Download How to evaluate the patient and family members for risk of sudden

How to evaluate the patient
and family members for risk of
sudden cardiac death: Role of
genetic testing
Robert L. Nussbaum, M.D.
Chief, Division of Medical
Genetics
Outline
• Describe how modern genetics views
“mendelian” diseases and “multifactorial”
diseases as sitting along a continuum rather
than being distinctly different entities
• Describe the characteristics of multifactorial
disease.
• Compare and contrast the terms polygenic,
multifactorial and complex disorder.
• Review the role of genetic counseling in
arrhythmia cardiology
Program in Cardiovascular Genetics
Take Home Messages
1.
2.
3.
4.
Taking a thorough family history is important and may
give subtle clues to familial disease
Genetic testing to identify the particular gene defect can
help with individual prognosis but may require a
sophisticated knowledge of molecular genetics
Knowing the gene and mutation is critical for proper
medical care of other family members
Genetic counseling plays an important role in the care
of patients with familial arrhythmias
Program in Cardiovascular Genetics
CASE 1: 33 yo woman with
palpitations who is concerned
about her children2 her
husband is said to have HCM
C
P
HCM
6 mo.
Program in Cardiovascular Genetics
Family History
|
Normal
echo
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C
Normal
echo
No echo
Normal
echo
Normal
echo
No echo
Normal
echo
Program in Cardiovascular Genetics
Upon referral to the UCSF
Program in Cardiovascular
Genetics:
• Cardiology evaluation of the proband
• Take a complete family history and prepare a
pedigree to assess inheritance pattern and at
risk relatives
• Identify family members whose records need
review and obtain records from the brother,
sister, and nephew
• After counseling, proceed to gene testing.
Which genes?
Program in Cardiovascular Genetics
Genes Implicated in Various
Cardiomyopathies
HCM
RCM
DCM
LV-
C
MYH7 (30%)
MYH7
MYH7 (5-8%)
MYH7
MYBPC3 (30%)
(MYBPC3?)
MYBPC3 (rare)
TT2 (5%)
TT2
TT2 (2-4%)
TI3 (5%)
TI3
TI3 (rare)
TPM1 (< 5%)
TPM1*
TPM1 (rare)
MYL3 (<5%)
MYL3*
TT2
MYL2 (<5%)
ACTC (<5%)
ACTC (<1-2%)
ACTC
LMA (7-8%)
LMA (7-8%)
LDB3/Cypher/ZASP
LDB3/Cypher/ZASP
TAZ/G4.5
TAZ/G4.5
DES (<1%)
DTA
(FKBP1A?)
Hypertrophic cardiomyopathy
Genetics:
.
• Autosomal dominant (usually)
• Prevalence ~ 1/500 individuals
• >15 genes associated with 1o HCM
• Genetic testing:
• Sequence 11-16 genes
• 60-70% sensitive
• Many “Private” mutations, no common mutations
Program in Cardiovascular Genetics
Test Results
Program in Cardiovascular Genetics
Variant of unknown
significance (VUS)
What is it?
• genetic variant (most commonly missense mutation)
• unknown whether it is benign or pathogenic
• not previously reported in association with disease
and often completely novel
Should we just go ahead and test at-risk relatives?
NOT RECOMMENDED!
Program in Cardiovascular Genetics
VUS detective work
•
•
•
•
•
Known single nucleotide polymorphism?
Prevalence in ethnically matched controls?
Conserved amino acid?
Predictive software (ex. polyphen)
Test affected family members - does it track
with phenotype?
• Functional studies
(ACMG Standards and Guidelines for Clinical Genetics Laboratories, 2006 Edition)
Program in Cardiovascular Genetics
VUS detective work: PolyPhen
V338M
Program in Cardiovascular Genetics
VUS testing
|
+
Who needs to be tested?
