Transcript Pedigree Interpretation

Pedigree
Interpretation
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Today’s Objectives:
• Discuss how family history is individual
preventive care
• Be able to note red flags in a family hx
• Identify common, chronic, adult-onset
diseases that have a genetic component
• Develop a plan of action when something
is noted in a pedigree
Results:
Overall, 64% of
respondents reported
receiving no genetics
education materials
from the provider type
named most important
in the management of
the condition in the
family.
Genetics in Medicine May 2007
What is the difference here?
Breast
Ca
Breast
Ca
Bilateral
Breast Ca
Requesting
counseling
Bilateral
Breast Ca
Requesting
counseling
What would you say to these patients?
Breast Ca
Bilateral
Breast Ca
Requesting
counseling
• 14% internists & Ob/Gyns did not know that risk is increased
• 75% would provide counseling
• 9% would refer to a geneticist, 15% to oncologist, 22% would
call a colleague
Source: Hayflick,SJ et al. Genetics in Medicine 1:13-21, 1998
Breast Ca
Bilateral
Breast Ca
Requesting
counseling
• 57% internists & Ob/Gyns did not know that risk is increased
• 55% would provide counseling
• 9% would refer to a geneticist, 15% to oncologist, 22% would
call a colleague
Source: Hayflick,SJ et al. Genetics in Medicine 1:13-21, 1998
Genetic testing for colorectal cancer
among primary care providers
• AIM of study: population-based survey of colon cancer
genetic referral practices for genetic testing among
urban PCPs in highly culturally diverse communities.
• None of the 245 PCPs completing the questionnaire
correctly identified a case of hereditary non-polyposis
colorectal cancer (HNPCC)
• Only 55% had ever heard of genetic susceptibility
testing for patients with a family history of colon cancer
Sheinfeld et al, American Society of Clinical Oncology, 2006
Family history is a risk factor for
diseases throughout all stages of life
birth defects
blood disorders
infants
children
asthma
autism
diabetes
depression
adolescents
alzheimer’s disease
osteoporosis
adults
cancer
heart disease
older adults
Our Job…
...is to look for patterns in the pedigrees
COLLECTION
INTERPRETATION
INTERVENTION
Family History:
Bridging the Gap
• Assesses influence of genetic and non-genetic
factors, and interactions between these factors
• Most people have access to their family hx
• Fam hx can assess risk for multiple conditions at
a low cost
• Family-based interventions can target
modification of non-genetic familial risk factors
• Individuals with the highest risk can be referred
for further evaluation, including genetic testing
Why focus on common,
chronic, adult-onset
conditions?
Common chronic adult-onset disease
• Leading causes of M & M
• Chronic nature allows for preventive
interventions
• New and innovative prevention efforts
are needed
• Genetics plays an important role in
etiology, natural hx, and response to
therapy
What do we know about
the genetics of common
chronic diseases?
Developing Chronic Disease
Environment
unfavorable
favorable
protective
predisposing
Genes
Gene x Environment
Predicting Health Outcomes
Risk Factor
Obesity +
Genes
Outcome
A, B, C, D
= Heart disease
C, D, E, F
= Type2DM
B, F, G, H
= Breast Ca
Family History…
What should we look for?
