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Controversies in HCM:
Who Should Undergo Genetic Testing?
Michael J. Ackerman, MD, PhD, FACC
Windland Smith Rice Cardiovascular Genomics Research Professor
Professor of Medicine, Pediatrics, and Pharmacology
Director, Long QT Syndrome Clinic and the Mayo Clinic Windland Smith
Rice Sudden Death Genomics Laboratory
President, Sudden Arrhythmia Death Syndromes (SADS) Foundation
ACC 2015
San Diego, CA
March 14, 2015
WINDLAND SMITH RICE
Sudden Death Genomics Laboratory
Conflicts of Interest to Disclose: • Consultant – Boston Scientific, Gilead Sciences, Medtronic, and
St. Jude Medical
• Royalties – Transgenomic/FAMILION
Learning Objectives to Disclose:
• REVIEW the guidelines regarding WHO should undergo
genetic testing for HCM
• EXAMINE the 3 controversies surrounding HCM genetic
testing: its yield, its role, and its noise.
Ackerman, Priori, et al. HRS/EHRA Guidelines 2011
Genetic Testing for HCM
1. Comprehensive or targeted (MYBPC3, MYH7,
TNNI3, TNNT2, TPM1) HCM genetic testing is
recommended for any patient in whom a
cardiologist has established a clinical diagnosis of
HCM based on examination of the patient’s clinical
history, family history, and electrocardiographic/
echocardiographic phenotype.
Genetic Testing for HCM
1. Genetic testing for HCM and other genetic
causes of unexplained cardiac hypertrophy is
recommended (I) in patients with atypical
clinical presentation of HCM or when another
genetic condition is suspected.
2. Genetic testing is reasonable (IIa) in the index
patient to facilitate identification of first-degree
family members at risk for developing HCM.
Gersh, Maron et al. ACCF/AHA Guidelines 2011
Genetic Testing for HCM
Van Driest … Ackerman. AJC 90:1123-1127, 2002
Mutation-specific genetic testing is recommended
for family members and other appropriate relatives
subsequently following the identification of the
disease-causative mutation in an index case.
Ackerman, Priori, et al. Heart Rhythm 8:1308-1339, 2011 (HRS/EHRA)
Gersh, Maron, et al. Circulation 124:2761-2796, 2011 (ACCF/AHA)
HCM Genes
MYH6
Ch 14q11
MYH7
Ch 14q11
MYBPC3
Ch 11p11
TNNT2
Ch 1q32
MYL2
Ch 12q23
MYL3
Ch 3p21
ACTC
Ch 15q14
TPM1
Ch 15q22
TNNC1
Ch 3p21
TNNI3
Ch 19p13 PRKAG2
Ch 7q35
LAMP2
Ch Xq24 GLA
Ch Xq22
FXN
Ch 9q21
JPH2
Ch 20q12
PLN
Ch 6q22
CALR3
Ch 19p13
CASQ2
Ch 1p13
LDB3
Ch 10q22.3
MYPN
Ch 10q21
TCAP
Ch 17q12 TTN
Ch 2q24 CSRP3
Ch 11p15
ACTN2
Ch 1q43
VCL
Ch 10q22
• Modified from Spirito P et al. NEJM 336:775, 1997 Adapted from Pyle et al. Circulation Research, 2004
Van Driest … Ackerman. Mayo Clin Proc 80:463-469, 2005
Cardiomyopathies
HCM
DCM
ARVC
RCM
LVNC
Yield of Genetic Testing
38% > 1000 Consecutive, Unrelated HCM Patients
Bos…Ackerman. Mayo Clin Proc 2014
What is the Yield of HCM Genetic Testing?
1. 10%
2. 25%
3. 50%
4. 75%
5. 100%
Septal Shape and Myofilament HCM
104/132 (79%)
+ve Genetic Test
15/181 (8%)
+ve Genetic Test
Binder, Ommen…Ackerman. Mayo Clin Proc 81:459-467, 2006
Sigmoidal-HCM
47%
Reverse Curve-
HCM
35%
ECHO-Guided Genetic Testing?
19%
+ve Genetic Test
59%
+ve Genetic Test
Bos…Ackerman. Mayo Clinic Proc 2014
Clinical Markers for
Positive Genetic Test
Marker Pts
Age Dx < 45 yrs 1
MLVWT ≥ 20 mm 1
FH of HCM 1
FH SCD 1
Reverse-curve HCM 1
Hx of Hypertension -1
Scoring range: -1 to 5 pts
p < 0.0001
-1
4/84
0
32/225
1
45/238
2
82/201
3
102/173
4
64/95
5
30/37
Yie
ld o
f G
en
eti
c T
es
tin
g (
%)
Total Score of Clinical Markers
5%
14%
19%
41%
59%
67%
81%
Predicting Positive Genetic Test
Bos…Ackerman. Mayo Clin Proc 2014
<5% ~80% Yield of Genetic Testing
Genetic Testing for HCM
Hypertrophic Cardiomyopathy
- Diagnostic +++ (HRS/EHRA)
++ (ACCF/AHA)
- Prognostic ++ (HRS/EHRA)
+ (ACCF/AHA)
- Therapeutic + (HRS/EHRA)
+/- (ACCF/AHA)
Ackerman, Priori, et al. Heart Rhythm 8:1308-1339, 2011 (HRS/EHRA)
Gersh, Maron, et al. Circulation 124:2761-2796, 2011 (ACCF/AHA)
Cardiologist’s Request
Will you screen my patient
to see if he/she has one of those bad
“thing a ma bobs” or “whatcha ma call its”
(i.e. disease-associated mutations)
so that I know whether or not to
implant an ICD?
