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