Transcript Slide 1

Introduction;
Genetic cardiology
The Heart Centre
Diagnostic
Centre
Juliane Marie
Centre
Henning Bundgaard
REAH, The Heart Centre
Background
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Several cardiovascular diseases are inherited
Mainly dominant inheritance
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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:
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Clinical guidelines
Establishment of a suitable organisation
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)
Benefits of family screening
and genetic testing
The benefits relates to the relatives
1. It is a risk factor that the proband is sick – i.e. the
relatives are in a high risk group
2. It is an advantage to offer prophylaxis or treatment
before overt disease
3. Enables prenatal diagnostics
4. Definitely confirm or reject the risk of developing the
disease
Benefits of screening - examples
Long QT or Brugada syndrome, HCM, ARVC Fir
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
Danish national recommendations
A working group under Danish Society of
Cardiology with significant contributions from
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Cardiologists representing several sub-specialities
Clinical geneticist
Paediatricians
National Board of Health
Specialists in legal aspects of medicine
Ethicist
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
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
The inherited cardiac diseases
1. Cardiomyopathies:
Hypertrophic, dilated, idiopathic restrictive and
arrhythmogenic right ventricle cardiomyopathy,
non-compaction, muscular dystrophies
2. Channelopathies:
Long QT syndrome, Brugada syndrome,
Catecholaminergic polymorf VT
3. Ischaemic heart disease:
Premature IHD, familial hypercholesterolemia
4. Storage diseases:
Hereditary hemochromatosis, familial amyloidosis,
Fabry disease
5. Others:
Pulmonary arterial hypertension, Marfan syndrome
6. Sudden cardiac death:
7. +…+…+…
The inherited cardiac diseases
1. Cardiomyopathies:
Hypertrophic, dilated, idiopathic restrictive and
arrhythmogenic right ventricle cardiomyopathy,
non-compaction, muscular dystrophies
2. Channelopathies:
Long QT syndrome, Brugada syndrome,
Catecholaminergic polymorf VT
3. Ischaemic heart disease:
Premature IHD, familial hypercholesterolemia
4. Storage diseases:
Hereditary hemochromatosis, familial amyloidosis,
Fabry disease
5. Others:
Pulmonal arterial hypertension, Marfan syndrome
6. Sudden cardiac death:
7. +…+…+…
The inherited cardiac diseases
1. Cardiomyopathies:
Hypertrophic, dilated, idiopathic restrictive and
arrhythmogenic right ventricle cardiomyopathy,
non-compaction, muscular dystrophia
2. Channelopathies:
Long QT syndrome, Brugada syndrome,
Catecholaminergic polymorf VT
3. Ischaemic heart disease:
Premature IHD, familial hypercholesterolemia
4. Storage diseases:
Hereditary hemochromatosis, familial amyloidosis,
Fabry disease
5. Others:
Pulmonal arterial hypertension, Marfan syndrome
6. Sudden cardiac death:
7. +…+…+…
The inherited cardiac diseases
1. Cardiomyopathies:
Hypertrophic, dilated, idiopathic restrictive and
arrhythmogenic right ventricle cardiomyopathy,
non-compaction, muscledystrofierne
2. Channelopathies:
Long QT syndrome, Brugada syndrome,
Catecholaminergic polymorf VT
3. Ischaemic heart disease:
Premature IHD, familial hypercholesterolemia
4. Storage diseases:
Hereditary hæmokromatosis, familial amyloidosis,
Fabry disease
5. Others:
Pulmonal arterial hypertension, Marfan syndrome
6. Sudden cardiac death:
7. +…+…+…
The inherited cardiac diseases
1. Cardiomyopathies:
Hypertrophic, dilated, idiopathic restrictive and
arrhythmogenic right ventricle cardiomyopathy,
non-compaction, muscular dystrophies
2. Channelopathies:
Long QT syndrome, Brugada syndrome,
Catecholaminergic polymorf VT
3. Ischaemic heart disease:
Premature IHD, familial hypercholesterolemia
4. Storage diseases:
Hereditary hemochromatosis, familial amyloidosis,
Fabry disease
5. Others:
Pulmonal arterial hypertension, Marfan syndrome
6. Sudden cardiac death:
7. +…+…+…
Family screening in hypertrophic
cardiomyopathy
Our experience; 145 probands – 630 relatives
1. In Denmark there is ~3 1. degree relatives pr.
proband
2. Gene mutations are found in ½ the families
3. Based on genetic findings 80% of relatives without
significant clinical findings had the “risk” rejected
4. 99%’s of the relatives accepted the offer of clinical
and genetic screening
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)
Approaching the relatives
1.
Contact through the proband
2.
Relatives are informed – rationale and
expected benefit AND possible ”side
effects”
3.
Relatives gives written consent
Family screening - content
1.
Clinical work-up - ALWAYS - preceding
genetic testing
2.
Genetic testing - IF - the probands
mutation has been identified
3.
Genetic counselling
Criteria for genetic testing
ALWAYS following clinical work-up
1. One or more relatives are expected to gain
from the result
2. If pre-natal diagnostic / pre-implantation
diagnostics may be requested
The prerequisite for genetic testing: The
probands mutation has been identified
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.
Results of genetic testing – follow-up
1.
Positive gene test – follow-up is offered
2.
Negative gene test – follow-up is ceased
3.
