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Cardiovascular Block: Week 7 > Genetic Diagnostic and Predictive Testing > Flashcards

Genetic Diagnostic and Predictive Testing Flashcards

1
Q

Define genetic testing.

A

The analysis of human DNA, RNA, chromosomes, proteins and certain metabolites in order to detect heritable disease related genotypes, mutations, phenoytpes or karyotypes for clinical purposes.

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2
Q

What is genetic screening?

A
  • Done for a particular condition(s)
  • In individuals, groups or populations
  • WITHOUT family history of the condition
  • Important Principles: Newborn screening, population specific screening
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3
Q

What is genetic diagnostic testing?

A
  • Done for a particular condition

- Individual is suspected of being at increased risk due to their family history or individual history

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4
Q

What are the genetic testing laboratory methodologies from lowest to highest resolution?

A
  1. Chromosome Analysis (Karyotype)
  2. Higher Resolution Chromosome Analysis (array techniques, MLPA)
  3. FISH
  4. PCR Aneuploidy
  5. Single Gene (PCR, Sequencing)
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5
Q

What is the traditional method of chromosome analysis?

A

Karyotyping

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6
Q

What is the resolution of a karyotype?

A

Resolution low: 1-5 Megabases

1-5 million bases before visible

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7
Q

What does a karyotype detect?

A

Analyzes all chromosomes simultaneously.

- Detects numerical and structural abnormalities

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8
Q

What needs to be done for a karyotype to be made?

A

Cells need to be cultured.

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9
Q

What type of structural abnormalities can be detected on chromosome analysis?

A

Translocations
Deletions
Duplications
Inversions

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10
Q

What common numerical abnormalities can be detected on chromosome analysis?

A

Aneuploidies: 21, 18, 13, and X / Y

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11
Q

What are the 4 types of higher resolution chromosome analysis?

A
  1. FISH (Fluorescent in situ Hybridization)
  2. PCR Aneuploidy
  3. MLPA (Multiplex Ligation Probe Amplification)
  4. Array Comparative Genome Hybridization
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12
Q

What is the resolution of higher resolution chromosome analysis?

A

Few 100 base pairs

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13
Q

What is significant about higher resolution chromosome analysis testing?

A
  1. Test is directed at region of interest (rather than giving a global view)
  2. Uncultured cells are used (no need to wait for culturing)
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14
Q

What are some of the uses of higher resolution chromosome analysis?

A
  1. Aneuploidy screen = numerical abnormalities (13, 18, 21, X and Y)
  2. Micro-deletion Syndromes (William syndrome, 22q11)
  3. Subtelomeric Deletions (ends of chromosome)
  4. Full screening of all chromosomes for abnormalities not visible under microscope
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15
Q

What is aneuploidy screening by PCR?

A

Quantitative fluorescent PCR (QF-PCR) assay

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16
Q

What are the benefits of aneuploidy screening by PCR?

A

Automation allows high thorough-put of samples compared to conventional karyotyping.
- Decreases cost
- Decreases turn-around time (24-48 hours after sampling)
- Minimal sample required
= NEWER, FASTER, CHEAPER

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17
Q

What are QF-PCR tests used to detect?

A

QF-PCR tests are performed for the detection of major numerical abnormalities affecting chromosomes X, Y, 21, 18 and 13.

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18
Q

What does biochemical single gene analysis measure?

A
  1. Enzyme activity
  2. Amount of substrate
  3. Amount of product
  4. Alternative products
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19
Q

Where is biochemical single gene analysis useful?

A

Still useful for the diagnosis of many inborn errors of metabolism
- Many available in SA

20
Q

What are the drawbacks of biochemical single gene analysis?

A

Carrier detection is difficult.

  • Wide range and overlap with normal
  • May need to assay specific tissue
21
Q

Single gene analysis: DNA how many genes are estimated?

A

20 000 - 25 000 genes estimated

- Mutations known to cause disease in over 1000 single genes

22
Q

Single gene analysis: DNA how common are these conditions?

A

Individually rare.
BUT focus of genetic testing at the moment
- Still complex at a molecular level

23
Q

Single gene analysis: DNA what is analyzed?

A

Analyze disease-specific genes

  • identify disease causing genetic mutations
  • tests directed at the region of gene of interest (50bp - 10 000 bp analyzed per test)
  • DNA identical in all tissues
24
Q

Single gene analysis: DNA what is the resolution of these tests?

