference: 1. Kimbrough J, Moss AJ, Zareba W, et al. Clinical implications for affected parents and siblings of probands with long-QT syndrome. Circulation. 2001;104:557-562. Gene/ Protein TABLE 1 Ğ Common Long QT Syndromes Inheritance Syndrome Associated with Induced by LQT1 RomanoWard - Exercise, emotional stress Jervell/LangeNielsen Syndrome Congenital Sensorineural deafness (Penetrance of arrhythmia only in ~25% in heterozygotes) Exercise, emotional stress - ? Congenital Sensorineural deafness ? - Rest or sleep Auditory stimuli Emotional stress - ? AD KCNQ1 Subunit of voltage-gated K+ channel I Ks AR AD KCNE1 Subunit of voltage-gated K+ channel I Ks AR KCNH2 KCNE2 SCN5A Subunit of inwardly rectifying potassium channel I Kr AD Subunit of inwardly rectifying potassium channel I Kr AD Voltage-gated sodium channel type V AD LQT5 RomanoWard Jervell/LangeNielsen Syndrome LQT2 RomanoWard LQT6 RomanoWard LQT3 RomanoWard and Brugada - (Table modified from Modell SM and Lehmann MH.(2006) Genetics in Medicine 8:143-155.) Rest or sleep Genetic Testing in the GreatNephew • Genetic testing at Mayo Clinic identified a mutation in KCNQ1 (LQT1) 1637C>T (Ser546Leu) • Not seen in 1300 controls (PGxHealth data) • Reported in 3 unrelated families with LQT1 (Tester et al 2005, Choi et al 2004) • Mutation is not in the transmembrane region of the protein Iks KCNQ1 (slow) KCNE1 KCNH2 Ikr (rapid) KCNE2 Genotype-phenotype correlation mutations in and out of the pore LQT2 LQT1 Adapted from: Moss AJ, et al. Clinical aspects of type-1 long-QT syndrome by location, coding type, and biophysical function of mutations involving the KCNQ1 gene. Circulation. 2007;115:2481-2489. Adapted from: Moss AJ, et al. Increased risk of arrhythmic events in longQT syndrome with mutations in the pore region of the human ether-a-go-gorelated gene potassium channel. Circulation. 2002;105:794-799. • Higher risk for cardiac events in LQT1 and LQT2 when mutations are located in the transmembrane/pore region.1,2 References: 1. Moss AJ, Shimizu W, Wilde AAM. Clinical aspects of type-1 long-QT syndrome by location, coding type, and biophysical function of mutations involving the KCNQ1 gene. Circulation. 2007;115:2481-2489. 2. Moss AJ, Zareba W, Kaufman ES, et al. Increased risk of arrhythmic events in long-QT syndrome with mutations in the pore region of the human ether-a-go-go-related gene potassium channel. Circulation. 2002;105:794-799. Pedigree + + Obligate carriers were told they did not have LQTS b/c they had normal ECGs and no family genetic testing done Family outreach • Genetic testing of at-risk relatives • Educate obligate carriers and at-risk relatives • Refer obligate carriers and mutation positive carriers to EP Current status . . + - + + - pending + - - - Points to Consider • Type of LQT based on genetic testing may guide treatment (ICD vs. beta-blockers). Could this patient have avoided an ICD if she had genetic testing first? • Importance of family outreach - testing allows direct diagnosis and rule out. Ideally, the entire maternal side of family should have genetic testing once mutation known. • The insensitivity of clinical symptoms or long QTc on ECG for making a diagnosis do NOT trump the family tree: obligate carriers are at risk! Genetic Testing in LQTs and other selected familial 1o heart diseases Disease Clinically Yield Clinically available? Useful? LQTS YES ~75% YES BRUGADA YES ~25% YES HCM ARVD DCM YES YES YES 60-70% ~50% ~35% YES YES YES/?? Genetic Counseling Genetic Counseling in hereditary cardiovascular disease • A collaboration!! • Coordinate genetic testing • Help interpret genetic test results – Diagnostic implication of genetic test results – Prognosis based on mutation • Risk stratification • Genotype-specific treatment – Variants of unknown significance – Further genetic testing needed? • Identify additional genetic testing as needed (including research studies if available) Genetic Counseling in hereditary cardiovascular disease • Provide family counseling, education, and outreach – Inheritance, reproductive implications – Clarify confusing concepts – Work with at-risk relatives - genetic counseling doubles uptake of services by at-risk relatives (Forrest et al 2008) • Provide psychological support and counseling – Uncertainty (borderline EKG, ambiguous genetic test results, unpredictable disease, ICD fears) – Anxiety – Denial and avoidance (asymptomatic at-risk or carrier) – Guilt (parental, survivor) • Connect patients with support resources – Support groups (SADS, CARE) – Psychologists – Other families Relief and reassurance for non-carriers • At-risk family members have ⇑ distress • Negative genetic test results ⇓ distress • Genetic testing did not ⇑ distress any more than at-risk status/EKG screening SUMMARY: Heart Rhythm UK: Familial Sudden Death Syndromes Statement on Genetic Testing Genetic Testing Indicated in: 1. The sudden unexplained death of a young person (<40 years) should prompt comprehensive and expert clinical assessment of surviving relatives. 2. Material appropriate for DNA analysis should be obtained from the deceased person at the time of the postmortem examination, and targeted genetic analysis from this material should be considered 3. Genetic testing is recommended for all patients with a firm clinical diagnosis of the congenital LQTS or CPVT irrespective of the presence of symptoms or the existence of other family members. Heart 2008. 94:502-507 “Genetic analysis is very important for identifying all mutation carriers within the LQTS family: Once identified, silent carriers of LQTS genetic defects may be treated with beta-blockers for prophylaxis of life threatening arrhythmias. Furthermore, silent mutation carriers should receive genetic counseling to learn about the risk of transmitting LQTS to offspring.” “Genetic analysis is very important for identifying all mutation carriers within an LQTS family.” ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death Drug Induced long-QT: A Multifactorial Disorder Most common cause of withdrawal or use restriction of drugs already on the market. What is the Genetic Contribution to Drug-Induced long QT? 1. Nonpenetrant congenital long QT. Up to 15% of drug-induced long QT patients carry mutations in LQT1 or LQT2 that are non-penetrant (clinically or by ECG) without drug. 2. Drug interferes with chaperoning of a mutant SCN5A protein out to cell surface 3. Most drug-induced QT prolongation is unexplained Take Home Messages 1. 2. 3. 4. Taking a thorough family history is important and may give subtle clues to familial disease Genetic testing to identify the particular gene defect can help with individual prognosis but may require a sophisticated knowledge of molecular genetics Knowing the gene and mutation is critical for proper medical care of other family members Genetic counseling plays an important role in the care of patients with familial arrhythmias Program in Cardiovascular Genetics Program in Cardiovascular Genetics