HCM GENETIC OR CLINICAL FAMILY SCREENING?

Transcription

1 HCM GENETIC OR CLINICAL FAMILY SCREENING? Division of Inherited Cardiac Diseases Heart Center for the Young and Athletes A Dpt of Cardiology University of Athens

2 GENETICS IN HCM DIAGNOSIS GENETIC RECOMFIRMATION PHENOCOPIES SUBCLINICAL FORMS- FAMILY SCREENING GENETIC INTERPRETATION GENETIC AND CLINICAL FAMILY SCREENING A TOOL FOR GENETIC INTERPRETATION GENETICS AND RISK STRATIFICATION FOR SCD GENETICS AND TREATMENT GRNETICS AND PRE IMPLANTATION DIAGNOSIS

3 Genetic diseases Γονιδιακή διαφοροποίηση Αφορά όλη την οικογένεια

4 Genetic analysis as a diagnostic tool Recomfirmation of clinical diagnosis SCREEN THE FAMILY

5 FAMILIAL DISEASE

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7 Mutation: Arg286Cys

8 Inherited cardiac disease VARIABLE PENETRANCE AND CLINICAL EXPRESION Typical form Silent form Subclinical form Normal gene carrier GENOTYPE NEGATIVE

9 CLINICAL AND GENETIC DIAGNOSIS CLINICAL DIAGNOSIS CLINICOGENETIC DIAGNOSIS GENETIC DIAGNOSIS 1. CLINICAL DIAGNOSIS UKNOWN GENES. 2. GENETIC DIAGNOSIS NO CLINICAL EXPRESSION. 3. CLINICAL AND GENETIC DIAGNOSIS..

10 GENETIC DIAGNOSIS AND GENETIC FAMILY SCREENING DIAGNOSIS CONFIRMED RECONFIRMED DIAGNOSIS IN SUBCLINICAL FORMS IDENTIFY CARRIERS,MUT (+),PHEN (-) IDENTIFY MUT (-),PHEN (-) CHAIN OF INHERITANCE CAN BE STOPPED LOGISTICS MINIMIZATION OF THE COST COST BENEFIT ANALYSIS

11 Anastasakis et al ESC Anastasakis et al ESC 2012 HCM ARVC DCM (LMNA) Positive probands (%) 13/18(72.2%) 23/46(50%) 2/3(66.7%) No of relatives from positive probands (Range per family) Mut(+)Phen(+)% (of total fam members) Mut(+)Phen(-)% (of total fam memb) 52 (0-10) 79 (0-12) 6 (3) 23.1% 15.2% 67.0% 26.9% 39.2% 0.0%

12 Family genetic screening HCM Positive probands (%) No of relatives from positive probands (Range per family) 13/18 (72.2%) 52 (0-10) Mut(+)-Phen(+)% (of total family members) 23.1% Mut(+) - Phen(-)% (of total family members) 26.9% Mut(-) - Phen(-)% (of total family members) 50%

13 P Charron et al Eur Heart J 2010 P Charron et al Eur Heart J 2010 PREDICTIVE POSITIVE DIAGNOSIS DIAGNOSIS ASYMPTOMATIC RELATIVES PREDICTIVE DIAGNOSIS IN IN SOME PTS DIAGNOSIS PROGNOSTIC TESTING IN SOME PTS PRENATAL OR PRE INPLATATION DIAGNOSIS

14 GENETICS IN HCM SUBCLINICAL FORMS- FAMILY SCREENING PHENOCOPIES SUBCLINICAL FORMS- FAMILY SCREENING GENETIC INTERPRETATION GENETIC AND CLINICAL FAMILY SCREENING A TOOL FOR GENETIC INTERPRETATION GENETICS AND RISK STRATIFICATION FOR SCD GENETICS AND TREATMENT GRNETICS AND PRE IMPLANTATION DIAGNOSIS

