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4 > Diagnostic Testing, Non-Mendelian Genetics and Mitochondrial Disorders > Flashcards

Diagnostic Testing, Non-Mendelian Genetics and Mitochondrial Disorders Flashcards

1
Q

What is prenatal diagnosis?

A
  • It aims to inform couples about the risk of a birth defect or genetic disorder in an unborn child and how to manage this risk
  • Involves genetic testing and other tests including biochemical testing
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2
Q

What are:

a. Non-invasive techniques
b. Invasive techniques

A

a. Non-invasive techniques:
- Maternal serum tests e.g. MSAFP
e. g. Ultraound

b. Invasive techniques:
e.g. Amniocentesis:
Amniotic fluid is sampled and takes place in 15th to 16th week
e.g. Chorionic villus sampling:
e.g. Chorion (part of placenta derived from embryonic tissue) is sampled and takes place in 10th to 12th week

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3
Q

What are the reasons for pre-natal diagnosis?

A

a. There is family history
b. The parents have been tested as carriers
c. Increasing maternal age
d. Risk of a NTD
e. Abnormal results from ultrasound
f. Routine screening test

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4
Q

What are the possible outcomes for pre-natal diagnosis?

A
  • A choice to terminate a pregnancy is the child is going to have a severe genetic disorder
  • Better planning for pre-natal care
  • Psychological preparation for the parents
  • Re-assurance that the child is not affected
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5
Q

What sort of tests are done for sporadic NTDs?

A
  • Maternal serum alpha-fetoprotein tests (MSAFP): high levels are associated with a NTD
  • If the result is high/inconclusive they can decide to do further testing
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6
Q

What analysis is done to detect chromosome abnormalities?

A 
Non-invasive: 
- Maternal serum protein tests:
1st trimester: PAPP-A 
2nd trimester: quadruple screen of proteins 
- Ultrasound for nuchal translucency

Invasive:

  • Offered to older mothers or if non-invasive analysis is positive/inconclusive:
  • Amniocentesis or chorionic villus sampling: feotus karyotype can then be determined and DNA can be tested
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7
Q

What are the potential problems with DNA based pre-natal screening?

A
  • Not all genetic diseases have a known gene

- Some alleles can give different severity in different individuals

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8
Q

What is the difference between genetic testing and genetic screening?

A

Genetic testing:
- A test given to individuals to test for the inheritance of specific mutations

Genetic screening:

  • A population-based method of identifying individuals with increased susceptibility or risk for a genetic disease
  • Aim is to examine all members in a population
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9
Q

What is:

  1. Clinical validity
  2. Clinical utility
A
  1. Clinical validity:
    - A test is valid if it is predictive for the disease:
    - Sensitivity: are there false positives?
    - Specificity: are there false negatives?
  2. Clinical utility:
    - The medical care of the individual can be changed based on the test results
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10
Q

Give an example of a routine newborn screening test:

A

e. g. PKU testing:
- Tests for disease PKU
- If a baby is diagnosed with it, it is given a specialised diet and brain damage is avoided

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11
Q

When is genetic screening for heterozygotes carried out?

  • What are some possible issues?
A

The screening is carried out:

  • In population swith a high frequency of carriers
  • There is a valid test
  • There is access to genetic counselling for couples who are heterozygotes
  • There is acceptance and voluntary participation by population targeted for screening

Issues:

  • Privacy issues
  • Is it voluntary?
  • Can all causative alleles be screened?
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12
Q

What is included in Non-Mendelian Inheritance?

A
  1. Extranuclear inheritance
  2. Maternal effect (nuclear genes)
  3. Imprinted genes (nuclear genes)
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13
Q

What is extranuclear inheritance?

A
  • Inheritance of genetic material not located within the nucleus
  • Refers to the inheritance of mitochondrial DNA/chloroplast DNA
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14
Q

How are cytoplasmic organelles inherited?

A

Somatic cell division: mitochondria and chloroplasts separate more or less evenly into daughter cells

Sexual reproduction: transmitted through the egg so show strict maternal inheritance every generation

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15
Q

What are maternal effect genes?