Normal
echo
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|
No echo
+
Normal
echo
Normal
echo
Normal
echo
+
No echo
Normal
echo
Program in Cardiovascular Genetics
Case 2: Long QT
Syndrome family
• 43yo woman referred for genetic
counseling because of concern for her
children
• Medical History:
– Dizziness, pre-syncope
– No hx of syncope
– QTc on ECG: 480 @ HR=70; 537 @ HR=75
– Holter monitor: QTc 480-540 msec (@ HR=52107) (2004)
• Therapy:
– ICD placed in 2006 before genotype was
known
Family History
• Sudden cardiac death in sister at 36
years of age, while at rest; history of
multiple syncopal events
– Did not lead to any family screening
• Great-nephew had bradycardia in the
newborn period, ECG revealed a
prolonged QTc
Pedigree
Clinical History
CANNOT Definitively Identify Asymptomatic
Gene Mutation Carriers1
Lack of penetrance in LQT syndromes:
• ~37% of individuals with LQT1: 37%
• ~54% of individuals with LQT2: 545
• ~82% of individuals with LQT3: 82%
are asymptomatic
Standard ECG Diagnostic Methods
CANNOT Definitively Identify Asymptomatic
Gene Mutation Carriers1
Adapted from: Priori SG, Napolitano
C, Schwartz PJ. Low penetrance in
the long-QT syndrome: clinical
impact. Circulation. 1999;99:529533.
Reference: 1. Priori SG, Napolitano C, Schwartz PJ. Low penetrance in the long-QT syndrome: clinical impact.
Circulation. 1999;99:529-533.
Risk of an Initial Cardiac Event for
Asymptomatic Parents of Probands
Extends Into Adulthood1
Reference: 1. Kimbrough J, Moss AJ, Zareba W, et al. Clinical implications for affected parents and siblings of
probands with long-QT syndrome. Circulation. 2001;104:557-562.
Gene/
Protein
TABLE 1 Ğ Common Long QT Syndromes
Inheritance Syndrome
Associated with
Induced by
LQT1
RomanoWard
-
Exercise,
emotional
stress
Jervell/LangeNielsen
Syndrome
Congenital
Sensorineural
deafness
(Penetrance of
arrhythmia only
in ~25% in
heterozygotes)
Exercise,
emotional
stress
-
?
Congenital
Sensorineural
deafness
?
-
Rest or sleep
Auditory
stimuli
Emotional
stress
-
?
AD
KCNQ1
Subunit of voltage-gated
K+ channel I Ks
AR
AD
KCNE1
Subunit of voltage-gated
K+ channel I Ks
AR
KCNH2
KCNE2
SCN5A
Subunit of inwardly
rectifying potassium
channel I Kr
AD
Subunit of inwardly
rectifying potassium
channel I Kr
AD
Voltage-gated sodium
channel type V
AD
LQT5
RomanoWard
Jervell/LangeNielsen
Syndrome
LQT2
RomanoWard
LQT6
RomanoWard
LQT3
RomanoWard and
Brugada
-
(Table modified from Modell SM and Lehmann MH.(2006) Genetics in Medicine 8:143-155.)
Rest or sleep
Genetic Testing in the GreatNephew
• Genetic testing at Mayo Clinic identified a
mutation in KCNQ1 (LQT1) 1637C>T
(Ser546Leu)
• Not seen in 1300 controls (PGxHealth data)
• Reported in 3 unrelated families with LQT1
(Tester et al 2005, Choi et al 2004)
• Mutation is not in the transmembrane region
of the protein
Iks
KCNQ1
(slow)
KCNE1 KCNH2
Ikr
(rapid)
KCNE2
Genotype-phenotype correlation mutations in and out of the pore
LQT2
LQT1
Adapted from: Moss AJ, et al. Clinical aspects of type-1 long-QT
syndrome by location, coding type, and biophysical function of mutations
involving the KCNQ1 gene. Circulation. 2007;115:2481-2489.
Adapted from: Moss AJ, et al. Increased risk of arrhythmic events in longQT syndrome with mutations in the pore region of the human ether-a-go-gorelated gene potassium channel. Circulation. 2002;105:794-799.
• Higher risk for cardiac events in LQT1 and LQT2 when mutations are
located in the transmembrane/pore region.1,2
References: 1. Moss AJ, Shimizu W, Wilde AAM. Clinical aspects of type-1 long-QT syndrome by location, coding
type, and biophysical function of mutations involving the KCNQ1 gene. Circulation. 2007;115:2481-2489. 2. Moss
AJ, Zareba W, Kaufman ES, et al. Increased risk of arrhythmic events in long-QT syndrome with mutations in the
pore region of the human ether-a-go-go-related gene potassium channel. Circulation. 2002;105:794-799.
Pedigree
+
+
Obligate carriers were told they did not have
LQTS b/c they had normal ECGs and no
family genetic testing done
Family outreach
• Genetic testing of at-risk relatives
• Educate obligate carriers and at-risk
relatives
• Refer obligate carriers and mutation
positive carriers to EP
Current status
.
