The Genomics Revolution and Optometric Practice
I.
II.
III.
IV.
V.
Introduction
A. Clinical optometry as currently practiced is undergoing a fundamental,
revolutionary transformation. This transformation will change the way
optometrists understand, classify, diagnose, treat and manage disease.
B. The Human Genome Project and other revolutionary advances have started to
increase and broaden the importance of genetics/genomics in all health care.
This revolution will alter eye care forever, and it involves a tremendous change
from the “old genetics” to the “new genetics.” Genetics is no longer an esoteric
academic specialty that involves rare diseases.
Basic concepts
A. A new vocabulary comes with the revolution.
1. The genome is the set of all genetic information (e.g., nuclear
genes/chromosomes, mitochondrial genes) in an organism.
2. The transcriptome is the set of all messenger RNA (mRNA) molecules or
transcripts in a cell or organism.
3. The proteome is the complete set of proteins expressed by a genome, cell,
tissue or organism. It is the set of expressed proteins at any given time
point.
4. The metabolome is the set of all metabolites (e.g., metabolic intermediates,
hormones) in an organism.
5. Systems biology is the study of an organism, viewed as an integrated and
interacting network of genes, proteins and biochemical reactions which give
rise to life. One of today’s challenges is to map the actions and interactions
of all of the molecules in our bodies. To learn how these complex systems
work, models of cells, tissues, and organs can be built. Knowing how these
systems work is important for understanding how the systems fail (i.e., when
disease occurs).
B. The flow of genetic information is from DNA to RNA to protein. A set of
three nucleotide bases in the DNA sequence specify an amino acid in the protein
sequence. Thus the “blueprint for life” consists of a 4-letter alphabet and 3-letter
words.
Human Genome Project (HGP)
A. This was a 15-year worldwide research effort (1990-2005).
B. It was considered so important that the National Human Genome Research
Institute was formed at NIH.
C. The HGP involved the sequencing of human DNA (3 billion base pairs).
D. The HGP was completed ahead of schedule and under-budget in April of 2003.
E. It identified the 20,000 to 25,000 genes in human DNA.
Paradigm shift
A. The “old genetics”.
B. The “new genetics”.
DNA Polymorphisms.
A. A Single Nucleotide Polymorphism (SNP) is a DNA sequence variation
occurring when a single nucleotide (A, T, C, or G) in the genome differs between
individuals or between paired chromosomes in an individual.
B. The DNA of any two people is 99.9% identical.
C.
D.
E.
VI.
International HapMap Project.
The 1000 Genome Project (started January 2008; www.1000genomes.org )
The Cancer Genome Atlas.
F. Genes, Environment, & Health Initiative (GEI).
Molecular optometry.
A. Clinical optometry is undergoing a fundamental, revolutionary transformation.
B. This will change the way optometrists:
1. Classify diseases
2. Understand disease
3. Diagnose diseases
1
4. Treat & manage diseases.
Look at the patient through a “genetic lens” (i.e., incorporate genetic
thinking & principles).
1. Using this lens effectively means rejecting the notion of normality &
embracing the idea of variation. The changing paradigm of medicine
is framed around individual variability rather than the distinct
separation between “normal” and “abnormal.”
2. Every patient is an individual & there is infinite variation on the spectrum
of health & disease.
3. The clinician should take into account the complex interrelationships
among genes, along with each patient’s protein profile,
environmental experiences & exposures.
4. We should no longer regard the human body & the visual system as a
biological machine in which the OD acts as a mechanic when the parts
break down. The clinician’s challenge is to understand the variability
of the genetic & environmental factors that lead to disease, develop
a prevention plan, and, if necessary, a treatment plan based on the
patient’s unique variability.
Improved classification of diseases.
Improved understanding of pathogenesis/pathophysiology.
A. We are moving toward a molecular level of understanding of diseases &
conditions.
B. Twin studies yield heritability estimates for a number of ocular traits
1. Cataracts: nuclear 48%; cortical 58% (In other words, genetics accounts
for about 48% of nuclear cataract variability & about 58% of cortical cataract
variability)
2. Myopia: 90%
3. Central corneal thickness: 95%
4. Intraocular pressure: 63%
5. Optic nerve head disc area and cup area: 80%
6. Anterior chamber depth: 90%
C.
VII.
VIII.
C.
D.
E.
F.