X
Clinical
Younger Patients
Syncope
BP drop w/
exercise
Thallium defects
VT on Holter
Massive LVH
“Malignant”
Mutations
DHE on CMR
+ve FHx
LVOTO
SCD Risk in HCM
Clinical
ICD Primary Prevention
2. Syncope
5. BP drop w/
exercise
4. NSVT
1. LVWT > 3 cm
3. +ve FHx
4. +ve Genetic
Test
“1 Point RFs”
3. Thallium
defects
2. DHE on CMR
“1/2 Point RMs”
1. LVWT 2 - 3 cm
6. > 2 mutations? 6. “Malignant”
Mutations
SCD Risk in HCM
Is the “X” that marks the spot truly
THE disease-causing mutation?
Genetic Testing’s Achilles’ Heel
- Class III (No Benefit/Harm) -
Ongoing clinical screening is not indicated in
genotype-negative relatives in families with
HCM. Gersh, Maron, et al. ACCF/AHA Guideline for Diagnosis and Treatment of
HCM, 2011
Mutation-specific genetic testing is recommended
for family members and other appropriate relatives
subsequently following the identification of the
disease-causative mutation in an index case.
Ackerman, Priori, et al. Heart Rhythm 8:1308-1339, 2011 (HRS/EHRA)
Gersh, Maron, et al. Circulation 124:2761-2796, 2011 (ACCF/AHA)
- “Maybe” Test Result ?
- What was my index of suspicion?
- Have I done my homework?
“Possible Deleterious”
“Variant of Uncertain Significance (VUS)”
“Genetic Purgatory” “Genetic Purgatory is a
Real Place and its
Scary!”
Genetic Testing’s Achilles’ Heel
Clinical Markers for
Positive Genetic Test
Marker Pts
Age Dx < 45 yrs 1
MLVWT ≥ 20 mm 1
FH of HCM 1
FH SCD 1
Reverse-curve HCM 1
Hx of Hypertension -1
Scoring range: -1 – 5 pts
p < 0.0001
-1
4/84
0
32/225
1
45/238
2
82/201
3
102/173
4
64/95
5
30/37
Yie
ld o
f G
en
eti
c T
es
tin
g (
%)
Total Score of Clinical Markers
5%
14%
19%
41%
59%
67%
81%
HCM Genetic Testing and its “Noise”
Bos…Ackerman. Mayo Clin Proc 2014 (June)
<5% ~80% Yield of Genetic Testing
Schematic for Clinical Approach to HCM Mutations
“Positive” HCM Genetic Test
Is Mutation Radical?
(e.g. frame-shift, splice-site,
nonsense) Yes
No
Probably
Pathogenic
(EPV > 99%)
Missense Mutation
(rare non-synonymous
single nucleotide variant)
Gene?
Probably
Pathogenic
(EPV > 90)
TNNI3
94 (84-98)
ACTC1
94 (71-97)
MYH7
93 (90-95)
TPM1
91 (79-97)
MYBPC3
81 (75-86)
MYL2
78 (49-91)
TNNC1
78 (29-93)
TNNT2
60 (19-80)
MYL3
0 (0-55)
Variant of Unknown
Significance
(< 80% EPV)
Conserved?
Yes 91 (85-95)
No 70 (57-80)
Carefully re-assess the pre-test probability of HCM
(e.g. personal and family history, Echo, etc.) Kapplinger…Ackerman. 2015
Genetic Testing for HCM
Genetic tests are NOT
binary (yes or no) tests,
but are fundamentally
probabilistic in nature!
Controversies in HCM:
Who Should Undergo Genetic Testing?
- TAKE HOME POINTS -
1. If you make a diagnosis of HCM, genetic testing
is indicated for the sake of the rest of the family!
2. Yield of genetic testing is phenotype dependent!
3. Never implant an ICD based solely on a positive
HCM genetic test!
4. “X” does not always mark the spot! Genetic
purgatory EXISTS!
Be a Wise User and a
Wiser Interpreter!
Dr. Scholl Foundation, CJ Foundation for SIDS
Hannah Wernke Memorial Foundation
National Institutes of Health
WINDLAND SMITH RICE
Sudden Death Genomics Laboratory