Recognize Genetic Red Flags
Family history of known or suspected
genetic condition
Multiple affected family members with
same or related disorders
Earlier age at onset of disease than
expected
Developmental delays or mental
retardation
Recognize Genetic Red Flags (cont)
Diagnosis in less-often-affected sex
Multifocal or bilateral occurrence in
paired organs
One or more major malformations
Disease in the absence of risk factors or
after preventive measures
Recognize Genetic Red Flags (cont)
Abnormalities in growth (growth
retardation, asymmetric growth,
excessive growth
Recurrent pregnancy losses (2+)
Consanguinity (blood relationship of
parents)
Ethnic predisposition to certain genetic
disorders
Family GENES Mnemonic
• Family: positive family history
• G: groups of congenital anomalies
• E: extreme/exceptional presentation of
common conditions
• N: neurodevelopmental delay or
neurodegenerative conditions
• E: extreme/exceptional pathology
• S: surprising laboratory values
Family History- Red Flags
Age of Onset
• Common disorders with earlier age
of onset:
– Breast cancer
– Colon cancer
– Heart disease
– Dementia
– Prostate cancer
– Vision loss
<
<
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<
<
<
50
45-50
45-50
60
50-60
55
Familial Risk Assessment
• Not enough to say family history is “positive” or
“negative”
• Ideally collect and interpret information re:
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Number of affected 1st and 2nd degree relatives
Age at diagnosis
Sex of affected relatives
Relationship of affected relatives
Presence of possibly related conditions
Genetic Risk Assessment
Personal preventive medicine…
• Individualize risk assessment:
• Individualize prevention recommendations
– Targeting lifestyle factors
– Screening at younger ages, and/or more frequently
with more comprehensive methods
– Chemoprevention
– Preventive procedures
…May improve compliance
Interpretation: Opportunities for
Patient Education
• Eliciting and summarizing a family
information can:
– help the pt understand the condition in question
– clarify pt misconceptions
– demonstrate variation in disease expression
(such as different ages of onset)
– provide a visual reminder of who in the family
may be at risk for the condition
– Emphasize the need to obtain medical
documentation on family members
Complicating Factors re Interpretation
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Missing information vs. unaffected relatives
Reliability of information
Non-traditional families
Unknown paternity
Adoptions
Cultural definitions of family
Cultural biases
Confidentiality
Consanguinity
Risk Stratification/Pedigree Analysis
CAD
dx 76
CAD
dx 76
CAD
dx 46
CAD
dx 65
Stroke
dx 50
Diabetes
dx 51
CAD
dx 48
CAD
dx 44
Average Risk
Moderate Risk
High Risk
Let’s look at your pedigrees
For Each Pedigree
Think about:
• What additional
information do you need?
• Are there any trends--e.g.,
Mendelian transmission
• Who might be at risk? For
what?
• Do they need testing?
• Do they need counseling?
By you? Do you need to
refer?
Pedigree structure reminders:
• Patient ID
• Date
• Who did the pedigree
• Ancestry
• Key/Code
• Age at dx of condition
• Age at death and cause
• Did they die from the
condition or other?
Let’s use the genetics of
CVD as a model…
Family history of
cardiovascular disease
• What more do you need to know?
– Identify specific relatives with heart disease
and associated complications
– Identify the ages at onset of the disease
– Identify the presence or absence of risk
factors in relatives with heart disease
• How can you help your patient?
Personal and Family History
Characteristics of Genetic
Susceptibility to CVD
• Early onset (CAD: men < 55, women < 65)
• Multi-focal disease/angiographic severity
• Multiple risk factors
• Refractory to conventional risk factor modification
• Relatives with CVD, especially females
• Relatives with related disorders, e.g., DM,
hypertension, hypercholesterolemia
CAD Risk Factors
Odds
Ratio
CAD 1st degree relative <55
CAD 1st degree relative <65
Chol > 270 mg/dl
Smoking > 1/2 ppd
10.4
7.1
4.3
4.0
Stroke 1st degree relative
Inactivity
DM2 in patient
3.5
3.4
2.7
CAD 2nd degree relative <65
2.4
207 cases with early onset disease and 621 controls
Nora et al, 1980
Some Genes Associated with CAD/MI
Lipid Metabolism
Apolipoprotein A1/CIII/AIV
Apolipoprotein B
Apolipoprotein E
Cholesterol ester transfer protein
Lipoprotein lipase
Paraoxanase
Insulin Resistance
Lipoprotein lipase
Apolipoprotein E
Insulin receptor substrate-1
Homocysteine Metabolism
Cystathionine beta synthase
Methylene tetrahydrofolate
Reductasemethionine synthase
Blood Pressure Regulation
Angiotensin converting enzyme
Angiotensin II receptor, type
angiotensinogen
Hemostasis
Factor V Leiden
Prothrombin G20210A
Factor Vii
Glycoprotein IIIa/Iib
Fibrinogen
Glycoprotein IIIa
Plasminogen activator inhibitor-1
Vessel/Endothelial Function
Connexin 37
Stromelysin
Inflammation/Leukocyte Adhesion
Endothelial leukocyte
Adhesion molecule-1
Miscellaneous
Ataxia telangiectasia
Helicase
Alcohol dehydrogenase
Genetic Tests for Atherosclerosis
Susceptibility
Biochemical
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Lipid panel
LDL particle size
HDL particle size
Lipoprotein(a)
Apolipoproteins B: A1
Homocysteine
Insulin
Glucose, HgA1C
Fibrinogen
PAI-1
CRP
Cystatin C
DNA-based
• MTHFR C677T and
A1298C
• Prothrombin G20210A
• Factor V Leiden
• Platelet glycoprotein
IIIAPlA1/A2
• Apo E
The clinical tests available to assess
risk in genetically susceptible
individuals measure traits related to
lipids, homocysteine metabolism,
thrombosis, fibrinolysis, inflammation,
& insulin sensitivity.
