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Outcomes of a diagnosis test:
Someone has the mutated gene:
True Positive (diagnosis is accurate)
False Negative (diagnosis is not accurate)
What is the implication for a person to receive
a False Negative diagnosis?
Outcomes of a diagnosis test:
Someone has the ‘normal’ version of the gene:
True Negative (diagnosis is accurate)
False Positive (diagnosis in not accurate)
What is the implication for a person to receive
a False Positive diagnosis?
Outcomes of a diagnosis test:
Someone has the mutated gene:
True Positive (diagnosis is accurate)
False Negative (diagnosis is not accurate)
Someone has the ‘normal’ version of the gene:
True Negative (diagnosis is accurate)
False Negative (diagnosis in not accurate)
Most of the genetic diseases that are
currently diagnosable are monogenic.
They are tested by:
Cytogenetics (microscopic evaluation)
PCR (a certain size PCR product)
PCR + RFLP (after digestion is a certain size)
SSCP (Single-Stranded Conformation Polymorphism)
Mass Spectrometry (a certain chemical is present)
Bioassays (e.g. growth of Bacillus in Phenylketonuria,
PKU, Phenylalanine doesn’t get broken down)
Deafness (DFNA1) = only one mutation (substitution & reading frame)
Huntington Disease & SCA1 = one mutation (repeats)
Alzheimers Disease = 22 different mutation (mostly missense)
Duchenne Muscular Dystrophy = 647 different mutations (all types)
Cystic Fibrosis = 1029 different mutations (all types, but 60% substitutions)
Clinical Applications of Genetic Tests
• Diagnostic Testing (determine the presence of a genetic
condition that is already being expressed)
• Predictive Testing (determine the presence of a genetic
condition when there are few symptoms)
• Carrier Testing (identify heterozygotes)
• Prenatal Testing (assess a fetus for genetic make-up)
Clinical Applications of Genetic Tests
How are patients affected by these tests?
• Diagnostic Testing (determine the presence of a genetic
condition that is already being expressed)
• Predictive Testing (determine the presence of a genetic
condition when there are few symptoms)
• Carrier Testing (identify heterozygotes)
• Prenatal Testing (assess a fetus for it’s genetic make-up)
29 diseases that every newborn baby in Kentucky is checked for:
Law passed in 2005 in Kentucky Legislature
In effect since January, 2006.
Why is counseling an important part of the
process of genetic testing?
Mary Bystrek on Williams Syndrome
Norrie Syndrome
Recessive mutation of NDP gene (X chromosome)
1 in 200,000 people
Causes blindness at birth due to abnormalities in retina.
Gets progressively worse….cataracts, clouding of the cornea,
Shrinking of globe.
Leads to complete blindness in childhood.
Mental retardation & hearing loss affect about a third
to one half patients.
Norrie Syndrome
Recessive mutation of NDP gene (X chromosome)
Gene product = ‘Norrin’
is a secreted protein that is believed to affect
development and maintenance of the retina
(especially providing blood supply to retina).
70% are point mutations at various places in gene.
Use SSCP (Single Stranded Conformation
Polymorphism) Analysis
24% are short deletions of part of gene…
detected with PCR.
Norrie Syndrome
No treatment for this disease.
Retinal surgery can sometimes help.
Hearing aids are used.
Special education.
Counseling.
Laura Lund on Achondroplasia
Smith-Lemli-Opitz Syndrome
pp. 550-552
•Autosomal recessive mutation (Chromo. 11)
• First described in 1964
•1 in 20,000 births (esp. European descent)
• Mental retardation
• Small brain at birth
• Fusion of 2nd and 3rd toes
• High, broad forehead
• Short nose with upward pointing nostrils
• Large ears
• Deformities of hands and feet, and heart, lungs, kidneys, etc.
• Autism – self-injury, temper tantrums, violent
outbursts, etc.
Smith-Lemli-Opitz Syndrome
Mutation of 7-dehydrocholesterol reductase
• Leads to a deficiency of cholesterol
• Cholesterol is important part of cell membranes,
myelin sheath, steroid hormones
Smith-Lemli-Opitz Syndrome
Mutation of 7-dehydrocholesterol reductase
• Primarily detected by high levels of 7-dehydrocholesterol
in blood, but there are also PCR tests.
• Diet rich in cholesterol is helpful (eggs, etc.)
• Surgery is often useful.
Wilson Disease
• Autosomal recessive mutation (Chromosome 13)
• 1 in 30,000 births
• Interferes with the normal removal of Copper
• Copper accumulates in the liver (which degrade)
• Copper is released to blood system
• Accumulates in brain, cornea of eye
• Copper poisoning occurs between 6-25 years
Wilson Disease
Symptoms:
• Liver Disease
• Psychiatric problems (depression, anxiety)
• Juandice, fatigue, abdominal pain, kidney failure
• Commonly have a brown ring of copper pigment
buildup in the cornea
http://www.gesundheit.de/roche/pics/p19542.000-1.html
Wilson Disease
• Copper poisoning occurs between 6-25 years
• Mutation of gene that codes for an ATPase
that transports Copper across membranes
• Over 200 different mutations of this gene
• Diagnosed by liver problem + psychiatric + eyes
• Also, can monitor Copper level in urine
Wilson Disease
• Oral doses of a Copper chelator
• Oral doses of Zinc which encourages a biochemical
change that chelate all metals
• Don’t eat liver, shellfish, chocolate, mushrooms, nuts
• Don’t drink water from Copper pipes
• Multivitamins
• Can live a long life if daily treated
Protecting genetic privacy and
preventing genetic discrimination
The results of diagnostic tests are always confidential,
but DNA testing could be considered a ‘special case’:
• Once you have someone genomic DNA it can be frozen
and kept for years…and it can be tested for multiple genes
• We can get DNA samples from hair or saliva without consent
• Whereas biochemical tests are based on changes in the
body at the time of testing, DNA analysis can predict diseases
that could occur in the future.
Protecting genetic privacy and
preventing genetic discrimination
Insurance Claim = “Financial reimbursement
for an unanticipated event to a member of a
group of insurance-holders who each make
a modest contribution to a pool of money”.
Protecting genetic privacy and
preventing genetic discrimination
Insurance Claim = “Financial reimbursement
for an unanticipated event to a member of a
group of insurance-holders who each make
a modest contribution to a pool of money”.
If DNA testing shows that an insurance holder has a
gene mutation that is going to cause disease later, then its not
really “unanticipated” is it?
Strategies for treating genetic diseases:
• Specially-formulated diets
1) reduce intake of something bad
2) supplement diet with something needed
• Inhibit certain enzyme reactions (e.g. inhibitor, proteolysis,
block transcription)
• Removal of toxic molecules (e.g. dialysis. copper)
• Replace the missing (or defective) gene product
1) medication containing proteing
2) organ transplant (e.g. bone marrow, a gland)
3) gene therapy