15 Causes of Left Ventricular Hypertrophy ACE Racial Gender Friedreich s Ataxia Noonan Syndrome LEOPARD syndrome Genetic Mitochondrial disease Fatty Acid Metabolism Fabry s disease Glycogen storage Hypertension Physiological Amyloid Amyloid Metabolic Infants diabetic mothers Phaeochromocytoma

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17 Pedigree Symptoms Physical exam ECG Laboratory Echo/MRI Other Rapezzi et al EHJ 2012 Autsomal dominant Autosomal recessive X-linked-Dystrophin, Danon. Maternal Deafness (AFD, Epicardin) Muscle pains/weakness (Dystrophin) Paraesthesia Muscle weakness Postural hypotension Rash (lentigenes, angiokeratomata) Ocular Premature conduction disease Pseudo-infarct pattern Creatinine kinase (dystrophic, Danon, Desmin) Serum creatinine Proteinuria Ferritin Lactate Pattern of hypertrophy Valve disease Pericardial effusion Pattern of gadolinium hyperenhancement Exercise test: premature acidosis Endomyocardial biopsy GENETICS

18 GENETICS IN HCM DIAGNOSIS GENETIC RECOMFIRMATION PHENOCOPIES SUBCLINICAL FORMS- FAMILY SCREENING GENETIC INTERPRETATION GENETIC AND CLINICAL FAMILY SCREENING A TOOL FOR GENETIC INTERPRETATION GENETICS AND RISK STRATIFICATION FOR SCD GENETICS AND TREATMENT GRNETICS AND PRE IMPLANTATION DIAGNOSIS

19 Disease paths and novel therapeutic targets in HCM Circ Res 2011 Myofilament mutations generally enhance Ca ++ sensitivity Maximal force production ATP ase activity These defects appear to converge On energy deficiency and Altered Ca++ handling As major common paths leading to the anatomic and functional features characteristic of HCM

20 GENETICS sometimes influence the TREATMENT CHOISE FABRY POMPE DANON

21 GENETICS IN HCM DIAGNOSIS GENETIC RECOMFIRMATION PHENOCOPIES SUBCLINICAL FORMS- FAMILY SCREENING GENETIC INTERPRETATION GENETIC AND CLINICAL FAMILY SCREENING A TOOL FOR GENETIC INTERPRETATION GENETICS AND RISK STRATIFICATION FOR SCD GENETICS AND TREATMENT

22 Myosin Binding Protein C Int1 M.X.Kotta, A.Anastasakis et al in press I:1 I:2 II:2 Normal Phenotype II:2 N I:2 SSCP Analysis Normal sequence (N)

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25 DAUGHTER 2002

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29 SIATISTA (KOZANI) SIATISTA (KOZANI) SIATISTA (KOZANI) THESSALONIKI (70) (72) (72) (55) (70) SIATISTA (KOZANI) ATHINA THESSALONIKI ATHINA (28)

30 Alternative follow up strategies for family screening Charron P. et al., European Heart Journal 2010

31 Clinically identified patients 1. Symptomatic individuals that fulfil diagnostic criteria of typical or subclinical HCM 2. Asymptomatic individuals that fulfil diagnostic criteria of typical HCM 3. Asymptomatic individuals that fulfil diagnostic criteria of subclinical HCM

32 Genetic testing as diagnostic tool 1. Symptomatic individuals that fulfil diagnostic criteria of typical or subclinical HCM 2. Asymptomatic individuals that fulfil diagnostic criteria of typical HCM 3. Asymptomatic individuals that fulfil diagnostic criteria of subclinical HCM 4. Carriers of pathogenic mutations that do not clinically express HCM

