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

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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