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INHERITED CARDIOVASCULAR DISEASE UNIT
Genetics of Cardiomyopathies
Genetics of cardiomyopathies
• Existing genetic paradigm for common forms of
cardiomyopathy
• Role of genetic testing in clinical management
• Potential for new therapies
• Future challenges
“A myocardial disorder in which the heart muscle is
structurally and functionally abnormal, in the
absence of coronary artery disease, hypertension,
valvular disease and congenital heart disease
sufficient to cause the observed myocardial
abnormality.”
Cardiomyopathy: Definition
ESC Working Group on Myocardial Pericardial Diseases (Elliott P et al. EHJ 2007)
Davies M. Heart 2000;83:469-474
Classification of Cardiomyopathies
Key Points
• All cardiomyopathies can be inherited
• Most are autosomal dominant
• Age related penetrance is usual
• Variable clinical expression
Hypertrophic Cardiomyopathy
42.5%
(95% CI 35.2% to
49.7%).
Heart. 2013 May 14. [Epub ahead of print]
Arrhythmogenic right ventricular
cardiomyopathy
Circulation 1982;2:65
Br Heart J 1984 51: 15-24
Cardiocutaneous syndromes (“Naxos
disease”)
Protonarious N and Tsatsopoulou
A. Cardiovas Res 2004;13:185-194
Plakoglobin
Desmoplakin
Plakophilin 2
Desmoglein 2
Desmocollin 2
ARVC: A Disease of Cell-to Cell Adhesion?
16
24
9
18
0 0
5
10
15
20
25
30
DSP PKP2 DSC2 DSG JUP
56/100 families
≥1 definite or
probable
mutation (6
digenic)
Circulation. 2011 Jun 14;123(23):2701-9
Author n Familial disease (%)
Fuster 1981 104 2
Michels 1985 169 6
Fragola 1988 12 33
Griffin 1988 32 10
Valentine 1989 184 9
Mestroni 1990 165 7
Michels 1992 59 20
Zachara 1993 105 13
Keeling 1995 40 25
Honda 1995 117 25
Gregori 1996 100 30
Dilated Cardiomyopathy
Goodwin, F. C., & Muntoni, F. (2005). Muscle & nerve, 32(5), 577–588.
Genetics
of DCM
0 1 2 3 4 5 6 7
LaminA/C
Alpha-myosinheavychain
Beta-myosinheavychain
Myopalladin
CardiactroponinT
Sodiumchannel
Myosin-bindingproteinC
RNA-bindingprotein20
Thymopoie n
Lamininalpha4
Metavinculin
LIMdomain-binding3;cypher;Z-bandalterna velysplicedPDZmo f-containingprotein
Ti n-cap;telethonin
Presenilin1/2
Alpha-ac nin2
AlphaBcrystallin
Alpha-tropomyosin
Sulfonylureareceptor2A
Cardiacac n
PDZLIMdomainprotein3
Integrin-linkedkinase
CardiactroponinC
CardiactroponinI
Phospholamban
Desmin
Delta-sarcoglycan
Cysteine-andglycine-richprotein3;muscleLIMprotein
Ti n
Eyesabsent4
Ankyrinrepeatdomain-containingprotein1
Dystrophin
Tafazzin
%
J Am Coll Cardiol 2011;57:1641–9)
40%
Dilated Cardiomyopathy
HCM DCM ARVC
Sarcomere Cytoskeleton
Sarcomere
Nuclear
envelope…
Desmosome
WHY OFFER GENOTYPING?
Why Offer Genotyping?
– Confirmation of Diagnosis?
– Management?
– Screening/management of family?
ECG/Echo
Biopsy
Cardiomyopathy
CMR
Genetics Blood screen
Cardiomyopathy is a clinical diagnosis
Cardiomyopathies
HCM DCM ARVC Unclassified
Familial/Genetic Non-familial/Non-genetic
Unidentified
gene defect
Disease sub-type* Idiopathic Disease sub-type*
RCM
Elliott P et al Eur Heart J. 2008 Jan;29(2):270-6
Elliott P et al Eur Heart J. 2008 Jan;29(2):270-6
DOES A (GENETIC)
DIAGNOSIS ALTER
MANAGEMENT?
Genetic “guided” therapies in
cardiomyopathy
• Pompe ERT
• Anderson-Fabry Disease ERT
• ATTR Amyloid Diflunisal,
stabilisers, Tx…
Lamin AC
NSVT, LVEF 45%, male + non-missense mutations (ins-del/truncating or
mutations affecting splicing)
(J Am Coll Cardiol 2012;59:493–500
Management of laminopathies
– Anti-failure therapy
– Anticoagulation
– ICD when bradycardia/AVB/ventricular arrhythmia
– Transplantation
INHERITED CARDIOVASCULAR DISEASE UNIT
Will it help the family?