33 Potential Benefits 1. May offer diagnostic value for symptomatic individuals by elucidating the exact molecular basis for the disorder 2. May establish a definitive molecular diagnosis or disease prediction when the clinical evaluation for the disorder is inconclusive 3. May help personalized therapeutic recommendations and management of a patient s specific disorder by characterization of the precise genotype 4. May confirm or exclude the presence of a disease-causing mutation in presymptomatic family members/relatives with a family history of a genetic disorder 5. May help on family planning and rupture of inheritance Tester, D.J and Ackerman, M.J., Circulation 2011 / Ingles J. et al., Heart, Lung and Circulation 2011

34 Cost-effectiveness analysis A cost-effectiveness model of genetic testing for the evaluation of families with hypertrophic cardiomyopathy Ingles J. et al., Heart, 2011 DNA testing for hypertrophic cardiomyopathy: a cost-effectiveness model Wordsworth S. et al., European Heart Journal, 2010 CONCLUSIONS The use of molecular genetic information in the diagnosis and management of HCM families is cost-effective approach in comparison with the conventional approach of regular clinical screening. This suggests that all should have access to specialised cardiac genetic clinics that can offer genetic testing.

35 Phen(+) Annual examination of affected individuals* Proband Clinical screening Clinical family screening n1 : Clinical exanimination* between 10 and 80** Every 1 2 years between 10 and 20 Every 2-5 years between 20 and 80 Phen(-) (cardiac examination to be performed if symptoms.) n2 : Clinical exanimination* between 10 and 80** Every 1 2 years between 10 and 20 Every 2-5 years between 20 and 80 Proband Clinical screening + Genetic screening Mut(-) Mut(+)Phen(+) Annual examination of affected individuals* Proband Clinical screening + Genetic screening Mut(+) Clinical family screening + Genetic screening known mutation Mut(+)Phen(-) n1 Clinical exanimination* between 10 and 80** Every 1 2 years between 10 and 20 Every 2-5 years between 20 and 80 (cardiac examination to be performed if symptoms.) Mut(-)Phen(-) n2 No future development of the disease Medical follow-up is no more required * Includes ECG, echocardiography, Holter-ECG and cardiopulmonary exercise test ** Includes ECG and echocardiography

36 Cost-minimazation analysis - HCM Two strategies: clinical screening and clinical-genetic screening have comparable effectiveness Which is the least costly option on a family level? No families 16 Mean No of family members (range) 5.9 (3-11) Mean age of fam members at 1rst screening 32.5 (± 7.6) Cost of clinical screening (per year) Phen(+) 180 Cost of clinical screening (per year) - Phen(-) 120 Cost of genetic screening - proband 1850 Cost of genetic screening known mutation 300 Phen(+) individuals have a lifetime annual follow-up (ECG, echo, Holter monitoring 24h, cardiopulmonary exercise test Phen(-) individuals repeat their cardiac evaluation (ECG, echo) very 3 years if performed before 10 years of age yearly between 10 and 20 years every 2 years for the rest of their life Individuals will remain in the same clinical profile as first found Both strategies were discounted at 3.5%.

37 Cost-minimazation analysis - HCM Clinical strategy Clinical-genetic strategy AVERAGE STDEV %LCI %UCI

38 Main outcomes associated with predictive diagnosis in cardiomyopathies Charron P. et al., European Heart Journal 2010

39 GENETICS IN HCM DIAGNOSIS GENETIC RECOMFIRMATION PHENOCOPIES SUBCLINICAL FORMS- FAMILY SCREENING GENETIC INTERPRETATION GENETIC AND CLINICAL FAMILY SCREENING A TOOL FOR GENETIC INTERPRETATION GENETICS AND RISK STRATIFICATION FOR SCD GENETICS AND TREATMENT GRNETICS AND PRE IMPLANTATION DIAGNOSIS

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41 GENETICS IN HCM DIAGNOSIS GENETIC RECOMFIRMATION PHENOCOPIES SUBCLINICAL FORMS- FAMILY SCREENING GENETIC INTERPRETATION GENETIC AND CLINICAL FAMILY SCREENING A TOOL FOR GENETIC INTERPRETATION GENETICS AND RISK STRATIFICATION FOR SCD GENETICS AND TREATMENT GENETICS AND PRE IMPLANTATION DIAGNOSIS

