establishing genetic links in cardiovascular diseases · role of genetic evaluation 5. importance...

Establishing genetic links in cardiovascular diseases

Amy R. Kontorovich, MD, PhDAssistant Professor, Cardiology

Medical Director, Adult Cardiovascular Genetics

Cardiology Nurse Practitioner SymposiumNovember 9, 2018

Objectives

1. Sample cases2. Genetic basis of cardiomyopathies3. Genetic basis of aortopathies4. Role of genetic evaluation5. Importance of genetic counseling

McCarthy et al, Nature Reviews Genetics, 2008

What is a genetic disease?

Hypertrophic CMDilated CMARVCLVNCRCM

HypertensionAtrial fibrillationStrokeCoronary artery disease

COMPLEXPOLYGENIC TRAITSINVESTIGATIONAL

NO CLINICAL TESTING YET!

CLINICAL TESTINGACTIONABLE RESULTS

75 M with cardiomyopathy

40 40’s40 36

75 “HCM”afib

d. 60s?

d. 60s?

d. 60s?

d. 60s?

d. 60s?

nno info

d. ?

?no info

d. ?

?no info

nA&W

CARDIOMYOPATHYEMDCRYABGATAD1

ACTN2ANKRD1CSRP3LAMP2MYH6MYPNNEXN

PLNTCAPTNNC1TNNI3TTRVCLRAF1

ACTC1MYBPC3MYH7

TNNT2TPM1

LDB3/ZASPTAZ

ABCC9BAG3DESDMDEYA4FKTNLAMA4

NKX2.5RBM20SCN5ATBX20TMPOTTN

TXNRD2

DSG2DSP

PKP2RYR2TGFB3

TMEM43

DSC2JUP

DCM

LVNC ARVC

HCMFXNGLAJPH2MYL2MYL3MYOZ2PRKAG2PTPN11

LMNA

Hypertrophic Cardiomyopathy

Unexplained LV hypertrophy associated with nondilated ventricular chambers in the absence of another cardiac or systemic disease that itself would be capable of producing the magnitude of hypertrophy evident in a given patient, with the caveat that patients who are genotype positive may be phenotypically negative without overt hypertrophy.

2011 ACCF/AHA Guideline for the Diagnosis and Treatment of Hypertrophic Cardiomyopathy

HCM: Epidemiology

• Prevalence 1:250 to 1:500• Males > Females• African Americans > Whites

Familial HCM

• Autosomal dominant• Incomplete penetrance• Age-dependent penetrance• De novo mutagenesis in ~1/3• Genetic heterogeneity

– Molecular heterogeneity

Penetrance

The probability of a gene or genetic trait being expressed. "Complete" penetrance means the gene or genes for a trait are expressed in all the population who have the genes. "Incomplete" penetrance means the genetic trait is expressed in only part of the population. The percent penetrance also may change with the age range of the population.

Definition from: Human Genome Project Information at the U.S. Department of Energy

Variable expressivity

Maron and Maron. The Lancet. 2013; 381:342-55.

Hypertrophic cardiomyopathy“Sarcomeric” “Phenocopies”

• Fabry disease• Danon syndrome• Hemochromatosis• Amyloidosis

Genotype-phenotype connection

• Phenotypic heterogeneity• Distinct clinical outcomes– Evidence controversial / conflicting• "Benign" vs. "Malignant" mutations

– Founding mutations in MYBPC3 • Milder phenotype, better prognosis

vs

Is genetic testing advised?

HFSA Guidelines 2018: Hershberger, et al, Journal of Cardiac Failure, 24(5):281-297

Guideline 4

HFSA Guidelines 2018: Hershberger, et al, Journal of Cardiac Failure, 24(5):281-297

Guideline 4

Is genetic testing advised?

~“Most affected”

~Potential impact on patient

~Potential impact on relatives

~Consequences for offspring

YES

40 40’s40 36

75 “HCM”afib

d. 60s?

d. 60s?

d. 60s?

d. 60s?

d. 60s?

nno info

d. ?

?no info

d. ?

?no info

nA&W

What does genetic

testing tell you?