(Predictive/Cascade Testing)
Reasons for PT in HCM
• Prevention of Complications
– Sudden Death
– Stroke
– (Heart failure)
• Psychosocial
– select career, sports activities
– relieve uncertainty
– time to adjust
– Family “well being” – anxious parents etc
Ingles J et al. Heart. 2012 Apr;98(8) 625-30
.....................................................................................................................................................................................
.....................................................................................................................................................................................
SPECIAL ARTICLE
DNA test ing for hypertrophic cardiomyopathy: a
cost-effect iveness model
Sarah W ordsworth 1*, Jose Leal 1, Edward Blair 2,3, Rosa Legood 4, Kate Thomson 5,
Anneke Seller 5, Jenny Taylor 6, and Hugh W atkins3
1Health Economics Research Centre, University of Oxford, Old Road Campus, Oxford OX3 7LF, UK; 2Department of Clinical Genetics, Churchill Hospital, Oxford, UK;3Department of Cardiovascular Medicine, University of Oxford, Oxford, UK; 4Health Services Research Unit, London School of Hygiene and Tropical Medicine, London, UK;5Molecular Genetics Laboratory, Churchill Hospital, Oxford, UK; and 6Oxford NIHR Biomedical Research Centre, Wellcome Centre for Human Genetics, University of Oxford,
Oxford, UK
Received 6 July 2009; revised 23 December 2009; accepted 21 January 2010; online publish-ahead-of-print 18 March 2010
A im s To explore the cost-effectiveness of alternative methods of screening family members for hypertrophic cardiomyo-
pathy (HCM), the most common monogenic cardiac disorder and the most frequent cause of sudden cardiac death
(SCD) in young people.
Met hods
and r esul t s
Economic decision model comparing cascade screening by genetic, as opposed to clinical methods. The incremental
cost per life year saved was E14 397 for the cascade genetic compared with the cascade clinical approach. Genetic
diagnostic strategies are more likely to be cost-effective than clinical tests alone. The costs for cascade molecular
genetic testing were slightly higher than clinical testing in the short run, but this was largely because the genetic
approach is more effective and identifies more individuals at risk.
Conclusion The use of molecular genetic information in the diagnosis and management of HCM is a cost-effective approach to
the primary prevention of SCD in these patients.- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -Keywor ds Hypertrophic cardiomyopathy † Genetics † Cost-effectiveness analysis
Int roduct ion
Hypertrophic cardiomyopathy (HCM) is the most common mono-
genic cardiac disorder1 and most frequent cause of sudden cardiac
death (SCD) in young people and trained competitive athletes.2
Hypertrophic cardiomyopathy isdefined by unexplained hypertro-
phy of the ventricular myocardium in the absence of a detectable
cause. Disease prevalence amongst adults is around 0.2% (1:500)3
and, in recent studies, the annual SCD rate from HCM varies
between 0.1 and 1.7%4 with a subset of patients having an esti-
mated annual SCD probability between 4 and 5%.5 Hypertrophic
cardiomyopathy is caused by mutations in at least ten sarcomeric
protein encoding genes and marked allelic heterogeneity has
been seen with the majority of disease genes. Hypertrophic cardi-
omyopathy is transmitted in an autosomal dominant fashion, with
the child of an affected parent having a 50% chance of inheriting
the disease causing allele.1,3,6,7 Most individuals with HCM are
asymptomatic and SCD can be the first manifestation of
disease.4,7–9 Ventricular arrhythmia is the most common mechan-
ism of sudden death and its many triggers include exercise and
atrial fibrillation.3,9
The HCM phenotype is dynamic and patients may present with
left ventricular hypertrophy by echocardiography or abnormal
electrocardiogram (ECG) during any phase of life.7 However, not
everyone with a disease causing mutation will manifest HCM, a
phenomenon known as incomplete penetrance.6,7 Clinically, this
presents a problem when assessing families with HCM, and the
currently recommended follow-up strategy involves repeat evalu-
ations every 5 years (surveillance) with echocardiography and
ECG.1
Hyper t rophic cardiomyopathy diagnosisand managementApproximately 50% of individuals currently diagnosed with HCM
are symptomatic and present to cardiology services, where the
* Corresponding author. Tel: + 44 1865 289268, Fax: + 44 1865 289271, Email: sarah.wordsworth@dphpc.ox.ac.uk
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2010. For permissions please email: journals.per missions@oxfordjournals.org.