Familial correlation and heritability analysis of data from the Beaver Dam Eye Study
yield heritability estimates for traits underlying refraction:
1. Spherical equivalent: 58%
2. Corneal curvature: 95%
3. Axial length: 67%
4. Anterior chamber depth: 78%
Estimates of heritability for various disorders from twin studies.
1. Obesity
0.80
2. Type 2 diabetes
0.75
3. Schizophrenia
0.65
4. Hypertension
0.55
5. Alcoholism
0.55
6. Cirrhosis
0.50
7. Atherosclerosis
0.40
8. Breast cancer
0.35
9. Type 1 diabetes
0.25
10. Open-angle glaucoma 0.13
Ex. The Glaucomas.
Ex. Age-related macular degeneration.
1. Introduction.
a. AMD is the most common cause of blindness in the elderly in the
Western world.
b. Its prevalence is 0.05% before the age of 50 and 11.8% after the age of
80.
c. 1st -degree relatives of patients with AMD have a 4.2 times increased
lifetime risk of late AMD.
2. CFH gene.
2
3.
IX.
LOC387715/ARMS2 (Age-Related Maculopathy Susceptibility 2) & a
secreted heat shock serine protease HTRA1 (High Temperature
Required Factor A-1) gene.
4. Complement Factor B (CFB) & Complement Component 2 (C2) genes
5. Other complement-related genes.
6. A risk model has been generated based on 5 variants of the CFH,
LOC387715/HTRA1, CFB, C2 genes.
a. About 1% of the population has high-risk homozygotes at all loci.
This confers about a 250-fold increase in risk for AMD.
b. About 10% of the population has a 40-fold increase in risk.
c. This is compared to patients carrying the lowest risk genotypes at all loci
(about 2% of the population).
7. A newer risk model has been generated using variants of the CFH,
LOC387715, C2, C3, & CFB genes, age (≥ 70), smoking, BMI,
education, & baseline AMD grade. Using a cutoff risk score of -1.5, this
model has a sensitivity of 83% and a specificity of 68% for
progression to advanced AMD. This is comparable to the Framingham
risk score prediction model for coronary heart disease (CHD).
8. Innate immunity and inflammation in general and complement
overactivation in particular appear to play a central role in AMD
pathogenesis.
9. The new data suggest new targets for early intervention & predictive
DNA testing as a future option. It may also lead to the development of
new biomarkers for the disease. The future challenge is to develop risk
models incorporating gene-gene interactions, gene copy-number
variations, epigenetics, environmental interactions, treatment
effects, and clinical covariates.
Improved diagnostic testing.
A. Microarrays (DNA chips, RNA chips, Protein chips)
B. “Lab-on-a-chip” microfluidics
C. Point-of-care testing
D. Tests will become available in the next 10 years to determine risk for common
diseases.
E. Types of genetic tests.
1. Molecular genetic test – tests for a genetic condition by testing for nucleic
acid (DNA or RNA)
2. Cytogenetic test – tests for anomalies of number or structure of
chromosomes.
3. Biochemical genetic test – test to study enzymes, proteins or metabolites
that may be altered by a genetic condition.
F. Thinking will shift to probabilities (statistical risks) instead of definitive
answers.
G. Goal of $100 genome sequencing. The cost of sequencing the first genome
(HGP) was about $3,000,000,000. Illumina will sequence your whole genome for
$4,000 for research purposes. Recent approaches in development for reading
genomes have resulted in a drop in cost to about $1,000 (Ion Torrent PGM &
Illumina MiSeq). Human exome sequencing can be obtained for $999 (BGI
Americas).
H.
Some currently available tests for ocular diseases:
1. arRP-1 sequencing array (U. of Michigan) for mutations causing autosomal
recessive forms of RP
2. ABCR (ABCA4) gene mutation detection assay (Asper Ophthalmics) for
mutations causing Stargardt disease
3. LCA microarray test for Leber congenital amaurosis (Asper Ophthalmics)
4. More than 2,900 genetic tests available from commercial labs
(including tests for various glaucomas, corneal dystrophies, retinal
dystrophies, cataracts, AMD, & various pathogens)
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5.
I.
The Carver Nonprofit Genetic Testing Laboratory (Univ. of Iowa)
(www.carverlab.org) offers relatively cheap testing with fairly fast turnaround times for 26+ ocular diseases.
Reasons for genetic testing.
