Download Genetic screening: any kind of test performed for the systematic

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Genetic screening: any kind of test performed for the systematic early detection or
exclusion of a genetic disease, genetic predisposition, genetic resistance, or to determine
whether a person is a carrier.
Screening may be concerned with the general population or specific subpopulations at
high risk
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Genetic screening aims to provide
o Informed choice (carrier status)
o Presymptomatic detection of disease
o Education of family members
o Early intervention
o Reduction in births of severly affecter homozygotes
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Criteria for screening programs
o Benefits > harm
o Must be optional
o Inexpensive
o Easy to perform
o Able to be validated (predictive value)
o Reliable
o Resources for diagnosis/counseling available
o Non-invasive
o Disease being tested must be common and have potentially serious side effects
with potential for intervention and treatment
o Must be accurate and precise with high sensitivity and specificity
 Accurate: proximity of measurements results to true test value
 Precision: the repeatability or reproducibility
 Discriminatory power:
 Sensitivity: ability to ID affected, proportion of true positives in
relation to all positive results
 Specificity: refers to the extent to which the test detects only
affected individuals, proportion of true negatives in relation to all
negative results
 Positive predictive value: shows proportion of population that are
true positives in relation to positive results
 Negative predictive value: shows proportion of population that are
true negatives in relation to all negative results
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Improving NPV and PPV
 Cascade testing: Only test those at risk for disease. Increases the
probability those being tested have disease (filter based on fhx or
risk factors)
Disadvantages to genetic screening
o anxiety raised by information that cannot be used to make positive personal
choices about therapies/preventive measures (Huntingdon’s Disease)
o genetic information that is difficult to understand and interpret
o undue pressure on individual choice
o social stigmatization of persons at increased genetic risk
o social stigmatization of persons who might decline an offer of genetic screening
o disclosure of information about family members who have not consented to
testing
o misuse of the information/discrimination based on the test results after disclosure
to third parties (insurers/ employers)
Ethical and social considerations
o Discrimination by employers using screening data
o Discrimination by insurance companies to exclude individuals
o Lack of effective treatment for at risk individuals with the screened for disorder
o Family members who did not wish to know their risks for the disorder
o Family members that know their risk may chose not to tell other family members
o “Survivor guilt” –those that do not test positive for disorder worry about other
family members who do test positive for disease potential
o Inappropriate anxiety in carriers
o Inappropriate reassurance (if test is not 100% accurate)
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Neonatal screening
o All 50 states test for:
 Galactosemia: RBC GALT activity, molecular mut
 PKU: plasma level > 16.5, mut for small deletions
 congenital hypothyroidism: thyroxine assay, serum T4
 SCD: HbS, PCR and RFLP analysis
o There is no DHEC consent form for newborn screening. The DHEC Newborn
Screening Manual; Law, Regulations, and Official Departmental Instructions
states, "The provision of the screening test is covered under the informed consent
signed by the parents at the hospital." Parents may refuse the tests only on
religious objections.
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Family genetic screening
o autosomal dominance with reduced penetrance or late onset (Huntingdon’s)
 number of CAG repeats
o familial adenomatous polyposis coli (FAPC)>> early detection
 protein truncation testing: IDs premature truncation of APC protein
 duplication and deletion analysis: MLPA
o hereditary non-polyposis colorectal cancer (HNPCC) where heterozygotes can be
identified
o autosomal genetic disorder (Cystic Fibrosis) where carriers can be identified
 mut in CFTR, gene sequence analysis, 5T/TG tract analysis,
duplication/deletion analysis
o X-linked recessive (DMD) where female carriers can be identified
 Some carrier present with milder form of disease
 Examples: ocular albinism
 Biochemical markers
 Example: hexosamidase A enzyme activity in Tay-Sachs
 Polymorphic markers
 Example: DMD dystrophin gene linked with CA nucleotide repeat
o PCR, mutation scanning, gene sequence analysis, MLPA
o Chromosomal rearrangement (translocations etc.)
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Population genetic screening
o systematic application of a genetic test in a population to identify high risk
individuals who have genotypes that may lead to genetic disorders in themselves
or theirdescendants
o Tay Sachs
o Alpha thalassemia: PCR and gene sequencing
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MLPA
o Multiplex ligation-dependent probe amplification (MLPA)[1] is a variation of the
multiplex polymerase chain reaction that permits multiple targets to be amplified with
only a single primer pair.[1] Each probe consists of two oligonucleotides which recognize
adjacent target sites on the DNA. One probe oligonucleotide contains the sequence
recognised by the forward primer, the other the sequence recognised by the reverse
primer. Only when both probe oligonucleotides are hybridised to their respective
targets, can they be ligated into a complete probe. The advantage of splitting the probe
into two parts is that only the ligated oligonucleotides, but not the unbound probe
oligonucleotides, are amplified. If the probes were not split in this way, the primer
sequences at either end would cause the probes to be amplified regardless of their
hybridization to the template DNA, and the amplification product would not be
dependent on the number of target sites present in the sample DNA. Each complete
probe has a unique length, so that its resulting amplicons can be separated and
identified by (capillary) electrophoresis. This avoids the resolution limitations of
multiplex PCR. Because the forward primer used for probe amplification is fluorescently
labeled, each amplicon generates a fluorescent peak which can be detected by a
capillary sequencer. Comparing the peak pattern obtained on a given sample with that
obtained on various reference samples, the relative quantity of each amplicon can be
determined. This ratio is a measure for the ratio in which the target sequence is present
in the sample DNA.