Genetic Testing

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proband

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-person who is first reported to have this disease

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genetics vs genomics

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-genetics scrutinizes the functioning and composition of a single gene, whereas genomics addresses all genes and their interrelationships in order to identify their combined influence on the growth and development of the organism

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cytogenetic testing

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-looks at the structure, the number and arrangement of chromosomes
-Karyotypes: systematic stained array of stained paired chromosomes

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FISH

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-technique used to identify the presence of specific chromosomes or chromosomal regions through hybridization (attachment) of fluorescently-labeled DNA probes to denatured chromosomal DNA

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FISH is useful for

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1. marker chromosome identification
2. translocation identification
3. interphase analysis
4. cancer cytogenetic analysis
5. subtelomer analysis
-can detect small chromosome deletions (Prader-Willi syndrome) and duplications

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DNA based tests

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-looks for specific gene changes
-gene deletions, additions, alterations, inactivity

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sequence analysis

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(or gene sequencing)
-process by which the nucleotide sequence is determined for a segment of DNA

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types of sequence alterations that may be detected in sequence analysis

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1. pathogenic sequence alteration reported in literature
2. sequence alteration predicted to be pathogenic but not reported in the lit
3. unknown sequence alteration of unpredictable clinical significance
4. sequence alteration predicted to be begin but not reported in the lit
5. benign sequence alteration reposted in the lit

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possible explanations for false negative sequence test results

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Patient does not have a mutation in the tested gene

Patient has a sequence alteration that can not be detected by sequence analysis

Patient has a sequence alteration in a region of the gene not covered by the lab’s test

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mutation scanning

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(mutation screening):
A 2 step process by which 1) a segment of DNA is screened via one of a variety of scanning methods to identify variant gene region(s) and 2) variant regions are further analyzed usually by sequence analysis to identify the sequence alteration

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targeted mutation analysis

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-Testing for the presence of a specific type of
mutation or set of mutations

Examples
Trinucleotide repeat expansion
Tay Sachs disease panel

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metabolic tests

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1. analytes: absent, reduced, increased ex. PKU
2. Enzymes ex. hexosaminidase A (tay sachs)

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diagnostic testing

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-to confirm or rule out a genetic disorder in symptomatic persons
ex. huntingtons, down's syndrome

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predictive testing

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-in at risk asymptomatic persons when monitoring or treatment is available

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carrier testing

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-to determine carriers of a gene alteration inherited in an autosomal recessive or X-linked recessive manner
ex. cystic fibrosis and sickle cell anemia

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predictive (presymtomatic) testing

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-to identify risk for future disease when no treatment is available
ex. huntingtons

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prenatal diagnosis

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-is used when carrier testing or other risk factors suggest genetic disease risk in pregnancy
ex. down syndrome

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preimplantation genetic diagnosis (PGD)

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-can be used in couples conceiving through in vitro fertilization (IVF) and desire to reduce the risk of a particular genetic condition occurring in the fetus

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pharmacogenetic testing

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-determines drug metabolizing gene variants to help predict the appropriateness and dosage of prescribed drugs

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minimum requirements for any genetic testing protocol

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1. A knowledgeable professional should be involved in the process of ordering and interpreting a genetic test
2. The consumer should be fully informed regarding what the test can and cannot say about his or her health
3. The scientific evidence on which a test is based should be clearly stated
4. The clinical testing lab must be accredited by CLIA, the State and/or other applicable accrediting agencies
5. Privacy concerns must be addressed

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risks of genetic testing

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Psychological impact
Challenge family relationships
Confidentiality concerns
Discrimination concern
Ethical concerns
Legal concerns
Access concerns
Disclosure concerns

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limitations of genetic testing

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Test information is not matched by modern diagnostics and therapies
Genetic mutations may be acquired and not inherited
Some mutations may never lead to disease
Some disease causing mutations may go undetected
Positive results can not establish exact risk of developing a disease
Positive tests typically do not predict the course/severity of a disease
Some results are noted as “inconclusive” or “indeterminate”
Cost of testing and insurance coverage
Education of health care providers

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what to consider when ordering genetic tests

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Choosing a laboratory
Pretest counseling and informed consent
Sample logistics and supporting documentation
Test result interpretation and follow-up