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Clinical Essentials of Ophthalmic Genetics
I. What makes a disease hereditary?
II. Family History
A. What to ask
B. How to ask it
III. Pedigree Construction
A. How to elicit the information
B. How to draw it
C. Clinical examples
IV. Modes of Inheritance
A. Autosomal dominant
B. Autosomal recessive
C. X-linked recessive
D. Maternal inheritance
E. Other Modes of Inheritance
1. X-linked dominant
2. Co-dominant
3. Uniparental disomy
4. Genomic imprinting
5. Horizontal gene transfer
6. “Jumping genes”
7. Digenic inheritance
V. Genetic Testing
A. DNA Primer
B. Human Genome Project (HGP)
1. Historical Overview and Outcomes
a. Initiated by Department of Energy
b. Human Genome Initiative 1986
c. HGP began 1990
d. Joint effort by DOE and NIH
e. Estimated completion 15 years
f. Working draft announced June 2000
2. HGP - Working Draft
a. 16 Sequencing centers
b. 22.1 billion bases of raw data
c. 30% high quality finished sequence
d. Map of 90% of genes on every chromosome
e. 3164.7 million bases
f. Only about 35,000 genes!!
g. Avg. gene is 3,000 bases
h. Largest is 2.4 million
i. All data rapidly available on Web
C. Retinal Disease Genes
1. Can only test for known mutations
a. Research studies may discover new mutations
2. A negative only means that a known mutation was not found
3. A positive offers little help until there is treatment
4. Resource – GeneTests website
VI. Ophthalmic Examples
A. Retinitis Pigmentosa
1. Autosomal dominant
2. Autosomal recessive
3. X-linked recessive
B. Leber hereditary optic neuropathy
C. Glaucoma
1. OcugeneTM Test
D. Unknown retinal dystrophy
E. Retinal Dystrophy
VII.
Genetic Counseling
A. Legal precedents
B. Negligent Acts Claimed by Plaintiffs
1. Failure to take a family history
2. Failure to identify high risks
3. Failure to perform diagnostic tests
4. Failure to provide counseling
5. Misdiagnosis of a previous child
6. Missed diagnosis of a previous child
7. Laboratory errors
C. Wrongful Birth
D. Wrongful Life
E. Economic Harm
F. Non-Economic Harm
1. Emotional pain and suffering
G. What the genetic counselor must know
1. Exact diagnosis
2. Risk estimate
3. Prognosis
4. Alternatives: Pre-conception and post-conception
5. Exact Diagnosis
6. Physical examination
7. Laboratory studies
8. Family studies
9. Study of previous abortus or stillborn
10. Molecular genetic analysis
11. Risk Estimate
a. How big a risk is 25%?
b. 25% risk means 75% normal which may sound good
c. It depends on the prognosis
(1) How will the offspring be different as an adolescent
or as an adult?
d. Parents must make a decision about future children before current
child has manifested the expected sequelae
12. Pre-Conception Alternatives
13. Post-Conception Alternatives
VIII. Gene therapy
A. Barriers to therapy
1. Targeting
2. Effectivity
B. Genetic manipulation of embryo
C. Ethical issues
D. Germline Gene therapy
1. Preconception manipulation of egg of sperm
E. Somatic Gene Therapy
F. In Vivo and In Situ Gene Therapy
G. Viral delivery vehicles
H. Non-viral delivery vehicles
1. delivery
2. Gene gun
I. Ophthalmic Gene Therapy
1. Lancelot dog model
IX. eyeGENE Initiative from NEI
A. Repository of DNA from patients with hereditary eye disease
B. Correlated phenotypic description
C. Contributors will be patients of ODs and MDs
D. How it will help
X. Resources for the Practitioner
A. Entrez
1. http://www.ncbi.nlm.nih.gov/Database/index.html
B. PubMed
1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi
C. OMIM
1. http://www.ncbi.nlm.nih.gov/omim/
D. HUGO
1. http://www.hugo-international.org/
E. RetNet
1. http://www.sph.uth.tmc.edu/Retnet/
F. GeneTests
1. http://www.geneclinics.org/
G. NEI Trials
1. http://www.nei.nih.gov/neitrials/
H. ClinicalTrials.gov
1. http://clinicaltrials.gov/ct/gui
I. eyeGENE
1. http://www.nei.nih.gov/resources/eyegene.asp