1. Predictive testing: offered to asymptomatic individuals with a family
history of a genetic disorder
a. Presymptomatic testing for predicting adult-onset disorders (e.g.,
Huntington disease)
b. Susceptibility (predispositional) testing.
2. Diagnostic testing of a symptomatic individual
3. Carrier testing.
Table 2. Examples of ethnicity-based carrier screening
Disease
Ethnic group
Hereditary
Northern European
hemochromatosis
Cystic fibrosis
European
Hispanic
African
Asian
Sickle cell anemia
Black
Gaucher disease
Ashkenazi Jewish
Tay-Sachs disease
Ashkenazi Jewish
Thalassemia
African/Asian/Mediterranean/Middle
Eastern
4.
5.
6.
J.
K.
L.
X.
Carrier frequency
1/8
1/25
1/46
1/60-65
1/150
1/14
1/12
1/26
Varies with
population
Prenatal diagnostic testing (aka antenatal testing)
Newborn screening.
Preimplantation genetic diagnosis (PGD).
Population screening.
1. Population screening involves the explicit and systematic application of a
diagnostic genetic test across a whole population of asymptomatic
people, or a subset of a population like newborn infants or pregnant
women.
2. Prenatal, neonatal, and carrier screening are examples of population screening.
Cascade genetic screening.
1. This involves screening for genetic variants that predispose individuals or
their offspring to disease by targeting relatives of previously identified
carriers.
2. Carrier risk of close relatives of known carriers is generally higher than the
population risk.
3. This type of screening is more efficient than population screening, in the
sense that fewer individuals have to be genotyped per detected carrier.
4. Example: glaucoma.
a. 10-fold increase in risk for 1st–degree relatives of glaucoma patients.
Evaluation of genetic tests. One important approach is the ACCE framework
developed by the Office of Genomics and Disease Prevention at the Centers for
Disease Control and Prevention (CDC). An ACCE evaluation begins with a
description of the relevant disorder and the setting in which the test will be used. It
then moves on to an assessment of the Analytical validity, Clinical validity, Clinical
utility, and the Ethical, legal, and social implications of the test.
1. Analytic validity.
2. Clinical validity.
3. Clinical utility.
4. Ethical, legal, and social implications.
Improved management and treatment.
4
A.
B.
C.
Identification of patients with susceptibility genes may help determine:
1. Risk level
2. Types of testing/treatment
3. Timing of surveillance visits
4. Appropriate lifestyle changes
Gene therapy.
1.
Gene therapy for age-related macular degeneration (AMD).
2.
Ciliary neurotrophic factor (CNTF) for human retinal degeneration.
3.
Gene therapy for steroid-induced glaucoma.
Antisense drugs.
1.
2.
3.
4.
D.
RNA interference (RNAi).
1.
2.
3.
4.
E.
These drugs are complementary strands of portions of messenger RNA
(mRNA).
The drugs bind to mRNA and inhibit transcription of the protein.
Fomivirsen was the first antisense drug marketed (1998). It is used for
treating CMV retinitis.
A 2nd-generation antisense inhibitor, iCo-007 (iCo Therapeutics Inc.), targets
C-raf kinase mRNA & has completed phase I clinical trials for treating retinal
neovascular diseases like diabetic retinopathy
Small double-stranded interfering RNAs (siRNAs) can silence messenger
RNAs carrying a complementary sequence. siRNAs occur naturally in
mammalian cells and can also be generated artificially and used in
therapeutic clinical trials.
RNAi is used to selectively inhibit gene expression in various diseases,
including infectious diseases, cancer, inflammation/immune dysfunction, CNS
disorders, and cardiology.
RNAi drugs for non-arteritic anterior ischemic optic neuropathy,
glaucoma, and diabetic macular edema.
RNAi drugs for AMD.
Complement-targeted therapeutics for AMD.
1. Complement component inhibitors:
2.
F.
Receptor antagonist: Jerini Ophthalmics, Inc. is in pre-clinical stages of
testing JPE-1375 (an antagonist for the pro-inflammatory C5a receptor) for
dry AMD.
Other anti-inflammatory treatments for AMD.
G.
XI.
Genetic counseling – new role for primary care clinicians (including
optometrists)
1. Genetic counseling will become more and more a primary care responsibility.
2. There are not enough genetics counselors or medical geneticists to handle
the increase in demand.
