International Seminar: New Insights in CardiomyopathiesThessaloniki - 10 June 2011
Luisa MestroniProfessor of Cardiology, Director
CVI Molecular Genetics & Adult Medical GeneticsUniversity of Colorado
Screening for Familial Dilated Cardiomyopathy
Genetics of Cardiomyopathies
Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D, Arnett D, Moss AJ, Seidman CE, Young JB. Contemporary definitions and classification of the cardiomyopathiesCirculation 2006;113:1807-1816
• A great deal of progress has recently been made in FDC
• Screening of 1st-degree family members will reveal FDC in at least 20% to 35% of DCM
• FDC Mutations in 33 genes
• Technology rapidly changing
• Guidelines for evaluation and testing of FDC and IDC are now available
Background
Screening for Familial Dilated Cardiomyopathy
33 DCM genes: 31 autosomal and 2 X-linked genes
frequency <1% to ~8%
genetic testing: positive in 30-35% of cases (~1/3)
sensitivity of genetic testing in the overall IDC population 15-25%
overlapping syndromes (muscular dystrophy, other cardiomyopathies, etc.)
incomplete and age-related penetrance, variable expressivity
Genetic Testing Criteria: Challenges
Screening for Familial Dilated Cardiomyopathy
Mutations that disrupt the protein sequence
Segregation in large families
Rare (<1%)
Not present in controls: ethnically and race matched controls
affecting highly conserved regions, tested by consensus algorithms (PolyPhen, etc.)
new sequencing methods extremely powerful but require robust bioinformatics
require genetic counseling to deliver the results
www.genetest.org
A careful family history for ≥
3 generations is recommended for all patients with cardiomyopathy:
Cardiomyopathy Phenotype Level of Evidence• Hypertrophic cardiomyopathy (HCM) A• Dilated cardiomyopathy (DCM) A• Arrhythmic right ventricular dysplasia (ARVD) A• Left ventricular non-compaction (LVNC) A• Restrictive cardiomyopathy (RCM) B• Cardiomyopathies associated with
extra-cardiac manifestations A
Hershberger R, Lindenfeld J, Mestroni L, Seidman CE, Taylor M, Towbin JA, J Card Failure 2009
Genetic Evaluation of Cardiomyopathies: a HFSA Comprehensive Heart Failure Practice
Guideline
Clinical screening:• recommended in asymptomatic first-degree relatives
• recommended at intervals in asymptomatic carriers
• recommended for asymptomatic at-risk first-degree relatives when genetic testing has not been performed or has not identified a disease-causing mutation.
Genetic Evaluation of Cardiomyopathies: a HFSA Comprehensive Heart Failure Practice
Guideline
Hershberger R, Lindenfeld J, Mestroni L, Seidman CE, Taylor M, Towbin JA, J Card Failure 2009
Time intervals for clinical screening:(Level of evidence B-C)
– asymptomatic mutation carriers: 1 – 3 years– asymptomatic at-risk first-degree relatives
(mutation not known): 3 – 5 years– if abnormal clinical screening tests: yearly
Genetic Evaluation of Cardiomyopathies: a HFSA Comprehensive Heart Failure Practice
Guideline
Hershberger R, Lindenfeld J, Mestroni L, Seidman CE, Taylor M, Towbin JA, J Card Failure 2009
Screening for Familial Dilated Cardiomyopathy
Hershberger & Siegfried, JACC 2011
Clinical ScreeningProband with
cardiomyopathy
Family history
Sporadic CMFamilial CM
1st degree relatives
CM screeningPhysical exam
ElectrocardiogramEchocardiogram
DNA, lab tests (CK-MM)
Special tests:SAECG (ARVD)
ETT (HCM)Holter (HCM, ARVD)
MRI (ARVD)
Hershberger R, Lindenfeld J, Mestroni L, Seidman CE, Taylor M, Towbin JA, J Card Failure 2009GCRC NIH grant MO1 # #RR00051 – Protocol 1575, PI Luisa Mestroni
FC Registry1668 subjectsF-u 20y
• Referral to centers expert in genetic evaluation and family-based management should be considered (level of evidence B)
• Genetic and family counseling is recommended for all patients and families with cardiomyopathy (Level of evidence A)
Hershberger R, Lindenfeld J, Mestroni L, Seidman CE, Taylor M, Towbin JA, J Card Failure 2009
Genetic Evaluation of Cardiomyopathies: a HFSA Comprehensive Heart Failure Practice
Guideline
NIH/Medicare/Medicaid
• Genetic testing should be considered for the one most clearly affected person in a family to facilitate family screening and management.
