I.
II.
Paradigm shift
A. The “old genetics”
1. Single gene
2. Rare
3. Genetic specialists
B. The “new genetics”
1. Multifactorial
2. Common
3. Primary care providers
Learn to use family history as a screening tool.
A. All clinicians take family histories.
B. Because of the genomics revolution, the purpose & scope of taking a FHx have changed.
C. Increased understanding of role of genetics in health means that you need to expand your FHx to
include info on genetic factors.
D. Risk factors for disease
1. Genes, environment, & behaviors interact with each other to cause disease.
2. Family history helps capture the effects of these interactions on disease risk.
E. An efficient, accurate family history can be used to:
1. Develop a differential diagnosis
2. Make a diagnosis
3. Distinguish genetic from other risk factors
4. Identify patterns of inheritance
5. Identify medical risks for other relatives
6. Calculate risks
7. Decide an approach to genetic testing (e.g., whom to test, which type of test to order)
8. Make decisions on management, prevention, & surveillance
9. Assess reproductive options
10. Develop patient rapport and trust
11. See family dynamics (e.g., sources of conflict and support)
12. Educate patients & families; clarify misconceptions
F. The family history is often the first way to identify patients who may benefit from genetic testing,
preventive measures, monitoring, and/or referral.
G. As the standard of care changes, you may be liable legally. Court cases have already occurred
where health care providers were taken to court for neglect for not identifying patients who were at
risk for inherited disorders.
H. In select cases, the FHx info should be converted into a diagram of the biological relationships of
your pt with his or her family members – a pedigree.
I.
Learn how to take a minimum of a three-generation pedigree in selected patients. Maintain and
update the pedigree in these patients.
J.
Glaucoma
1. Life-time risk of glaucoma in:
a. Relatives of pts with glaucoma = 22%
b. Relatives of normal controls = 2.3%
c. (Rotterdam study; Wolfs et al., 1998)
2. Prevalence of:
a. OAG among relatives of pts = 10%
b. Probable OAG among relatives = 13%
(Barbados Study; Nemesure et al., 2001)
3. Up to 50% of people with glaucoma have a positive FH.
4. For OAG pts, risk of OAG developing:
a. In siblings = 65%
b. Children = 13%
c. Other relatives = 22%
(Nguyen RL et al., 2000)
5. FHx of glaucoma is a very important risk factor for POAG
6. Risk indicators of OAG correlate highly in families – heritability estimates:
a. Intraocular pressure
0.36
b. Optic cup diameter
0.55
c. Optic disc diameter
0.57
d. Cup-to-disc ratio
0.48
7. Patterns consistent with genetic determinants
8. Clinical point: Chase the Family!
a. Relatives of pts with glaucoma have a strongly increased risk of glaucoma.
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b. Immediate & other relatives should be evaluated for glaucoma.
Family History Tools
1. Jointly designed tool (American Society of Human Genetics, Genetic Alliance, National Society
of Genetic Counselors)
a. Pt accesses tool online
b. Have pt fill out form & bring to office
2. Pamphlet: “Family Medical History in Disease Prevention”: available at AMA web site
3. March of Dimes clinical genetics program: contains section on family history
4. Book: “The Practical Guide to the Genetic Family History” by R.L. Bennett
5. U.S. Surgeon General’s Family History Initiative. Goals include:
a. Increase the public’s awareness of the importance of FHx in health.
b. Give the public tools to gather, understand, evaluate, & use FHx to improve their health.
c. Increase the awareness of health professionals about the importance of FHx.
d. Give health professionals tools to gather, evaluate, and use FHx information.
Learn to recognize the genetic flags (using the Family GENES pneumonic).
A. F – Family history: Look for multiple affected siblings or individuals in multiple generations.
B. G – Groups of congenital anomalies
1. Two or more anomalies are much more likely to indicate the presence of a syndrome with
genetic implications.
2. Look for the presence of any other anomaly in an individual with a common, multifactorial
malformation.