No genetic findings – follow-up is offered
Genetic counselling
By cardiologists – genetic counsellors (prenatal
diagnostics, <18 y, others)
Neutral information of probands and
relatives
- prior to screening
- during screening
- following screening
Screening of children?
Problem: If the parents make the decision the childs rights
to know and rights not to know – may be jeopardised
Recommendations:
1. No genetic testing if the disease does not develop until
the age at which the child can make his/her own decision
(~15 y)
2. If the disease is seen in childhood clinical screening is
offered from that age
3. If clinical screening may be false negative - genetic
testing is offered – if a positive answer a priori is thought
to lead to active treatment
Disease specific recommendations
For each disease entity
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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
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Who (age – children?)
How often
What - content of follow-up assessment
Participation in sports
Other inherited diseases with
cardiac involvement
1.
Hemochromatoses (Cardiomyopathy)
2.
Fabry disease (Cardiomyopathy)
3.
Marfan syndrome (Aorta+mitral dx) (Skejby Sygehus & RH)
4.
Muscular dystrophies (Cardiomyopathy + arrhythmia)
(Haematologists)
(Endocrinologists, RH)
(Neurologists)
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Guidelines for the for the cardiological follow-up
Family screening remains in other specialities
Proposed patient-flow
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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 followup is offered further management in
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4.
In the centre - or
Locally, according to specific arrangements
Conferences and exchange of data between the local
department and the centre
Sudden cardiac death –
Danish figures
Annual death rate
60.000
SCD in DK
10.000
(Rates in Belgium/USA15-25%)
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
SCD in Denmark – actual
management by authorities
The police investigate mode of death
The police decide if autopsy is needed
Yes
Cause of Identified
Death
~1.500/y
No
Buried
?/y
The key in family screening
Estimate of quantity of screening
of inherited cardiac diseases
Out-patient clinic – number of relatives (1. visit)
EKG
Blood samples (routine testing)
Echocardiographies
Exercise EKG
MRI
Signal-average EKG (late potentials)
”Heavy” genetic tests
Number per year
1.000
1.000
650
400
60
60
60
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
Rigshospitalets Enhed for
Arvelige hjertesygdomme
The Heart Centre
Department of Cardiology
Identification, counselling,
dx. work-up and treatment
Diagnostic Centre
Depart. of Biochemistry
Genetic testing
Rigshospitalets
Enhed for
Arvelige
Hjertesygdomm
e
Ledelse /
Ekspertgruppe
Juliane Marie Centre
Clinical Dep. of Genetic
Genetic counselling
Research and development Co-operators and advisers
Paediatricians, psychologists, obstetricians, forensic medicine, neurologists, etc
Take home message
1 = 4 (1 proband + 3 relatives)
Generelle aspekter af
familieundersøgelser
Krav til screening / familieudredning
ved arvelig hjertesygdom
WHO’s krav
1. Sygdommen skal udgøre et alvorligt sundhedsproblem
2. Der skal være en acceptabel behandling
3. Diagnose og behandling skal være tilgængelig
4. Sygdommen skal kunne påvises i et latent eller
tidlig stadium
5. Der skal være en egnet test/undersøgelsesmetode
6. Testen skal være acceptabel for befolkningen
7. Sygdommens ubehandlede forløb skal være
tilstrækkeligt belyst
8. Behandlingsindikationerne skal være klart definerede
9. Omkostningerne ved sygdomsopsporing skal stå i et
rimeligt forhold til sundhedsvæsenets samlede udgifter
10. Screeningsindsatsen skal være en fortløbende proces
SST/Etisk Råds simplificerede liste:
Kommentar vedrørende FH
FH har ubehandlet ofte har fatalt forløb (AMI, død)
Behandlingen er effektiv, uden væsentlige bivirk.
Diagnose og dokum. behandling er tilgængelig
FH kan oftest påvises i barndommen,
dvs. længe før symptomgivende aterosklerose
Familieanamnese, serum-kolesterol, gen-us.
De fleste FH slægtninge modtager kontroltilbud
Genbærere risiko for præmatur iskæmisk
hjertesygdom og tidlig hjertedød
Der er retningslinier for kolesterolsænk. behandl.
Der foreligger dokumentation for at tidlig diagnose
og behandling af FH er ”cost-effective”.
Kontrolprogrammet iværksættes livslangt
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?
Stamtavlen – et arbejdsredskab
  = mand,  = kvinde,
= proband,
= afdød
Nomenklatur
Proband:
Fænotype:
Genotype:
Locus heterogenitet:
Allel heterogenitet:
Dominant arv:
Recessiv arv:
(= Index case) - Den første i en familie, der diagnosticeres
Den kliniske fremtoning
Den genetiske information – oftest brugt ift. et bestemt locus eller gen
Mutationer i forskellige gener kan medføre ét bestemt sygdomsbillede
Forskellige mutationer i ét gen kan medføre ét bestemt sygdomsbillede
Abnormitet i kun et af de to allele gener (heterozygot) giver sygdom
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: (= førsteledsslægtninge = 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
Den genetisk undersøgelse
1.
2.
3.
4.
5.
6.
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?
Vanskeligheder / fælder i den
genetiske undersøgelse
1.
2.
3.
4.
5.
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”
Er mutationen skyld i sygdommen?
1.
2.
3.
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 ionkanal, us. af ændring i regulatorisk område
Teknik, pris og svarafgivelse
1.
2.
3.
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
Take home message
1 = 4 (1 proband + 3 relatives)