Identify DNA variant(s) in affected individuals

and estimate probability that the variant is the cause

Estimate probability of disease risk in family

members who may not yet have clinical

features

PAD

WHO?Suspected heritable CV disease

+ NO/few risk factors

+/- family history +/- syndromic features

HOW?Genetic evaluation

+ genetic counseling

Genetic Counseling• 3-generation pedigree• Test selection (WHAT)• Counsel on outcome types• What is a VUS?• Actions by outcome• Interpretation of variant(s)• Post-test counseling• Genotype-based recommendations• Family screening recommendations

WHY?• Define etiology / clarify diagnosis• Optimize medical therapy• Timing for surgery• Determine risk in relatives• Prenatal diagnoses

Misconceptions!Genetic testing…1. …is not covered by insurance2. …is complicated3. …will cause patients to lose insurance

Costs

• Transmission guilt• Survivor guilt• Tension about testing children• Privacy concerns/deception• Uncover unexpected relationships

HFSA Guidelines 2018: Hershberger, et al, Journal of Cardiac Failure, 24(5):281-297

ACMG Practice Resource, Genetics in Medicine, 2018

Cardiomyopathy testing & yield

Genetic variation

Ruark E, Münz M, Renwick A et al. F1000Research 2015, 4:883

Affected GENEClinical designation of variant

McNally, E.M., and George, A.L. Trends in Cardiovascular Medicine, 2015. 25: 646-652

Interpretation of VUSCo-segregation with phenotype

Type of mutation (i.e. frameshift vs. synonymous)

Population-based frequency

Evolutionarily conserved?

“Hot spots” / protein domains

In silico analysis

Experimental evidence of altered protein function

What next?

• Is it actionable? • Testing others for segregation• Reclassification

Case 1: Results

• Most frequent TTR mutation in US• 4% of black Americans• AD cardiomyopathy in 6th decade• 80% penetrance• ? increased risk of heart failure

acc.org

Hypertrophic cardiomyopathy“Sarcomeric” “Phenocopies”

• Fabry disease• Danon syndrome• Hemochromatosis• Amyloidosis

Implications for treatment• Liver transplantation• Supportive/GDMT• Novel therapeutics

http://www.acc.org/latest-in-cardiology/articles/2015/10/13/08/35/emerging-therapies-for-transthyretin-cardiac-amyloidosis

Who’s at risk?

40 40’s40 36

75 ATTRafib

d. 60s?

d. 60s?

d. 60s?

d. 60s?

d. 60s?

nno info

d. ?

?no info

d. ?

?no info

nA&W

+

??

HFSA Guidelines 2018: Hershberger, et al, Journal of Cardiac Failure, 24(5):281-297

Guideline 2

HFSA Guidelines 2018: Hershberger, et al, Journal of Cardiac Failure, 24(5):281-297

Baseline testing for FDR

HFSA Guidelines 2018: Hershberger, et al, Journal of Cardiac Failure, 24(5):281-297

Guideline 4

PATIENT

Clinical screening

ECG

Echo

CMR

Genetic testing

FAMILY SCREENING “Mutation”

found

Pathogenic VUS

+

+

+_

++_ _

+ _ _+

_

+

+_ _

+ __+

_

40 40’s40 36

75 ATTRafib

d. 60s?

d. 60s?

d. 60s?

d. 60s?

d. 60s?

nno info

d. ?

?no info

d. ?

?

no info

nA&W

+

TTR carrier screening

GOAL: treatment ASAP• Progressive neuropathy• Autonomic dysfunction• GI complaints• Unexplained weight loss• Cardiac hypertrophy• Arrhythmias• LV dysfunction• Bilateral CTS• Renal disease• Ophthalmologic issues

Next case…

My sister has Marfan syndrome”

KEYDilated aortic root

Suspected MFS

• 31F no past history• Family history of aortic

dilatation• Familial FBN1 VUS

• Mild myopia• Occasional chest pains

• 5’3”• No dysmorphisms• Elongated fingers, positive wrist

sign, weakly positive thumb sign• Pes planus

Marfan syndrome

• Autosomal dominant• Fibrillin-1 (FBN1)• 1:3000-5000• Multi-system disease• Variable expression• Aortic disease

Marfan.org

Dormand, H., and Mohiaddin, R.H. J Cardiovasc Magnetic Res, 2013. 15:33.

