Download Genetic Testing - Why, When and Whom

GENETIC TESTING – WHY, WHEN AND WHOM
Denise Goh Li Meng
Genetic Testing has become part of clinical medicine and its role will continue to grow.
An awareness of the availability, advantages, limitations and interpretation of genetic
testing is important to ensure its correct use and benefits to the patient.
Contents
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Definition
Why
When
Whom
How to achieve informed consent?
Accuracy of genetic tests
Interpretation of results
Follow up of results of genetic tests (Post- testing genetic counseling)
Special issues to pay attention to
Bulletin 33; November 2003
MITA (P) No: 275/05/2003
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Definition
Genetic tests are laboratory techniques used to determine if a person has a genetic
disorder or is likely to get the disorder. In Singapore, there are many genetic tests
available on a clinical basis. Clinical genetic testing is mainly physician initiated viz. a
patient presents with a complaint that the physician recognizes as a possibly genetic in
origin, and orders or refers the patient for genetic testing. A small proportion is patient
driven and this tends to be in the area of carrier, pre-natal and pre-symptomatic
diagnosis.
Why?
The main reasons for genetic testing are
1. to confirm a specific diagnosis in a symptomatic individual (diagnostic testing)
2. to ascertain the risk of having a particular condition in an individual who is
asymptomatic at the time of the testing (predictive testing)
3. to ascertain the risk of transmitting a condition (carrier testing)
4. to ascertain the risk of a fetus having a clinically significant genetic disorder (prenatal diagnosis)
When?
Genetic testing is offered when (1) there is suspicion that a gene contributes to the
pathogenesis of the disease, and (2) when such testing is available. This is dependent
on the type of genetic disorder involved. There are three main groups of genetic
disorders: single gene disorders, chromosomal disorders and multifactorial disorders.
1. Single Gene Disorders
A single gene disorder is caused by a change in a single gene. There are many
different types of single gene disorders. Individually, they are usually rare but
overall they affect ~2 percent of the population over a lifetime. If the gene for the
disease has been identified, it is likely that genetic testing is available or will be
available soon for clinical use.
2. Chromosomal Disorders
Individuals with chromosomal disorders have either a deficiency or excess of a part
or whole chromosome. As chromosomes contain genes, a chromosomal disorder
causes problems because many genes are either deficient or in excess.
Chromosomal disorders are relatively common. About half of the miscarriages that
occur in the first trimester are due to chromosomal defects, and about 0.7 per cent
of babies are born with a chromosomal defect. An example is Down’s syndrome.
Common tests done to look for chromosomal disorders include a karyotype and
fluorescent in-situ hybridization (FISH).
Bulletin 33; November 2003
MITA (P) No: 275/05/2003
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3. Multifactorial Disorders
These are a group of diseases that arise due to multiple factors that include both
genetic and environmental factors. They can cause many types of diseases ranging
from birth defects in babies to common disorders in adults e.g. heart disease,
diabetes mellitus. It is estimated that this group of disorder affects more than 60
percent of the population. Genetic testing is not usually available for this group of
diseases as the effect of genetic variation on disease is not yet fully understood.
Whom?
Anyone who is an adult capable of making an informed consent can undergo genetic
testing. There are, however, certain vulnerable groups that may need to be protected.
These include
1. Minors (children)
2. Mentally incompetent
3. Individuals with language difficulties
4. Prisoners and students
Minors with genetic diseases tend to fall into one of these groups
1. Symptomatic at diagnosis
2. Asymptomatic at evaluation, at risk of developing disease childhood/adulthood,
availability of intervention or treatment during childhood
3. Asymptomatic at evaluation, at risk of developing disease adulthood, availability of
intervention or treatment only during adulthood
4. Asymptomatic at evaluation, at risk of developing disease, no intervention or
treatment available
Minors in groups (1) and (2) can be tested as the results of the tests are likely to be
directly benefit them. Minors in groups (3) and (4) should not be tested during
childhood as prior knowledge usually has no direct benefit to the child, whereas the
person giving consent may have a vested interest in the outcome of the genetic tests.
The counter argument is that science is rapidly advancing and intervention or treatment
in childhood may become available. To maximally benefit from such advancement,
there is a need to know that one has the disease. In balance, effort must be made to
protect the privacy of the child and his right not to know his genetic risk.
Genetic testing of mentally incompetent individuals raise similar issues as the legal
guardian who provides consent may benefit more from the results than the affected
themselves. Non-educated persons and individuals with language issues e.g. deaf,
foreigners are another vulnerable group as they may not be able to comprehend and
hence not capable of truly informed consent. Prisoners and students are vulnerable as
they may feel coerced to consenting to participating in genetic tests.