3. Every health care provider will become a genetic counselor in the next 10
years.
Pharmacogenetics / Pharmacogenomics.
A.
B.
C.
D.
E.
View interactive tutorial on Pharmacogenomics
(http://www.phgfoundation.org/tutorials/home/)
Each year, 100,000 people die from adverse reactions to drugs & over 2 million
have serious reactions.
Some drugs work well in some patients & not as well in other patients.
DNA variations (SNPs, insertion/deletions, & copy-number variations) in genes
that are involved in drug metabolism, drug transportation, drug targets, &
intracellular signaling pathways can account for much of the ability of some
drugs to cause adverse reactions and/or to be ineffective.
Pharmacogenomics (PGx): This is a branch of pharmacology concerned with using
DNA and amino acid sequence data to inform drug development and testing. An
important application of pharmacogenomics is correlating individual genetic variation
(e.g., polymorphisms) with drug responses. PGx is also often used as the more all-
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F.
G.
H.
I.
J.
K.
XII.
XIII.
encompassing, or default, term when referring to the general study or use of genetic
variation in drug response.
The Amplichip CYP450 Microarray (Roche/Affymetrix) is now commercially
available for testing two of the genes involved in drug metabolism (CYP2D6 &
CYP2C19). This test accounts for ~99% of known poor and ultra-rapid
metabolizer genetic variation in these genes.
Suggestive studies in eye diseases:
ODs will prescribe medications and determine drug doses based on the patient’s
genotype and SNP pattern:
1. Improving efficacy & safety of drugs
2. Decreasing morbidity & mortality
3. Decreasing overall cost of health care.
“Personalized medicine” will evolve for many drugs and diseases by the year 2020.
Example: Aminoglycoside-induced ototoxicity.
1. A1555G mutation in the mitochondrial gene MTRNR1 can cause hearing
loss in patients exposed to aminoglycoside antibiotics.
2. Clinical testing is offered in 22 labs.
3. Prevention of hearing loss in maternal relatives is achievable.
4. Every patient with NSHL should be screened – unless maternal
inheritance can be excluded.
Pharmacogenomic biomarkers that help predict drug-related toxic effects.
Pharmacogenomics has entered day-to-day clinical practice. Today, about 10% of
labels for FDA-approved drugs contain phamacogenomic information. For example,
when considering the following drugs for your patient, the patient should be
genotyped first.
Ethical, legal, social implications (ELSI).
A. Informed consent
B. Confidentiality/privacy
C. Discrimination (e.g., employers, insurers)
D. Psychological impact
E. Fairness in access to genetic services
F. Conceptual/philosophical/religious implications
G. Clinical issues including education of clinicians, patients, & the general public
Why the genomics revolution is important for optometric practice.
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A.
B.
C.
D.
E.
F.
G.
Virtually all diseases have a genetic component. This means optometric
physicians will need to:
1. raise genetic hypotheses with every patient (i.e., look at each patient through a
“genetic lens”)
2. realize when genetic factors play a role in a patient. Thus, we will have to be
aware of genetic contributions to the common diseases seen in practice
3. improve family history taking skills and, in selective cases, draw a threegeneration pedigree
4. be able to identify patients who need genetic services and/or referral
5. know how, when, and where to obtain advice and refer patients
a.
Find a genetic counselor in your area by using the Website of the
National Society of Genetic Counselors (http://www.nsgc.org, click on
“Find a Genetic Counselor”).
b.
Find a medical geneticist in your area by using the Website of the
American College of Medical Genetics (ACMG) (http://www.acmg.net,
click on “Find a member”).
c.
Find genetic services in your area by using the ACMG Website
(http://www.acmg.net, click on “Find genetic services”)
d.
Identify patient support groups for specific conditions by using the
Website of the Genetic Alliance (http://www.geneticalliance.org).
6. know how to access new knowledge on medical genetics and use it in patient
care
Everyone has 5-50 significant genetic flaws.
There is an exponential rise in genetic knowledge.
New diagnostic/prognostic/treatment options are increasing. This means
optometric physicians will need to:
1. learn the indications for genetic testing and the availability of genetic
tests for specific ocular conditions
2. deal with “risk” and genetic predisposition
3. manage low and moderate risk patients
4. use genetics to individualize patient care and preserve health
5. be able to read the increasing number of ophthalmic journal articles on
genetic/genomic issues, and thus to keep current
6. be able to identify, understand, and address the ethical, legal, social, and
financial issues associated with genetic conditions as they arise in
primary and specialty (e.g., pediatric optometry and low vision) practice.
