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Introduction; Genetic cardiology

Introduction; Genetic cardiology. The Heart Centre. Henning Bundgaard REAH, The Heart Centre. Diagnostic Centre. Juliane Marie Centre. Background. Several cardiovascular diseases are inherited Mainly dominant inheritance i.e. 50% of 1. degree relatives carry the same mutation

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Introduction; Genetic cardiology

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  1. Introduction; Genetic cardiology The Heart Centre Henning Bundgaard REAH, The Heart Centre Diagnostic Centre Juliane Marie Centre

  2. Background • Several cardiovascular diseases are inherited • Mainly dominant inheritance • i.e. 50% of 1. degree relatives carry the same mutation • Relatives ”at risk” can be identified • Early treatment is expected to reduce morbidity and mortality • Management of families rather than individual patients calls for changes: • Clinical guidelines • Establishment of a suitable organisation

  3. Why family screening? • To enable primary prophylaxis: • 50% of the relatives (1. degree) are at risk for developing the family disease (low cost/effectiveness-ratio) • Pre-requisite for screening: Significant outcome of treatment modalities (WHO, National Board of Health)

  4. Benefits of family screening and genetic testing • The benefits relates to the relatives • It is a risk factor that the proband is sick – i.e. the relatives are in a high risk group • It is an advantage to offer prophylaxis or treatment before overt disease • Enables prenatal diagnostics • Definitely confirm or reject the risk of developing the disease

  5. Benefits of screening - examples Long QT or Brugada syndrome, HCM, ARVC First symptom in relatives may be sudden cardiac death Familial hypercholesterolemia or premature ischaemic heart disease (m<55, w<65) Early tx of modifiable risk factors increases life-expectancy Sudden cardiac death Common denominator in several inherited cardiac diseases

  6. Danish national recommendations A working group under Danish Society of Cardiology with significant contributions from • Cardiologists representing several sub-specialities • Clinical geneticist • Paediatricians • National Board of Health • Specialists in legal aspects of medicine • Ethicist

  7. The working group and other contributors Henrik Kjærulf Jensen, Henning Mølgaard, Lars Køber, Jesper Hastrup Svendsen, Peter Clemmensen, Jens Erik Nielsen-Kudsk, Ole Havndrup, Michael Christiansen, Paal Skytt Andersen, Jens Mogensen, Jørgen Kanters, Lars Søndergaard, Keld Sørensen, Flemming Skovby, Stig Djurhuus, Bent Raungaard, Ib Klausen, Peter Riis Hansen, Jim Hansen, Niels Gadsbøll, Egon Toft, Niels Vejlstrup, Henning Bundgaard Kirsten Rasmussen, Odense Universitetshospital, Dansk Selskab for Med. Genetik Ulrik Baandrup, Århus Sygehus, Dansk Selskab for Patologisk Anatomi og Cytologi Øvrige bidragydere Lektor, dr.jur. Mette Hartlev, Forskningsafdeling II, Det Juridiske Fakultet, KU Afdelingslæge Ida Hastrup Svendsen, BBH Klinikchef, overlæge, dr.med. Ulla Feldt Rasmussen, Endokrinologisk afd. PE, RH Overlæge, dr.med. John Vissing, Neurologisk Klinik N, RH

  8. The working group and other contributors Henrik Kjærulf Jensen, Henning Mølgaard, Lars Køber, Jesper Hastrup Svendsen, Peter Clemmensen, Jens Erik Nielsen-Kudsk, Ole Havndrup, Michael Christiansen, Paal Skytt Andersen, Jens Mogensen, Jørgen Kanters, Lars Søndergaard, Keld Sørensen, Flemming Skovby, Stig Djurhuus, Bent Raungaard, Ib Klausen, Peter Riis Hansen, Jim Hansen, Niels Gadsbøll, Egon Toft, Niels Vejlstrup, Henning Bundgaard Kirsten Rasmussen, Odense Universitetshospital, Dansk Selskab for Med. Genetik Ulrik Baandrup, Århus Sygehus, Dansk Selskab for Patologisk Anatomi og Cytologi Øvrige bidragydere Lektor, dr.jur. Mette Hartlev, Forskningsafdeling II, Det Juridiske Fakultet, KU Afdelingslæge Ida Hastrup Svendsen, BBH Klinikchef, overlæge, dr.med. Ulla Feldt Rasmussen, Endokrinologisk afd. PE, RH Overlæge, dr.med. John Vissing, Neurologisk Klinik N, RH

