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Briefly define different types of genetic testing

1. Diagnostic – confirms diagnosis in an affected person, and may be prognostic as well
2. Predictive – testing of unaffected individuals, usually in the absence of corroborating evidence, for:
- pre-symptomatic (will they develop the disease?)
- carrier
- prenatal/pre implantation
3. Screening – testing of individuals at population-level risk of disease (i.e. newborn), where there is an advantage of detecting conditions early
4. Somatic – testing of tumor tissue (not germline) for:
- diagnostic
- monitoring
- choice of therapeutic agents
5. Pharmacogenetic – metabolism/drug toxicity


Be aware of appropriate sample sources for genetic testing

1. Peripheral blood (whole blood)
- DNA extracted from WBCs
- preferred source of DNA for testing – plentiful and easy to access, minimally invasive

2. Buccal cells, urine, skin
- collected by swab inside cheek, early morning urine or biopsy
- used as a second source of DNA is suspicion of mosaicism,
- used for comparison of tumor DNA to constitutional DNA, OR
- used when it is difficult to get blood for some reason

3. Chorionic villus Sampling (placenta, 11-14 weeks) and Amniocentesis (amniotic fluid, 15-18 weeks)
- invasive, therefore risks of bleeding, infection, loss of pregnancy and incorrect results due to contamination with maternal cells
- used for chromosomal or molecular testing
- used for studying metabolic diseases

4. Cell free DNA (cfDNA)
- DNA not contained by membranes but floating free in circulation can be isolated
- Sources of cfDNA:
- haematopoeitic cells
- foetal cells
- tumor cells
- used for non-invasive prenatal screening – aneuploidies, can be used early in pregnancy
- used for tumor detection and monitoring – not widely available


How do we choose what to test within the DNA sample?

Depends on:
1. Change to be detected
- size
- where it occurs
- type of change
2. Volume of samples being tested
3. Purpose of testing (known or unknown mutation). If you know where it is, focus on that region on which the variant occurs, i.e. Sanger sequencing of a single exon.


Explain the difference between targeted and untargeted genetic testing

Targeted – specific alleles of copy number variants are tested for

Untargeted – whole or multiple genes, whole genome. More than one variant may be found – which is the mutation?


What are the key factors in determining whether a genetic variant is disease-causing or benign ?

5 tier classification system:

Class 1 - Benign
Class 2 – Likely Benign
Class 3 – Uncertain significance
Class 4 – Likely pathogenic
Class 5 – Pathogenic

Look to:
- public resources – literature and databse
- in silico prediction – algorithms
- Key, powerful factors:
- segregation of genotype with disease
- functional studies

Segregation of genotype:
- testing of proband’s parents usually recommended to test this
- based on family history and inheritance pattern expected to be observed
- AD: i. de novo – neither parent
ii. Inherited – an affected parent should have variant
- AR: both parents should be carriers

RNA and functional studies:
- focus on dynamic effects of changes at the DNA level on gene transcription, translation and protein-protein interaction
- tests on cells, animal models etc


Understand the concept of clinical utility, using example clinical scenarios

Utility: How can genetic testing actually improve patient management?

Ask yourself:
- why am I requesting this test?
- how does it help my patient? BRCA genes – can get prophylactic surgery, but there is nothing you can do about Huntington’s.
- can the result harm my patient or their family?
- is there a better approach or test I could use?
- could I be using resources more wisely?
- Eg – full genome testing as last resort


What are some of the ethical challenges of testing?

- may affect life choices
- may affect continuation of pregnancy
- access to insurance
- implications to extended family

EG – one family member of 2 cousins is congenitally deaf (unknown cause, often recessive mutation). Another 2 are going to get married and what children – should they be tested? Is deafness a real problem? Will knowing the risks make a difference? Will knowing the mutation make a difference to the deaf child? Should the deaf child be tested for the benefit of her aunt/uncles future children? Etc

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