There are not enough genetic specialists to handle the increase in demand.
There is a growing demand for genetic information and services by patients.
Thus, optometrists will need to be able to:
1. address the increasing number of patient’s questions and concerns about new
genetic technologies and information related to eye care
2. explain genetic concepts
Direct marketing of genetic tests to health care professionals & potential
customers is occurring.
1. 23andme.com – For $99 they will take a saliva sample and genotype
~1,000,000 of your SNPs. Their report will give you your risk for 203 diseases
& traits (including AMD) as well as trace your ancestry.
2. decodeme.com – For $1100 they will take a buccal sample and genotype
~1,000,000 of your SNPs. Their report will give you your risk for 47 diseases &
traits (including AMD and XFG) as well as trace your ancestry. DeCODE
recently declared bankruptcy, but the genetics testing services are still
operating.
3. The DeCODE Glaucoma test ($285)
4. Counsyl – For $349 (or free with insurance) they will take a saliva sample and
check for 458 causal genetic variants for 105 monogenic recessive disorders
(“Universal Genetic Test”).
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cyGene Direct’s Glaucoma & Macular Degeneration DNA Analysis
($99.95).
6. Nutrigenetic testing. Some companies say they can use genetic information
to develop an individualized diet plan. Such tests may be misleading or even
harmful. They tend to make claims that can’t be proven scientifically.
7. Direct-to-consumer (DTC) genetic testing has raised concerns about :
a.
The potential for inadequate pretest decision-making
b.
Misunderstanding of test results
c.
Access to tests of questionable clinical value
d.
Lack of necessary genetic counseling & follow-up
e.
Unexpected additional responsibilities for primary care providers.
f.
Different risk assessments for samples from the same individual sent to
different companies
g.
Testing that is unregulated & unvalidated
h.
Testing often done without a physician’s intercession.
8. The FDA is planning to regulate DTC testing
National Ophthalmic Disease Genotyping Network (eyeGENE).
1. Created by NEI in partnership with 12 CLIA-approved laboratories
2. Register on-line at their Website
(http://www.nei.nih.gov/resources/eyegene.asp)
3. Submit the patient sample (blood draw & shipping are the only costs).
4. Currently, 65 genes for 32 diseases are assessed.
5. You receive the report.
6. The referring OD must ensure that the patient receives genetic counseling
before & after.
7. eyeGENE goals:
a. to facilitate research into genetic causes of ocular diseases
b. to provide accurate diagnostic genotyping to patients with inherited eye
diseases
c. to identify, engage, & enhance patient recruitment for therapeutic clinical
trials
d. to provide a repository of DNA coupled to de-identify phenotypic info for
researchers.
Enhanced genetic literacy & competency of ODs is necessary.
What you can do now.
1. Start learning about genetics & eye diseases (see references below).
2. Read & start working on “Recommended Core Competencies in Genetics
for Doctors of Optometry
(http://www.opted.org/i4a/pages/index.cfm?pageid=3400)
a. These competencies have been endorsed by the American Academy of
Optometry, the American Optometric Association, & the Association of
Schools & Colleges of Optometry.
3. Become familiar with: Online Mendelian Inheritance in Man (OMIM).
a. Catalogues all known diseases with a genetic component
b. Assigns a 6-digit number to every gene & disease (the MIM code)
c. The 1st number indicates the type of inheritance
d. Check out the short video tutorial at http://techtv.mit.edu/videos/3042-bit32-omim-and-omia
4. Identify patients that could benefit from gene testing.
a. Many disease genes are available for testing now.
b. An excellent resource for the clinician is the GeneTests Website
(http://www.ncbi.nlm.nih.gov/sites/GeneTests/?db=GeneTests).
(1)
This site is user friendly and has links to laboratories at which feefor-service testing for each disorder is performed. The site also has
detailed information on how to send a sample. Information on labs
that offer research-based testing is also available.
5.
H.
I.
J.
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(2)
K.
L.
XIV.