42 HARPER et al UCLH 2012 Preimplantation diagnosis

43 HEART RHYTHM SOCIETY (HRS) AND EUROPEAN HEART RHYTHM (EHRA) EXPERT CONSENSUS STATEMENT OF GENETIC TESTING FOR THE CHANNELOPATHIES AND CARDIOMYOPATHIES Michael J. Ackerman, MD, PhD, Silvia G. Priori, MD, PhD, Stephan Willems, MD, PhD, Charles Berul, MD, FHRS, CCDS, Ramon Brugada, MD, PhD, Hugh Calkins, MD, FHRS, CCDS, A. John Camm, MD, FHRS, Patrick T. Ellinor, MD, PhD, Michael Gollob, MD, Robert Hamilton, MD, CCDS, Ray E. Hershberger, MD, Daniel P. Judge, MD, Herve` Le Marec, MD, William J. McKenna, MD, Eric Schulze-Bahr, MD, PhD, Chris Semsarian, MBBS, PhD, Jeffrey A. Towbin, MD, Hugh Watkins, MD, PhD, Arthur Wilde, MD, PhD, Christian Wolpert, MD, and Douglas P. Zipes, MD, FHRS HEART RHYTHM 2011 EUROPACE 2011

44 STATE OF GENETIC TESTING FOR HCM Class I (is recommended) Comprehensive or targeted (MYBPC3, MYH7, TNNI3, TNNT2, TPM1) HCM genetic testing is recommended for any patient in whom a cardiologist has established a clinical diagnosis of HCM. Mutation-specific genetic testing is recommended for family members and appropriate relatives following the identification of the HCM-causative mutation in an index case. HEART RHYTHM 2011 EUROPACE 2011

45 GENETIC COUNSELLING AND TESTING IN CARDIOMYOPATHIES P Charron et al Eur Heart J 2010 DIAGNOSIS PROGNOSTIC EVALUATION TREATMENT AT PRESENT INDICATIONS FOR GENETIC TESTING IN ICVD SHOULD BE CONSERVATIVE

46 CAN GENETIC TESTING IMPROVE OUR AIM IN HYPERTROPHIC CARDIOMYOPATHY? Circ Res 2010 Has remained a mainstay of evaluation of the family with a previously identified gene mutation rather than screening tool for the general population

47 CLINICAL AND GENETIC DIAGNOSIS CLINICAL DIAGNOSIS CLINICOGENETIC DIAGNOSIS GENETIC DIAGNOSIS 1. CLINICAL DIAGNOSIS UKNOWN GENES. 2. GENETIC DIAGNOSIS NO CLINICAL EXPRESSION. 3. CLINICAL AND GENETIC DIAGNOSIS..

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49 Next-generation sequencing (NGS) Increased throughput of Sanger method by sequencing DNA in a massively parallel fashion NGS allows the study of many genes or even complete exome at a lower cost We study all the known genes that are related to the inherited cardiac disease of interest James S Ware, et al., Heart. 2012

50 Network for SCD prevention in the Young INHERITED CV DISEASES SD FAMILIES ATHLETES Clinical Cardiology MOLECULAR CARDIOLOGY Genetics FAMILY SCREENING TYPICAL DISEASE SUBCLINICAL DISEASE GENE CARRIER

51 Family genetic screening GREEK REGISTRY 2012 HCM Positive probands (%) No of relatives from positive probands (Range per family) 13/18 (72.2%) 52 (0-10) Mut(+)-Phen(+)% (of total family members) 23.1% Mut(+) - Phen(-)% (of total family members) 26.9% Mut(-) - Phen(-)% (of total family members) 50%

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53 The clinical challenge of managing a hereditary heart condition