Marfan syndrome

Aortic• Aneurysmal dilatation of root

• Aortic insufficiency• 50% of childrenàprogressive

• 60-96% of adults• Other aortic segments, PA,

carotid/intracranial

• Dissection common if untreated (Type 1)

Mitral valve prolapse• 40-54%

• None-mild-severe MR• 25% progressive

• Most with MVP not MFS• Tricuspid prolapse

Left ventricle• 25% with dysfunction

• Usually EF>40%

Diagnostic criteria

Ghent systemic score

≥ 7 is positive

• “Normal” depends on age and body size• Dilation: diameter > ULN• Aneurysm: ≥ 1.5x ULN• Normal adult ascending aortic growth

rate ~ 1.5mm/decade

Saura et al, European Heart Journal- Cardiovascular Imaging 2017 18(2):167-179 Davis, et al, J Cardiovasc Mag Res 2014, 16:9

MRA: SoV 3.5cm “normal”

“My sister has Marfan syndrome”

Aortopathies (non-acquired)

GENETIC CONGENITALMarfan syndrome Bicuspid aortic valve

Loeys-Dietz syndrome Aortic coarctationvascular Ehlers-Danlos syndrome Tetralogy of Fallot

Turner syndrome Transposition of the great arteriesNon-syndromic hTAAD

ACTA2BGNCBS

COL5A1COL5A2FBN2FLNALOX

MAT2A

MED12MFAP5MYH11MYLK

NOTCH1PRKG1SKI

SLC2A10

TGFBR1TGFBR2TGBF2TGFB3SMAD3SMAD2

Loeys-Dietz

Vascular Ehlers-Danlos

syndrome

Turner

Marfan

FBN1

(45,X)

COL3A1

Heritable thoracic aortic aneurysm and dissection

(hTAAD)

Progress in Heritable Soft Connective Tissue Diseases, ed. J. Halper, New York: Springer, 2014

Aortic interventionThoracic aortic aneurysm with… Size threshold (cm)

Trileaflet aortic valve/degenerative 5.5

Aortic valve repair/replace or other cardiac sx 4.5

Bicuspid aortic valve5.55.0 if +FH of dissection

Marfan syndrome5.0 or growth ≥ 5mm/yr4.5 if FH of dissection at <5.0

Loeys-Dietz syndrome4.2 (by echo)4.4-4.6 (by CT/MRA)

Vascular Ehlers-Danlos syndrome? High risk of operative vascularcomplications

Non-syndromic hTAAD ≥ 5.0 or by FH pattern

Saura et al, European Heart Journal- Cardiovascular Imaging 2017 18(2):167-179 Davis, et al, J Cardiovasc Mag Res 2014, 16:9

MRA: SoV 3.5cm “normal”

NEXT STEP: single-site genetic test (familial FBN1 VUS)

“My sister has Marfan syndrome”

VUSà pathogenic

•Atenolol or losartan •Pan-aortic imaging•Activity restrictions•Annual ophthalmologic exam•No LASIK•Testing the kids!!

“Now I have Marfan syndrome”

“My sister has Marfan syndrome”

6Tall for ageLong fingersSevere myopia

10Chrom 12. dup“vision problems”

9Severe myopiaSpont. bruising

31 5’6”myopia

5’6”Chrom 12 dup

d. 65HTN

d. 51 5’8”“heart probs”“arteries were destroyed”

33Ao root dil.tall & skinny

d. 6“heart”tall & skinny

n

“tall & skinny”

2

31 39

2

9v. tall & skinnyseizure d/o

43tall & skinny

2d. 30“heart issue”tall & skinny

2

40

5Ao root dil.

7Ao root dil. FBN1+ FBN1+

FBN1+

FBN1+

FBN1+

FBN1+ FBN1-

FBN1- FBN1+

KEY

Dilated aortic root

Diagnosed MFS

FBN1+ FBN1+FBN1-

31M with acute chest pain

What’s coming…

ACMG recommendations for 2o findings

• 2016: 59 medically actionable genes• 78% include cardiovascular phenotypes– Familial hypercholesterolemia– 17 (29%) cardiomyopathy

Cardiovascular Genetics?

1. Clarify the phenotype2. Determine appropriateness of molecular diagnostic testing3. Test selection4. Pre-test counseling!!!!!!5. Lab selection / minimize financial expense6. Variant interpretation7. Post-test counseling8. Genotype-based recommendations9. Family screening recommendations

NY Daily News, AP