Hershberger R, Lindenfeld J, Mestroni L, Seidman CE, Taylor M, Towbin JA, J Card Failure 2009
Genetic Evaluation of Cardiomyopathies: a HFSA Comprehensive Heart Failure Practice
Guideline
Phenotype Gene tests available* Yield of positive results
DCM LMNA, MYH7, TNNT2, SCN5A, DES, MYBPC3, TNNI3, TPMI, ACTC, PLN, LDB3 and TAZ.
LMNA: 5-8%, MYH7: 4.2%,TNNT2: 2.9%, All data are from research cohorts
• 19 genes associated with DCM• CardioChip™ sensitivity 98%• Clinical sensitivity 26-29%• Cost and turnaround time 50%: $3,700
See Harvard Partners:http://www.hpcgg.org/LMM/comment/DCM_Info_Sheet.jsp?name=LMM&subname=genetictests
Therapy Based on Genetic Testing• Medical and device therapy as outlined in the general
guidelines
• DCM: LAMIN A/C mutations ICD may be considered before LVEF < 35% if family history of SD
• HCM sarcomeric mutation carriers (w/o hypertrophy)*:– Ca++ antagonists (Diltiazem)
altered Ca++ homeostasis
– Simvastatin, Atorvastatin
hypertrophy– Candesartan
fibrosis
– N-acetylcysteine (mycomyst)
oxidative stress
• Fabry: α galactosidase replacement therapy
Hershberger R, Mestroni L, et al. J Card Failure 2009Wang l, Seidman CE, et al. Ann Int Med 2010;152:513*animal models, ongoing clinical trial
Variable expressivity in FDC: modifier genes
CUVISmith N.L., Vasan R.S. CHARGE Consortium. Circ Genet May 5, 2010Morrison A.C. et al, CHARGE Consortium. Circ Genet May 5, 2010
Meta-analysis of 4 GWAS with incidental HF:Framingham, Rotterdam, Atherosclerosis Risk in Community (27% AA), Cardiovascular Health (15% AA)
23,000 patients2.5 M SNPs testedFollow-up ~11 y
HF: European ancestry: 15q22 (1.4x10-8) USP3African ancestry: 12q14 (6.7x10-8) LRIG3
Mortality: European 3p21 (3.2x10-7)
CMTM7
Limitations: 1. different HF criteria, 2. meta-analysis
Future Perspectives
1. DCM: • Diagnosis: Next Generation Sequencing: 1Mbp $100,000 <$1 • Therapy: Personalized based on genetic defect• Research: Gene discovery: Whole Genome ($50,000)
or Whole Exome Sequencing ($2,000 - 4,000)Functional genomics: small RNA molecules
2. Variability of expression: GWAS to identify modifier genesgene-environment
3. Pharmacogenomics: genetic screening to identify responders/non-responders
Lifton. NEJM 2010
Screening for Familial Dilated Cardiomyopathy
Personalized medicine in DCM
DNA Variation
DCM
DIAGNOSISIdentification of the mutation
monogenic diseasecomplex traits
• early intervention • efficient• proof of equivocal cases
DIAGNOSIS PREVENTION• early therapy• screening of relatives• “sudden death”• change of lifestyle (sports)
DNA Variation
DCM
Personalized medicine in DCM
DIAGNOSIS PHARMACOGENOMICSTherapy selection based
on genetic profile
PREVENTION
DNA Variation
DCM
Personalized medicine in DCM
Personalized medicine: Hippokrates of KosKos approx. 460 B.C.–377 B.C.
It is more important to know what sort of person has a disease
than to know what sort of disease a person has
www.ama-assn.org/
University of Colorado - Cardiovascular InstituteMolecular Genetics Program
CUCVI Molecular GeneticsMatt TaylorDobromir SlavovCarl BarnesElisa Carniel*Park McNairXiao Zhu
DIV. OF CARDIOLOGY, TRIESTEGianfranco SinagraAndrea Di LenardaFrancesca Brun*Michele Moretti*Marco Merlo*Stelios Pyxaras
HUMAN MEDICAL GENETIC PROGRAMPam FainRichard SpritzSharon GrawElaine Spector
DIV. OF CARDIOLOGY, UCHSCMike BristowDebbie Ferguson, Kathy Petersen & HF teamJoAnn LindenfeldDoug RobertsonErnesto Salcedo and Steve Belcher
THE DENVER CHILDREN’S HOSPITALShelley MiyamotoJean Lascor-Cavanough
VAGregory Schwartz
CUCVICarlin Long*Kika Sucharov
UNIVERSITY OF TRIESTE & ICGEBOrfeo Sbaizero & CEMS teamMaurizio Prato. Laura BalleriniMauro Giacca, Lorena ZentilinValentina Martinelli