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