A
  • Affect traits where the mother’s nuclear genotype determines the phenotype of offspring
  • Often these genes act in setting up the developing egg
  • During maturation the oocyte is surrounded by Nurse cells (somatic cells of the mother) for nutrient supply
  • Products of the maternal effect genes are RNA and proteins important for embryogenesis that are incorporated into the egg
  • Mutations only affect the offspring
    e. g. bicoid mutation causes offspring of mutated fly to develop without a head, but that fly with the mutated genotype is phenotypically normal
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16
Q

What is genomic imprinting?

A
  • Refers to chromosomal events that silence the expression of genes inherited by one of the two parents
  • Called an epigenetic effect: the alternation of the DNA or chromatin is not an actual change in DNA sequence
  • The imprint (silenced gene) remains throughout life but is then erased during production of the gametes
17
Q

What is the mechanism of single gene imprinting?

A
  1. Methylation of CpG islands: the promoter region of DNA is differentially methylated in eggs or sperm and causes the gene to be inactivated
  2. Deacetylation of histones: the deacetylation of histone tails occurs whrn the DNA is methylated and this makes the DNA more compact
18
Q

What are some features of mtDNA?

A
  1. 93% is coding sequence
    - encode RNA product to synthetise mitochondrial proteins involved with OXPHOS
  2. There are no introns
  3. Coding sequence are often overlapping
  4. The non-coding region (7%) is called the D-loop and is regulatory
19
Q

What pattern of inheritance does mtDNA show?

A
  • Maternal only inheritance
  • mtDNA of progeny is normally identical to that of the mother
  • Therefore mitochondrial diseases can affect both sexes but are only passed on by the mother
  • There is no recombination to make gametes and the variations in mtDNA arise from the accumulation of mutations
20
Q

What are the two types of mitochondrial mutation?

A

Homoplasmy: every mitochondrial genome carries causative mutation

Heteroplasmy: mixed population of normal and mutant mitochondrial genomes

  • There is often a threshold, a certain proportion of mt that must be mutated to show a disease phenotype
21
Q

Why is mtDNA so prone to mutations that cause disease?

A
  1. 93% of mtDNA is coding- therefore there is a high likelihood that a mutation will occur in a functional coding region
  2. Undergo many more rounds of replication than nuclear DNA
  3. There is no histone protection and significant oxidative damage can accumulate (oxphos can produce free radicals)
  4. mtDNA lacks an adequate DNA repair mechanism
  5. Mitochondrial bottleneck: within a female feotus only some mitochondria are within cells that differentiate to form PGCs- this means that a female may have 20% mtDNA mutation but a higher proportion of cells creating PCGs have the mutated mitochondria so she may produce oocytes with much higher e.g. 75%, heteroplasmy
22
Q

How are mitochondrial diseases diagnosed?

A
  • Unusual combination of symptoms, including:
    Neurological issues, ataxia, dystonia, myopathic signs, seizures, hypotonia, weakness etc.
  • As well as deafness and diabetes
  • Heteroplasmy can be tissue specific so a blood test may not detect a mitochondrial test that is affecting the brain
23
Q

Give:

  • 2 homoplasmic mt diseases:
  • 2 heteroplasmic mt diseases:
A

2 homoplasmic mt diseases:

  • LHON (retinal degredation)
  • NARP (neurodegeneration, ataxia and retinitis pigmentosa)

2 heteroplasmic mt diseases:

  • MELAS
  • MERFF
24
Q

What are the advantages of using mtDNA for forensics/study of evolution?

A
  • mtDNA has a higher mutation rate so:
  • it is easy to assay diversity
  • it is easy to find polymorphisms
  • all maternal relatives have identical mtDNA
  • mtDNA has a high copy number (many copies per cell) so only a small amount of DNA is needed from a sample to test
25
Q

What are Problems with mtDNA use in Forensics?

A
  • Nuclear DNA typing has greater discriminatory power
  • mtDNA analysis cannot distinguish between individuals related on maternal line
  • Best if sample is unsuitable for nuclear DNA testing

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