A

Resolution = Single base pair

25
Q

Single gene analysis: DNA what are these tests definitively useful for?

A

Useful for definitive:

  • Clinical diagnosis
  • Pre-clinical (pre-symptomatic) diagnosis
  • Carrier testing
  • Prenatal testing
26
Q

Single gene analysis: DNA what may these tests be useful for in the future?

A
  1. Phenotype prediction

2. Directing therapy (pharmacogenetics)

27
Q

What is pre-clinical diagnosis?

A

Identification of “at-risk” individuals prior to onset of symptoms

28
Q

What is the significance of pre-clinical diagnosis for mutation negative individuals?

A

Follow-up is unnecessary

29
Q

What is the significance of pre-clinical diagnosis for mutation positive individuals?

A
  • Early intervention
  • Appropriate monitoring and improved management
  • Positive test does not always indicate patient will develop disease
30
Q

What is the significance of pre-clinical diagnosis for childhood onset disease?

A
  1. Improved outcome with early initiation of treatment (e.g. CF, beta-thalassaemia)
  2. Donor for affected sibling (Fanconi Anaemia)
31
Q

What is the significance of pre-clinical diagnosis for adult onset disease?

A
  1. Benefits of surveillance
    - early detection of disease
    - improved prognosis (e.g. familial breast / colon cancer)
  2. No treatment available: need to know and need to plan (e.g. Huntington’s Disease)
32
Q

What is important to consider when offering predictive testing?

A
  1. Need for pre/post test counseling (international predictive testing protocols)
  2. Need for choice free from coercion
  3. Full INFORMED consent
  4. Insurance / employment issues
33
Q

What is important to consider regarding the emotional impact when offering predictive testing?

A
  • Emotional impact of shortened lifespan

- Survivor guilt - family obligations

34
Q

What is carrier testing done for?

A

To detect clinically asymptomatic carriers

  • Autosomal recessive conditions
  • X-linked recessive conditions
35
Q

What population specific carrier testing is done?

A

Population specific carrier testing for common disorders:

  • Offer testing on an equal basis to all individuals in a defined population (detect common mutations but do not detect rare mutations)
  • Detect those at risk for a genetic disease themselves or their offspring (reproductive options)
  • Community education and input vital
36
Q

Population specific carrier testing: Which populations are tested for Beta-Thalassaemia?

A
  • Mediterraneans

- Indians

37
Q

Population specific carrier testing: Which populations are tested for Sickle Cell Anaemia?

A
  • Sub-Saharan Africans

- Indians

38
Q

Population specific carrier testing: Which populations are tested for Cystic Fibrosis?

A
  • North-west Europeans
39
Q

Population specific carrier testing: Which populations are tested for Tay-Sachs?

A

Ashkenazi Jews

40
Q

Why is prenatal testing done?

A

For detection of disease in utero

  • Reproductive options
  • Early management
41
Q

What does prenatal testing require?

A

Requires family work-up

  • ideally pre-pregnancy
  • genetic counseling
  • each family is unique
  • identification of specific mutations (time consuming)
42
Q

What is prenatal diagnosis DNA analysis performed on?

A

Need to perform on fetal material:

  • Amniotic cells
  • Chorionic villus biopsy
  • Chordocentesis
  • Blastocysts (pre-implantation diagnosis)
43
Q

What are the limitations of genetic testing?

A
  1. Need for genetic literacy
  2. Genetic complexity (heterogeneity)
  3. No common mutation for many gene disorders
  4. Technical limitations
  5. Insurance and employement
  6. Family confidentiality
  7. Cost (expensive, need to weigh up against benefits)
44
Q

Why is genetic literacy needed?

A

For both test requests and test interpretation

45
Q

How is genetic complexity a limitation of genetic testing?

A
  • Gene mutations in different genes cause the same disease (locus heterogeneity: hard to know which gene to test)
  • Other unusual mechanisms (epigenetic mutations not detected)
46
Q

How is no common mutation for many gene disorders a limitation of genetic testing?

A

Each patient has unique mutation(s):

  • individual testing
  • no quick test even if gene is known
47
Q

What are the technical limitations of DNA analysis?

A
  • mutations may be “missed”

- multiple techniques required to detect different types of mutations

Cardiovascular Block: Week 7 (5 decks)

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