  9. The inherited cardiac diseases • Cardiomyopathies: Hypertrophic, dilated, idiopathic restrictive and arrhythmogenic right ventricle cardiomyopathy, non-compaction, muscular dystrophies • Channelopathies: Long QT syndrome, Brugada syndrome, Catecholaminergic polymorf VT • Ischaemic heart disease: Premature IHD, familial hypercholesterolemia • Storage diseases: Hereditary hemochromatosis, familial amyloidosis, Fabry disease • Others: Pulmonary arterial hypertension, Marfan syndrome • Sudden cardiac death: • +…+…+…

  10. The inherited cardiac diseases • Cardiomyopathies:Hypertrophic, dilated, idiopathic restrictive and arrhythmogenic right ventricle cardiomyopathy, non-compaction, muscular dystrophies • Channelopathies: Long QT syndrome, Brugada syndrome, Catecholaminergic polymorf VT • Ischaemic heart disease: Premature IHD, familial hypercholesterolemia • Storage diseases: Hereditary hemochromatosis, familial amyloidosis, Fabry disease • Others: Pulmonal arterial hypertension, Marfan syndrome • Sudden cardiac death: • +…+…+…

  11. The inherited cardiac diseases • Cardiomyopathies: Hypertrophic, dilated, idiopathic restrictive and arrhythmogenic right ventricle cardiomyopathy, non-compaction, muscular dystrophia • Channelopathies:Long QT syndrome, Brugada syndrome, Catecholaminergic polymorf VT • Ischaemic heart disease: Premature IHD, familial hypercholesterolemia • Storage diseases: Hereditary hemochromatosis, familial amyloidosis, Fabry disease • Others: Pulmonal arterial hypertension, Marfan syndrome • Sudden cardiac death: • +…+…+…

  12. The inherited cardiac diseases • Cardiomyopathies: Hypertrophic, dilated, idiopathic restrictive and arrhythmogenic right ventricle cardiomyopathy, non-compaction, muscledystrofierne • Channelopathies: Long QT syndrome, Brugada syndrome, Catecholaminergic polymorf VT • Ischaemic heart disease: Premature IHD, familial hypercholesterolemia • Storage diseases: Hereditary hæmokromatosis, familial amyloidosis, Fabry disease • Others: Pulmonal arterial hypertension, Marfan syndrome • Sudden cardiac death: • +…+…+…

  13. The inherited cardiac diseases • Cardiomyopathies: Hypertrophic, dilated, idiopathic restrictive and arrhythmogenic right ventricle cardiomyopathy, non-compaction, muscular dystrophies • Channelopathies: Long QT syndrome, Brugada syndrome, Catecholaminergic polymorf VT • Ischaemic heart disease: Premature IHD, familial hypercholesterolemia • Storage diseases: Hereditary hemochromatosis, familial amyloidosis, Fabry disease • Others: Pulmonal arterial hypertension, Marfan syndrome • Sudden cardiac death: • +…+…+…

  14. Family screening in hypertrophic cardiomyopathy • Our experience; 145 probands – 630 relatives • In Denmark there is ~3 1. degree relatives pr. proband • Gene mutations are found in ½ the families • Based on genetic findings 80% of relatives without significant clinical findings had the “risk” rejected • 99%’s of the relatives accepted the offer of clinical and genetic screening

  15. Screening strategy Clinical work-up-diagnostics-treatment – unaltered The new aspect Is it an inherited disease? Yes Family screening; Are there any relatives? Benefit from screening? (Pre-natal diagnostics)

  16. Approaching the relatives • Contact through the proband • Relatives are informed – rationale and expected benefit AND possible ”side effects” • Relatives gives written consent

  17. Family screening - content • Clinical work-up - ALWAYS - preceding genetic testing • Genetic testing - IF - the probands mutation has been identified • Genetic counselling

  18. Criteria for genetic testing ALWAYS following clinical work-up • One or more relatives are expected to gain from the result • If pre-natal diagnostic / pre-implantation diagnostics may be requested The prerequisite for genetic testing: The probands mutation has been identified

  19. Value of genetic testing in addition to clinical screening? • In ~ ½ the families a gene mutation can be identified • definitely confirm or reject the risk of developing the disease – independent of clinical findings • examples: • Long QT syndrome – some have normal EKG – and yet at risk • Hypertrophic cardiomyopathy – age dependent development • Amyloidosis – age dependent development • Athletes, the pilot, etc.