Management of Genetically Determined
Atherosclerosis Risk Factors
Disorder
Frequency in
Cases
RR for CAD
Treatment
Small LDL
particles
50%
3-fold
Avoid very low fat
diets; niacin, fibrates
Elevated Lp(a)
33%
3-fold
Niacin; apheresis if
severe
Elevated LDL
cholesterol
20%
2 to 3-fold
Low saturated fat diet;
statins, niacin, bile acid
sequestrants
Elevated
triglycerides
15%
2 to 3-fold
Avoid alcohol and high
fat diets; niacin,
fibrates
Hypoalphalipoproteinemia
5%
3-fold
Exercise; niacin,
fibrates may help
Adapted from www.BerkleyHeartLab.com
Some current tests available to
detect CAD earlier
• EKG
• EBCT
• ETT
• CCA-IMT
• Thallium ETT
• MRI
• Stress echo
• Brachial reactivity
• Angiogram
• Intravascular
ultrasound
Prevention Strategies for Genetically
Susceptible Individuals
• Modify risk factors (traditional and novel) with
targeted therapies and lifestyle changes.
• Avoid aggravating factors specific to genetic risk
(e.g., use of HRT in women with Prothrombin
G20210A mutation).
• Early detection of CAD to guide decision making.
More aggressive risk factor modification and
consideration of interventions (e.g., angioplasty,
bypass surgery).
Family history of diabetes
• What more do you need to know?
• How can you help your patient?
Family history of obesity
• What more do you need to know?
• How can you help your patient?
Family history of cancer
• What more do you need to know?
• How can you help your patient?
Family history of blood clots or
pulmonary embolism
• What more do you need to know?
• How can you help your patient?
Family history of mental illness
• What more do you need to know?
• How can you help your patient?
So what can we do as clinicians?
• Recognize patterns and/or red flags
• Use family history for preventive care
• Know what surveillance is possible and
necessary for common genetic
conditions
What can we do?
• Be aware of need for follow-up on
potential genetic health issues
• Know resources for questions you and
your patients may have
• Know who to talk to, and establish a
connection in the community, to refer
further
Where do we go for answers?
• A textbook?
– Usually out of date
• A journal article?
– Often too focused
• A web site?
– Need to know its validity
GeneTests GeneReviews NLM
GeneReviews
• Genetic disease descriptions
• >520 Reviews (Oct 2010)
• ~ one new review added each week
• Expert-authored, peer-reviewed, updated regularly
• Current information on genetic test use in diagnosis,
management, genetic counseling
• Links to genomic databases, patient resources,
PubMed citations, policy statements/guidelines
Genetic Counseling
Mode of Inheritance:
• Caused by mutation in one of the genes currently known to encode
different components of the sarcomere is inherited in an autosomal
dominant manner.
Risk to Family Members
• Some individuals diagnosed have an affected parent.
• A proband may also have the disorder as the result of a new gene
mutation. The proportion of cases caused by de novo mutations is
unknown.
Management
Evaluations Following Initial Diagnosis
• Risk assessment for SCD is essential
• The clinical parameters analyzed to assess an individual’s risk for SCD
include the following:
– Personal history of aborted/resuscitated sudden death or cardiac arrest
– Family history of SCD
– Extreme LVH (>30mm)
– Hypotensive blood pressure response to exercise
– Significant ventricular ectopy on Holter monitoring
– Unexplained syncope
The reality…
Family Hx Collection by PCPs
• Fam hx is collected at ~50% of new
visits and 22% of established pt visits
• Avg duration of a visit=10 min; avg
duration of family hx discussion=2.5 min
• Only 29% of PCPs feel prepared to take
a fam hx and draw pedigrees
• Even when collected, they often failt to
recognize high risk family hx
Acheson et al 2000, Suchard et al 1999, Sweet et al 2002, Frezzo et al 2003
Let us, as a profession, try to
change this…
Genetic Thinking in Practice
You don’t have to be an expert,
but you should:
take an informative
3-generation
pedigree
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recognize
patterns & red
flags
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use
available
resources
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know when,
where, and
how to refer
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QUESTIONS??