For many disorders, the site has expert-authored, peer-reviewed,
current disease descriptions that apply genetic testing to the
diagnosis, management, and genetic counseling of patients and their
families with specific inherited conditions.
c. A number of CLIA-certified labs can perform these tests (e.g., through
eyeGENE)
5. Identify patients for studies & clinical trials.
a. eyeGENE – become familiar with this resource, register for it, and start
sending blood samples of patients who have genetic diseases that it
addresses
b. ClinicalTrials.gov (http://clinicaltrials.gov/ ) is a registry of federally and
privately supported clinical trials conducted in the US and around the world.
It gives you information about a trial's purpose, who may participate,
locations, and phone numbers for more details.
c. PubMed comprises more than 20 million citations for biomedical literature
from MEDLINE, life science journals, and online books. Citations may
include links to full-text content from PubMed Central and publisher web
sites. Articles pertinent to your patient will give information about where the
research was done and who was involved.
Final caveat.
1. The coming deluge.
a. The $100 genome is coming.
b. We will be awash with new highly complex genetic information.
c. It will often be touted as ready to revolutionize healthcare.
d. It does hold great promise, especially for drug development and laying bare
the molecular foundation of disease.
e. But the rules of medicine haven't changed.
(1)
There’s nothing magical about genetic information.
(2)
Take a good family history!
(3)
Insist on actual outcome data before embracing attractive ideas.
2. The need for clinical outcome data.
a. The history of medicine is riddled with the corpses of good ideas that didn’t
pan out:
(1)
EC/IC bypass to prevent stroke
(2)
HRT to prevent every possible bad outcome of female aging
(3)
PSA?
b. Good ideas are not enough to guide medical care.
(1)
We have the power to harm.
(2)
Even through “non-invasive” testing
(3)
Such information has the potential to put our patients on a
trajectory that leads to dangerous and harmful interventions.
c. We need to insist on data to prove that our good ideas actually result in
improved outcomes.
d. We have to be leery of shortcuts and attractive theories.
Two quotes from Edwin M. Stone, MD, PhD, are instructive (Arch Ophthalmol
2007;125:205-12):
1. “We can reasonably expect the deployment of useful tests for nearly all
inherited eye diseases during the next 5 to 10 years.”
2. “In 1990, it may have been true that the rate-limiting steps of genetic testing for
rare eye diseases were mostly in the laboratory. However, in 2006, the most
rate-limiting steps in the translation of genomic information from the laboratory
to the clinic are to inform clinicians about the availability of these tests and to
educate them about their proper use and interpretation.”
Selected References.
A.
Books.
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Bennett RL. The practical guide to the genetic family history. 2 nd ed. WileyBlackwell, 2010.
2. Humphries P, et al. Hereditary retinopathies: progress in development of
genetic and molecular therapies. New York: Springer, 2012; vii, 46 p.
3. Kumar D (ed.). Genomics and clinical medicine (Oxford Monographs on
Medical Genetics). Oxford University Press: New York, 2008 (there is a chapter
on complex ophthalmic disorders).
4. Lorenz B, Borruat F-X (eds.). Pediatric ophthalmology, neuro-ophthalmology,
genetics. Springer: New York, 2008.
5. Merin S. Inherited eye diseases: diagnosis and management. 2nd ed. Taylor &
Francis: Boca Raton, 2005.
6. Samples JR (ed.). Ophthalmic genetics: diagnosis and therapy. Ophthalmology
Clinics of North America (vol. 16, no. 4), W. B. Saunders Co.: Philadelphia,
December 2003.
7. Wang MX (ed.). Corneal dystrophies and degenerations. A molecular genetics
approach (American Academy of Ophthalmology Monograph Series, 16).
Oxford University Press: New York, 2003.
8. Wissinger B, Kohl S, Langenbeck U (eds.). Genetics in ophthalmology
(Developments in ophthalmology, v. 37). Karger: New York, 2003.
Journal articles.
1. Berger W, et al. The molecular basis of human retinal and vitreoretinal diseases.
Prog Retin Eye Res 2010;29:335-375.
2. Brooks BP et al. Genomics in the era of molecular ophthalmology: reflections on
the National Ophthalmic Disease Genotyping Network (eyeGENE). Arch
Ophthalmol 2008;126:424-5.
3. Burdon KP. Genome-wide association studies in the hunt for genes causing
primary open-angle glaucoma: a review. Clin Experiment Ophthalmol
2012;40(4):358-63.
4. Campochiaro PA. Potential applications for RNAi to probe pathogenesis and
develop new treatments for ocular disorders. Gene Ther 2006;13:559-62.