  20. Results of genetic testing – follow-up • Positive gene test – follow-up is offered • Negative gene test – follow-up is ceased • No genetic findings – follow-up is offered

  21. Genetic counselling By cardiologists – genetic counsellors (prenatal diagnostics, <18 y, others) Neutral information of probands and relatives - prior to screening - during screening - following screening

  22. Screening of children? Problem: If the parents make the decision the childs rights to know and rights not to know – may be jeopardised Recommendations: • No genetic testing if the disease does not develop until the age at which the child can make his/her own decision (~15 y) • If the disease is seen in childhood clinical screening is offered from that age • If clinical screening may be false negative - genetic testing is offered – if a positive answer a priori is thought to lead to active treatment

  23. Disease specific recommendations For each disease entity • Background, characteristics, diagnosis, treatment • Criteria for clinical screening of relatives • Specific clinical tests / examinations • Criteria for genetic testing • Criteria for treatment • Guidelines for follow-up • Who (age – children?) • How often • What - content of follow-up assessment • Participation in sports

  24. Other inherited diseases with cardiac involvement • Hemochromatoses(Cardiomyopathy)(Haematologists) • Fabry disease(Cardiomyopathy)(Endocrinologists, RH) • Marfan syndrome(Aorta+mitral dx) (Skejby Sygehus & RH) • Muscular dystrophies (Cardiomyopathy + arrhythmia)(Neurologists) • Guidelines for the for the cardiological follow-up • Family screening remains in other specialities

  25. Proposed patient-flow • Locally, the indication for family screening is assessed • In the center the proband is evaluated and the relatives are contacted and offered screening • Following screening the relative with a need for follow-up is offered further management in • In the centre - or • Locally, according to specific arrangements • Conferences and exchange of data between the local department and the centre

  26. Sudden cardiac death – Danish figures Annual death rate 60.000 SCD in DK (Rates in Belgium/USA15-25%) 10.000 Cardiac arrest w/resussitation 3.500 - hereoff are 20% (~650) < 50 y - if 20% of SCD < 50 y then; SCD < 50 y in DK ~ 1.500-2.000

  27. SCD in Denmark – actual management by authorities The police investigate mode of death The police decide if autopsy is needed Identified Buried Yes No Cause of Death ~1.500/y ?/y The key in family screening

  28. Estimate of quantity of screening of inherited cardiac diseases Number per year Out-patient clinic – number of relatives (1. visit) 1.000 EKG 1.000 Blood samples (routine testing) 650 Echocardiographies 400 Exercise EKG 60 MRI 60 Signal-average EKG (late potentials) 60 ”Heavy” genetic tests 100 (I.e. identification of the families mutation in the proband) ”Easy” genetic tests 150 (I.e.testing for the families specific mutation) Genetic counselling 100

  29. Rigshospitalets Enhed for Arvelige hjertesygdomme The Heart Centre Department of Cardiology Identification, counselling, dx. work-up and treatment Rigshospitalets Enhed for Arvelige Hjertesygdomme Ledelse / Ekspertgruppe Juliane Marie Centre Clinical Dep. of Genetic Genetic counselling Diagnostic Centre Depart. of Biochemistry Genetic testing Research and development Co-operators and advisers Paediatricians, psychologists, obstetri-cians, forensic medicine, neurologists, etc

  30. Take home message 1 = 4 (1 proband + 3 relatives)

  31. Generelle aspekter af familieundersøgelser

  32. Krav til screening / familieudredning ved arvelig hjertesygdom WHO’s krav Kommentar vedrørende FH 1.Sygdommen skal udgøre et alvorligt sundhedsproblem FH har ubehandlet ofte har fatalt forløb (AMI, død) 2.Der skal være en acceptabel behandling Behandlingen er effektiv, uden væsentlige bivirk. 3.Diagnose og behandling skal være tilgængelig Diagnose og dokum. behandling er tilgængelig 4.Sygdommen skal kunne påvises i et latent eller FH kan oftest påvises i barndommen, tidlig stadium dvs. længe før symptomgivende aterosklerose 5.Der skal være en egnet test/undersøgelsesmetode Familieanamnese, serum-kolesterol, gen-us. 6.Testen skal være acceptabel for befolkningen De fleste FH slægtninge modtager kontroltilbud 7.Sygdommens ubehandlede forløb skal være Genbærere risiko for præmatur iskæmisk tilstrækkeligt belyst hjertesygdom og tidlig hjertedød 8.Behandlingsindikationerne skal være klart definerede Der er retningslinier for kolesterolsænk. behandl. 9.Omkostningerne ved sygdomsopsporing skal stå i et Der foreligger dokumentation for at tidlig diagnose rimeligt forhold til sundhedsvæsenets samlede udgifter og behandling af FH er ”cost-effective”. 10.Screeningsindsatsen skal være en fortløbende proces Kontrolprogrammet iværksættes livslangt SST/Etisk Råds simplificerede liste: 1. Er der en sikker diagnose? 2. Er der en høj penetrans? 3. Er der tale om en alvorlig sygdom? 4. Er der en effektiv profylakse eller behandling?