Bulletin 33; November 2003
MITA (P) No: 275/05/2003
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How to achieve informed consent
Informed consent is the process by which a person is made fully aware of their options
and participate in his/her choices about health care. To achieve informed consent in
genetic testing is challenging because it involves many complex issues that may not be
intuitive to the physician or patient. Hence, pre-testing genetic counseling given by an
appropriately trained person is both prudent and essential. The aims of pre-testing
genetic counseling are to explain the following to the patient/guardian
1. Genetic testing is voluntary and consent is required to proceed.
2. Time should be taken to ask all questions needed to make an independent personal
decision. After consent is given, withdrawal of consent can be done at any time or
the disclosure of the results postponed
3. The major medical facts of the disorder (diagnosis, prognosis, treatments available,
inheritance pattern, and risks of recurrence in the family)
4. The implications of genetic testing (implications to other family members,
detection of non-paternity, and possibility of psychological stress)
5. Sample required and possible side effects of the sample taking procedure.
6. Test procedure and expected turn around time
7. Accuracy of test results
8. Confidentiality of results
9. Alternative to gene testing
Only after informed consent, is the sample is taken and sent for testing. The turn
around time varies from days to weeks depending on the test and laboratory involved.
Accuracy of genetic tests
Accuracy in genetic testing is dependent on several factors
1. Integrity of the diagnostic chain i.e. ensuring no sample switch, contamination etc.
2. The test methodology.
Test methodologies are broadly grouped into those based on DNA, RNA,
chromosomes and/or proteins. Each group has its advantages and limitations, and these
have implications on the interpretation of the results.
Interpretation of results
One of the biggest challenges in genetic testing is accurate interpretation of the results.
This is greatly dependent upon experience and having up to date knowledge.
In the context of diagnostic testing (i.e. a test used to identify or confirm the diagnosis
of a disease in an affected individual), a positive test result is relatively straightforward
to interpret. It confirms the clinical diagnosis, may give a prediction of the course of
illness, can lead to a better choice in treatment and can be used to identify at-risk
Bulletin 33; November 2003
MITA (P) No: 275/05/2003
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family members. If an affected person tests negative, this does not imply that the
clinical diagnosis is wrong. This negative test result may have arisen because (1) a
mutation is present but test could not find it or (2) another gene is causing the disease.
What it does mean is that outlook and treatment is not tailored and at risk family
members are not likely to benefit from predictive testing.
In the context of predictive testing (i.e. a test used to determine if an asymptomatic
person is at risk of developing a genetic disorder), its utility hinges on whether we
know the mutation in the family.
If we know the mutation in the family, the genetic tests serves to answer the question
“Does this individual have the family mutation?”. If this person tests negative, then
he/she is very unlikely to develop that disease. If this person tests positive, then he/she
has a risk of developing that disease. However, this risk may be complicated to
quantify because (1) the certainty of having disease may not be 100% (nonpenetrance), (2) lack of genotype-phenotype correlation, (3) modification by preventive
measures.
If we don’t know the mutation in the family, the genetic tests serves to answer the
question “Is there a significant mutation present in this gene?”. If this person tests
positive, then he/she has a risk of developing that disease. Similar to the above
situation, this risk may be complicated to quantify because (1) the certainty of having
disease may not be 100% (non-penetrance), (2) lack of genotype-phenotype
correlation, (3) modification by preventive measures. If the person tests negative, this
does not exclude the possibility of still being at because (1) a mutation present but test
could not find it or (2) another gene is causing the disease.
Follow up of results of genetic tests (Post- testing genetic counseling)
As illustrated above, interpretation of genetic tests are complicated and hence a follow
up visit is recommended so that a qualified person can explain the results and
implications of the test in simple layman language. The patient’s reaction, expectations
and questions will have to be addressed and several visits may be necessary.
Special issues to pay attention to
Genetic testing not only has medical implications, it also has many ethical, social and
legal implications. With the evolution and advancement of genetic testing technology,
issues raised include
• Confidentiality
• Equitable accessibility to testing
• Revelation of non paternity and undisclosed adoption
• Risks for discrimination
• Risks for psychological stress e.g. guilt, anxiety, self doubt, ostracized, despair
because no treatment is available etc.
Bulletin 33; November 2003
MITA (P) No: 275/05/2003
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There are no easy answers to these solutions. Several developed countries have come
up with their own set of recommendations and Singapore is currently also developing
her own especially since the governance and management of bioethical issues is critical
to her development in the biomedical sciences. The Bioethics Advisory Committee,
appointed by the Cabinet in December 2000, is tasked to address the potential ethical,
legal and social issues arising from biomedical sciences research in Singapore. This
includes the issue of genetic testing and its recommendations on this matter are
expected with the next year.
Diagnostic testing
Test positive
Test negative
• Confirm the diagnosis
• May give a prediction of the course
of illness
• Can help choose the better treatment
• Can Identify at-risk family members
• Does not exclude the possibility of
having the disease.
– Mutation present but test could
not find it
– Another gene is causing the
disease
• Outlook and treatment not tailored
• At risk family members not likely to
benefit from predictive testing
Predictive Genetic Testing
Family mutation known
• Tests positive: has a risk of
developing that disease
– What is the certainty of
disease? (Penetrance)
– How severe? (Genotypephenotype correlation)
– Do preventive measures
work?
– Is there early treatment?
• Tests negative: unlikely to
develop that disease
Bulletin 33; November 2003
MITA (P) No: 275/05/2003
Family mutation not known
• Tests positive: has a risk of developing
that disease
– What is the certainty of disease?
(Penetrance)
– How severe? (Genotype-phenotype
correlation)
– Do preventive measures work?
– Is there early treatment?
• Tests negative: Does not exclude the
possibility of having the disease.
– Mutation present but test could not
find it
– Another gene is causing the disease
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