5. Challa P. Genetics of adult glaucoma. Int Ophthalmol Clin 2011;51(3):37-51.
6. Challa P. Genetics of pseudoexfoliation syndrome. Curr Opin Ophthalmol
2009:20:88-91.
7. Chen Y, et al. Assessing susceptibility to age-related macular degeneration with
genetic markers and environmental factors. Arch Ophthalmol 2011;129(3):34451.
8. Chu XK, Tuo J, Chan CC. Genetics of age-related macular degeneration:
application to drug design. Future Med Chem 2013;5(1):13-5.
9. Churchhill A, Graw J. Clinical and experimental advances in congenital and
paediatric cataracts. Philos Trans R Soc Lond B Biol Sci 2011;366:1234-49.
10. Cideciyan AV. Leber congenital amaurosis due to RPE65 mutations and its
treatment with gene therapy. Prog Retin Eye Res 2010;29:398-427.
11. Deangelis MM, et al. Genetics of age-related macular degeneration: current
concepts, future directions. Semin Ophthalmol 2011;26(3):77-93.
12. Demetriades AM. Gene therapy for glaucoma. Curr Opin Ophthalmol
2011;22(2):73-7.
13. Downs K, et al. Molecular testing for hereditary retinal disease as part of clinical
care. Arch Ophthalmol 2007; 125:252-8.
14. Drack AV, Lambert SR, Stone EM. From the laboratory to the clinic: molecular
genetic testing in pediatric ophthalmology. Am J Ophthalmol 2010;149:10-17.
15. Fan BJ, et al. LOXL1 promoter haplotypes are associated with exfoliation
syndrome in a U.S. Caucasian population. Invest Ophthalmol Vis Sci
2011;52(5):2372-8.
16. Feero WG, Guttmacher AE, Collins FS. Genomic Medicine – an updated primer.
N Engl J Med 2010;362:2001-11.
1.
B.
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17. Fingert JH. Primary open-angle glaucoma genes. Eye (Lond) 2011;25(5):58795.
18. Gemenetzi M, Yang Y, Lotery AJ. Current concepts on primary open-angle
glaucoma genetics: a contribution to disease pathophysiology and future
treatment. Eye (Lond) 2012;26(3):355-69.
19. Hageman GS, et al. Clinical validation of a genetic model to estimate the risk of
developing choroidal neovascular age-related macular degeneration. Hum
Genomics 2011;5(5):420-40.
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Selected Websites
1. Disease specific information for health care professionals
a. OMIM (Online Mendelian Inheritance in Man):
http://www.ncbi.nlm.nih.gov/sites/entrez?db=OMIM
b. GeneTests (select “Gene Reviews”): http://www.genetests.org/
c. Genes and Disease (NCBI): http://www.ncbi.nlm.nih.gov/disease/
d. RetNet (Retinal Information Network): http://www.sph.uth.tmc.edu/Retnet/
2. Genetic tests
a. GeneTests (select “Laboratory Directory”): http://www.genetests.org/
b. American College of Medical Genetics (select “Find Genetic Services”):
http://www.acmg.net//AM/Template.cfm?Section=Home3
c. eyeGENE: http://www.nei.nih.gov/resources/eyegene.asp
d. The John & Marcia Carver Nonprofit Genetic Testing Lab:
https://www.carverlab.org/
3. Family history tools
a. U.S. Surgeon General’s Family History Initiative:
http://www.hhs.gov/familyhistory/
b. Centers for Disease Control & Prevention:
http://www.cdc.gov/genomics/famhistory/famhist.htm
4. Directories of clinical genetics specialists
a. National Society of Genetic Counselors (select “Find a Genetic Counselor):
http://www.nsgc.org/
b. American College of Medical Genetics (select “ Find a Member”):
http://www.acmg.net//AM/Template.cfm?Section=Home3
5. General genetics resources
a. National Human Genome Research Institute: http://genome.gov/Education/
b. Genetic Science Learning Center: http://learn.genetics.utah.edu/
c. Genetics Education Center: http://www.kumc.edu/gec/
d. March of Dimes – Genetics & Your Practice:
http://www.marchofdimes.com/gyponline/index.bm2
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e. National Coalition for Health Professional Education in Genetics
(NCHPEG): http://www.nchpeg.org
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