  33. Stamtavlen – et arbejdsredskab  = mand,  = kvinde, = proband, = afdød

  34. Nomenklatur Proband: (= Index case) - Den første i en familie, der diagnosticeres Fænotype: Den kliniske fremtoning Genotype: Den genetiske information – oftest brugt ift. et bestemt locus eller gen Locus heterogenitet: Mutationer i forskellige gener kan medføre ét bestemt sygdomsbillede Allel heterogenitet: Forskellige mutationer i ét gen kan medføre ét bestemt sygdomsbillede Dominant arv: Abnormitet i kun et af de to allele gener (heterozygot) giver sygdom Recessiv arv: Abnormitet i begge allele gener (homozygot) kræves, før der udvikles sygdom (undtaget x-bundet recessiv) Kønsbunden arv: Arv knyttet til kønskromosomet Konsangvine slægtninge: Slægtninge med blod (- eller rettere gen) –fællesskab 1.ledsslægtninge: (= første- ledsslægtninge = 1. gradsslægtninge) - Forældre, søskende, børn Penetrans: Inkomplet; ikke alle med mutationen får sygdommen – komplet; alle får sygdommen Expressivitet: Sværhedsgraden af arvelig sygdom i forhold til alle genetisk disponerede Heterozygot: De to allele gener er ikke ens Homozygot: De to allele gener er ens Polymorfi: Genvariation med frekvens  1%, - som ikke skønnes selvstændig sygdomsfremkaldende Mutation: En ændring i genomet – følgende typer ses: - Missense: Udskiftning af et basepar, medførende indsættelse af anden aminosyre i proteinet - Nonsense: Udskiftning af basepar, medførende at der ikke kodes for aminossyre - Deletion: Tab af basepar, medførende manglende indsættelse af aminosyre

  35. Den genetisk undersøgelse • Fastlægge, hvilke gener der skal undersøges • Blodprøve (leucocytter) fra pt. til DNA oprensning • Opformering af de ønskede gen-sekvenser vha PCR-teknik • Mutations-us. /DNA-sekventering af ALLE relevante gener • Sammenligne med sekvensen phylogenetisk og i EN ETNISK RELEVANT KONTROLGRUPPE (~100 personer) • - Er genændringen sygdomsfremkaldende?

  36. Vanskeligheder / fælder i den genetiske undersøgelse • ER DEN KLINISKE DIAGNOSE KORREKT? • Kun positive fund i 15-75% af familierne • ”Private mutationer” – dvs. hver familie sin mutation – kræver us. af hele genet – modsat f.eks. CF, hvor >90% har samme mut. • Hos en del (20%?) er der ændringer i 2 gener (compound heterozygote) – hvilke(n) giver sygdom? • Polymorfier (>1%) - gen-varianter - betragtes ikke som sygdomsfremkaldende – men evt. ”modifiers”

  37. Er mutationen skyld i sygdommen? • Familieundersøgelse; Segregerer mutationen med sygdommen, dvs. findes mutationen hos alle de syge? (svært i små familier) • Bioinformatik; Litteratur /database us af om mut. er kendt / polymorfi; Er mut. i en fylogenetisk bevaret del (sekvenshomologi); Findes mutationen hos kontrollerne (~100)? Påvirkes funktionelle områder+ • (Funtionelle us.); Undersøge mutationens konsekvens på protein-niveau – f.eks. funktion af ion-kanal, us. af ændring i regulatorisk område

  38. Teknik, pris og svarafgivelse • Teknik; Kompliceret teknik og fortolkning • Pris; 1500 – 18.000 dkr for den første <1000 dkr for hver af de øvrige familiemedlemmer • Svar; Varer 1-6 mdr. HUSK ~½ får ikke noget svar. Alle svar (pos. og neg.) gives ved personlig fremmøde

  39. Take home message 1 = 4 (1 proband + 3 relatives)

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