C. E – Extreme or exceptional presentation of common conditions
1. Look for a common disorder with an earlier age of onset than typical (especially in multiple
family members). Some examples include: Vision loss: < age 55 years; Corneal arcus: < age
50 years
2. Look for unusually severe reaction to infectious or metabolic stress.
D. N – Neurologic symptoms including developmental delay
E. E – Extreme or unusual pathology
1. Bilaterality of pathologic findings in paired organs or structures (e.g., retinoblastoma in both
eyes is an indication that the patient has inherited a mutation in the RB1 gene).
2. Appearance of multiple primary neoplasms (e.g., multifocal sites of retinoblastoma).
3. Rare physical finding like congenital hypertrophic retinal pigment epithelium (CHRPE) may be
associated with familial adenomatous polyposis (FAP).
F. S – Surprising laboratory values
1. Abnormal lab values in an otherwise healthy patient may be a clue to a genetic disease (e.g.,
high cholesterol in familial hypercholesterolemia or high serum transferring saturation or
ferritin levels in hereditary hemochromatosis).
2. Extreme lab values for a typical clinical situation may also be a red flag.
Assume all disorders have a genetic component.
A. Essentially all disorders (except possibly trauma) have a genetic component.
B. Common systemic disorders that have genetic components include: Type 1 and Type 2 diabetes,
hypertension, heart disease, asthma, cancers, and Alzheimer disease.
C. Common ocular disorders that have genetic components include: AMD, the glaucomas, cataracts,
myopia, and diabetic retinopathy.
D. The more common diseases are multifactorial in that they involve multiple genes interacting with
environmental influences.
E. Expand your differential diagnosis to include genetic disorders. Set a low threshold for genetic
hypotheses.
F. Try to develop a unifying hypothesis for disparate findings.
G. Learn to “think genetically.” Look at your patients through a new
genetic/developmental/environmental lens.
Learn the genetics of the disorders you see most often in your practice.
A. Tremendous advance in knowledge of genetics of common ophthalmic disorders
B. As more and more is discovered, more diagnostic tests will become available. You will have more
information to help your pts understand their conditions, help them make decisions, provide
supportive counseling
C. Excellent reviews are available on the genetics of most ocular disorders.
D. Example: the genetics of the glaucomas.
E. Look for clues in the presentation and setting.
Learn how to appropriately order and interpret selected genetic tests.
A. In the future, the number & availability of genetic tests for ocular conditions will increase. The
pressure to use these tests will increase.
B. Become familiar with the GeneTests web site.
K.
III.
IV.
V.
VI.
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VII.
VIII.
1. Identify labs that offer specific genetic tests
2. Identify research labs that may provide opportunities for your pt to be a research subject
C. PubMed is an excellent source for articles on particular conditions
(http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed)
1. Gives you info on the condition
2. Allows you to identify researchers whom you can contact
D. Glaucoma:
1. Myocilin gene mutations are responsible for:
a. ~10-20% of pts with juvenile-onset OAG (autosomal dominant inheritance)
b. 3-5% of pts with adult-onset OAG (multifactorial inheritance)
c. Most mutations occur in pts with a FHx of glaucoma
2. There is about a 50% risk of transmission of the risk factor.
3. OcuGene Test: designed to detect a mutation in the promoter (mt-1) region of myocilin. This
test does not check for any known disease-causing mutations (most occur in exon 3).
4. mt-1 promoter mutation in MYOC gene: significance is controversial
5. If a pt does not have glaucoma & has no FHx of glaucoma, the currently identified glaucoma
gene mutations are not common enough to justify DNA testing
a. 2% of population has glaucoma
b. 5% caused by mutations in MYOC
c. Thus only 1 in 1000 of general population would have such a mutation
6. The cost effectiveness of genetics screening will need to be weighed against cost of
conventional screening with consideration for the benefits of early treatment
7. Possible indications for genetic testing for essentially all mutations of MYOC
a. Pt has multiple family members affected with JOAG
b. Pt’s family exhibits autosomal dominant inheritance of JOAG or POAG
8. For pts positive for a DNA mutation
a. Pt has about a 50% risk of glaucoma
b. Glaucoma work-up is indicated
c. If pt is negative for glaucoma, more frequent screening is indicated
9. For pts negative for a DNA mutation
a. Pt has normal risk for glaucoma (2%)
b. Less frequent follow-up is needed
10. Genetic testing in POAG will make sense when the test:
a. Is highly sensitive and specific for glaucoma
b. Is cost effective
c. Screens for all common disease-causing mutations in several genes collectively
responsible for a large proportion of glaucoma cases
Learn how genes flow through populations and how this influences individual risk.