European Heart Journal (2010) 31, 926–935
doi:10.1093/eurheartj/ehq067
by g
uest o
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aded
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The incremental cost per
life year saved was Euro
14 397
Euro 587 per quality-
adjusted life-year gained,
Euro 9509 per additional life-
year gained
Wordsworth S et al. Eur Heart J. 2010
Apr;31(8):926-35
Economic
MUTATION GUIDED
THERAPY?
Gene transfer: Viral Vectors
Duchenne Muscular Dystrophy
Gene Transfer: DMD
Human Molecular Genetics, 2011, Vol. 20,
Exon Skipping
Myotonic Dystrophy
Genetics
DM1 Chromosome
19q 13.3
DM Protein kinase
(DMPK)
DM2 Chromosome
3q21
Zn Finger 9
Science 2001: 293:816-17
RNA Toxicity
HUMAN GENE THERAPY 24:499–507 (May 2013)
RNA Toxicity: DM1
HUMAN GENE THERAPY 24:499–507 (May 2013)
NOVEL THERAPIES IN
SARCOMERE DISEASE
Spudich JA. Biophysical Journal Volume 106 March 2014 1236–1249
“Down-stream” targets
• Cross-bridge kinetics
• Calcium sensitivity & cycling
• Signalling pathways and protein degradation
• Cardiomyocyte-fibroblast cross-talk
• Energetics
• Gene therapy
JACC: Heart Failure Vol. 2, No. 1, 2014
Key Message
• Aetiology and pathogenesis are critical in the
development of new therapies
FUTURE CHALLENGES
Hershberger R et al. Nature Rev Cardiol 2013
Figure 2
1x coverage [%] 20x coverage [%] 50x coverage [%] mean coverage
ABCC9 ACTC1 ACTN2
CRYAB
DES
DMD
DSP
EYA4
ILK
JUP
LDB3
LMNA
MYBPC3
MYH6
MYH7
MYL2
MYL3 MYOZ2 MYPN
NEXN
PLN
PSEN1
PSEN2
RBM20
RYR2
SCN5A
SGCD
TMPO
TNNC1
TNNI3
TNNT2
TPM1
TTN
VCL
covera
ge
[%
]
0
20
40
60
80
100
3200 2400 1600 800
mean coverage [reads]
A
B
known disease mutations
0 10 20 30 40 50
PK
P2
MY
BP
C3
DS
P
DS
C2
SC
N5A
RB
M2
0
RY
R2
TT
N
LD
B3
LM
NA
AN
KR
D1
MY
H7
TN
NT
2
BA
G3
DM
D
MY
PN
CS
RP
3
TC
AP
MY
H6
CA
SQ
2
TN
NI3
AB
CC
9
CR
YA
B
KC
NQ
1
CA
LR
3
MY
L2
MY
OZ
2
TM
PO
TP
M1
va
ria
nts (n
)
Figure 1
A B
mapping
indel
realigment
mark
duplicates
calling
variants
annotation
filtering
dbSNP
prediction
ACTG
T A C
G A T
Germany 98
Denmark 100
France 92
Spain 82
Italy 78
UK 70
Sweden 49
Netherlands 70
Table 2: Multiple mutations affecting single patients.
Number of
mutations
HGMD1 variant pos
Patients, (%)
Category Ib-III2 variant pos
Patients, (%)
0 345 (54.0%) 171 (26.7%)
≥1 294 (46.0%) 468 (73.2%)
≥2 82 (12.8%) 243 (38.0%)
≥3 14 (2.2%) 82 (12.8%)
≥4 2 (0.3%) 16 (2.5%)
1 = category Ib. 2 = either category Ib or category II or category III.
Unpublished Data
• 243 (48%) : 173 distinct rare variants in the 8 sarcomeric protein genes most commonly associated with HCM
• 317 (63%) : 278 rare variants in genes previously associated with HCM
sarcomere variants
48%
only Z-disc or calcium-handling variants
15%
only titin variants
24%
without any sarcomere, Z-
disc or calcium-handling variants
13%
Lopes, L. R., et al. (2013). Journal of Medical Genetics,
50(4), 228–239.
95 candidate variants in desmosomal protein genes in 122 patients (24%) [26 published]
121 rare variants in ion-channel disease genes in 133 patients (26%) [25 published]
Lopes, L. R., et al. (2013). Journal of Medical Genetics,
50(4), 228–239.
Severe hypertrophy ANK2
Left Atrium SCN5A
Diastolic dysfunction SCN5A
LVEF PKP2
LVed PKP2
Genotype-phenotype associations :
NON SARCOMERE genes
Lopes et al. Heart. 2015 Feb
15;101(4):294-301
Kathiresan et al. Cell 2012
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