who should undergo genetic testing

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.


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


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


Hypertrophic Cardiomyopathy

- Diagnostic +++ (HRS/EHRA)

++ (ACCF/AHA)

- Prognostic ++ (HRS/EHRA)

+ (ACCF/AHA)

- Therapeutic + (HRS/EHRA)

+/- (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.



- “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 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

WINDLAND Smith Rice

Sudden Death

Genomics Laboratory

“To heal the sick and advance the science” Dr. Charles W. Mayo

who should undergo genetic testing

Healthcare