A. The risk of a specific disease may be greatly increased in a specific population or ethnic group. This
may warrant screening in patients of that population.
1. Congenital glaucoma in Amish
2. Retinoschisis in pts with Finnish background
3. Oguchi disease in pts with Japanese ancestry
4. Tay-Sachs or Gaucher disease in Ashkenazi Jewish pts
5. Sickle-cell trait in pts with African, SE Asian, or Mediterranean ancestry
B. Prevalence of OAG (40 years & older)
1. Whites
1-2%
2. Latinos
5%
3. Blacks
3-9%
C. Part of the differences in prevalence is due to genetic differences.
D. Learn the characteristics of:
1. Chromosomal disorders
2. Monogenic disorders (autosomal dominant, autosomal recessive, X-linked, mitochondrial)
3. Multifactorial disorders
E. Allows you to recognize inheritance patterns via FHx & pedigree analysis.
Develop a referral network for genetic conditions.
A. Identify the genetic professional in your area
B. Establish an ongoing relationship with one or more of these professionals
C. Learn how to refer pts to these professionals
D. Seek advice from them as you begin to acquire competency
E. Find a genetic counselor in your area using web site of the National Society of Genetic Counselors
(http://www.nsgc.org/)
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F.
IX.
X.
XI.
Find a medical geneticist in your area using the web site of the American College of Medical
Genetics (http://www.acmg.net/)
G. Identify pt support groups for specific conditions using web site of the Genetic Alliance
(http://www.geneticalliance.org).
Learn to recognize the ethical, legal, and social issues raised by genetic diagnosis.
A. Issues of privacy & confidentiality
B. Learn how to obtain informed consent for genetic testing.
C. Consider possibility of genetic discrimination via employers and insurance companies.
D. May have to deal with conflict between duty to maintain privacy & duty to warn family members of
possible risk.
E. Pt may experience feelings of stigmatization, guilt/shame, loss & grief.
F. Genetics issues raise implications for whole family.
G. Optometric primary care providers are in a good position to handle genetic conditions. Typically
they know the pts & their families.
Most importantly, learn how to locate genetic information and resources when you need
them.
A. Develop life-long learning skills
B. Learn how to use some of the excellent web-based resources
C. Learn how to use Web-based resources. Examples include:
1. Online Mendelian Inheritance in Man (http://www.ncbi.nlm.nih.gov/omim).
2. GeneTests (http://www.genetests.org).
3. National Coalition for Health Professional Education in Genetics (http://www.nchpeg.org).
4. National Human Genome Research Institute (http://www.nhgri.nih.gov).
5. RetNet (Retinal Information Network) (http://www.sph.uth.tmc.edu/Retnet/).
6. Genetics and Your Practice (http://www.marchofdimes.com/gyponline/index.bm2).
7. National Organization for Rare Disorders (http://www.rarediseases.org/).
8. PubMed (http://www.ncbi.nlm.nih.gov/entrez/).
D. Learn how to use selected journals and textbooks for genetic information.
E. Learn how to evaluate the accuracy and validity of Websites, journal, book, and other forms of
information.
F. Knowledge of databases, decision-support tools, and information technology is becoming essential
in clinical practice.
Getting the new genetics into practice.
A. Crucial role players: primary care optometrists, pediatric optometrists, low-vision optometrists
B. Increased genetics/genomics education in schools & colleges of optometry
C. Increased CE opportunities for practicing optometrists
D. Increase your skills in: case recognition, diagnosis, management, pt education, referral of genetics
cases
E. Establish relationships with colleagues who specialize in genetics
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