.
+
-
+
+
-
pending
+
-
- -
Points to Consider
• Type of LQT based on genetic testing may guide
treatment (ICD vs. beta-blockers). Could this patient
have avoided an ICD if she had genetic testing
first?
• Importance of family outreach - testing allows
direct diagnosis and rule out. Ideally, the entire
maternal side of family should have genetic testing
once mutation known.
• The insensitivity of clinical symptoms or long QTc
on ECG for making a diagnosis do NOT trump the
family tree: obligate carriers are at risk!
Genetic Testing in LQTs and other selected familial 1o heart diseases
Disease
Clinically
Yield
Clinically
available?
Useful?
LQTS
YES
~75%
YES
BRUGADA
YES
~25%
YES
HCM
ARVD
DCM
YES
YES
YES
60-70%
~50%
~35%
YES
YES
YES/??
Genetic Counseling
Genetic Counseling in hereditary
cardiovascular disease
• A collaboration!!
• Coordinate genetic testing
• Help interpret genetic test results
– Diagnostic implication of genetic test results
– Prognosis based on mutation
• Risk stratification
• Genotype-specific treatment
– Variants of unknown significance
– Further genetic testing needed?
• Identify additional genetic testing as needed
(including research studies if available)
Genetic Counseling in hereditary
cardiovascular disease
• Provide family counseling, education, and outreach
– Inheritance, reproductive implications
– Clarify confusing concepts
– Work with at-risk relatives - genetic counseling doubles uptake of services by
at-risk relatives (Forrest et al 2008)
• Provide psychological support and counseling
– Uncertainty (borderline EKG, ambiguous genetic test results, unpredictable
disease, ICD fears)
– Anxiety
– Denial and avoidance (asymptomatic at-risk or carrier)
– Guilt (parental, survivor)
• Connect patients with support resources
– Support groups (SADS, CARE)
– Psychologists
– Other families
Relief and reassurance for
non-carriers
• At-risk family members have ⇑ distress
• Negative genetic test results ⇓ distress
• Genetic testing did not ⇑ distress any more than
at-risk status/EKG screening
SUMMARY: Heart Rhythm UK: Familial Sudden
Death Syndromes Statement on Genetic Testing
Genetic Testing Indicated in:
1. The sudden unexplained death of a young person
(<40 years) should prompt comprehensive and expert
clinical assessment of surviving relatives.
2. Material appropriate for DNA analysis should be
obtained from the deceased person at the time of the
postmortem examination, and targeted genetic analysis
from this material should be considered
3. Genetic testing is recommended for all patients with a
firm clinical diagnosis of the congenital LQTS or CPVT
irrespective of the presence of symptoms or the
existence of other family members.
Heart 2008. 94:502-507
“Genetic analysis is very important for
identifying all mutation carriers within the LQTS
family: Once identified, silent carriers of LQTS
genetic defects may be treated with beta-blockers
for prophylaxis of life threatening arrhythmias.
Furthermore, silent mutation carriers should receive
genetic counseling to learn about the risk of
transmitting LQTS to offspring.”
“Genetic analysis is very important for
identifying all mutation carriers within an LQTS
family.”
ACC/AHA/ESC 2006 guidelines for management
of patients with ventricular arrhythmias and the
prevention of sudden cardiac death
Drug Induced long-QT: A Multifactorial Disorder
Most common cause of withdrawal or use restriction of
drugs already on the market. What is the Genetic
Contribution to Drug-Induced long QT?
1. Nonpenetrant congenital long QT. Up to 15% of
drug-induced long QT patients carry mutations in
LQT1 or LQT2 that are non-penetrant (clinically or by
ECG) without drug.
2. Drug interferes with chaperoning of a mutant
SCN5A protein out to cell surface
3. Most drug-induced QT prolongation is unexplained
Take Home Messages
1.
2.
3.
4.
Taking a thorough family history is important and may give subtle
clues to familial disease
Genetic testing to identify the particular gene defect can help with
individual prognosis but may require a sophisticated knowledge of
molecular genetics
Knowing the gene and mutation is critical for proper medical care
of other family members
Genetic counseling plays an important role in the care of patients
with familial arrhythmias
Program in Cardiovascular Genetics
Program in Cardiovascular Genetics