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MCBHD- Molecular and Cellular Basis of Health and Disease > S3: Chromosome Disorders and the Clinical Consequences > Flashcards

S3: Chromosome Disorders and the Clinical Consequences Flashcards

1
Q

Describe meiosis

A

Meiosis is the type of cell division used to produce the gametes (egg/sperm cells) and involves a reduction in the amount of genetic material. It is a special division for sexual reproduction.

  • Parent cell has 23 pairs of chromosomes however 4 resulting daughter cells at the end of meiosis II have 23 chromosomes (haploid).
  • The 23 chromosomes are also different to that in the parent cell and different to each other. This is because of crossing over of genetic material during meiosis (metaphase) which helps increase diversity.
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2
Q

Describe mitosis

A

Mitosis is how the majority of cells in our body divide. it contributes to our growth and healing.
- In mitosis, two daughter cells are produced that are genetically identical to the parent cell and to each other. The parent cell has 23 pairs of chromosomes and the daughter cells have 23 pairs of chromosomes (a replica of parent cell).

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3
Q

Describe chromosomal abnormalities

A
  • May be inherited or de novo. If inherited there may or may not be a family history.
  • May carry recurrence risk for patient or family.
  • Are variable (some genome affected can have different presenting complaints).
  • Are individually very rare.
    We can have syndromes due to aneuploidy, chromosomal rearrangements or microdeletions .
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4
Q

List chromosomal disorders

A
  • Aneuploidy
  • Translocation
  • Microdeletions and Microduplications
  • Mosaicism
  • Unparental disomy (UPD) and imprinting
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5
Q

Why do we look at chromosomes in a clinical context?

A
  • Responsible for childhood growth and development abnormalities
  • Responsible for history of recurrent miscarriage/neonatal death
  • Can be responsible for infertility
  • Pregnancies can be predicted to be increased risk following a genetic screening
  • Family history, e.g. for things like cancer
  • May be carried in families without symptoms
  • Financial burden to NHS
  • Emotional burden to affected people and their relatives
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6
Q

List of chromosome terminology

A
  • Autosome - Not the sex chromosome
  • Monosomy - Missing a chromosome
  • Trisomy- Extra chromosome
  • Triploidy - Extra of everything
  • Karyotype - number and appearance of chromosomes in nucleus of a cell
  • Centromere - links the short and long arms of chromosome
  • Acrocentric - centromere at one end
  • Translocation - rearrangement of parts between nonhomologous chromosomes.
  • Deletion - part of chromosome or sequence of DNA is lost
  • Duplication - part of chromosome or sequence of DNA is repeated
  • Band - stripes on a chromosome when stained
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7
Q

List techniques for chromosome analysis

A
  • Karotypes
  • FISH
  • Quantitative PCR
  • Array- CGH
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8
Q

Describe karotypes

A
  • Can look for extra/missing chromosomes and large rearrangements (>Mb)
  • Gold standard to look for aneuploidies/translocations
  • Will miss small rearrangements e.g. microdeletion
  • May pick up clinically irrelevant things
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9
Q

Terminology for reading a karyotype

A

p - short arm
q - long arm
t - translocation
del/ins/inv - deletion/insertion/inversion
ter - end of chromosomes
der - derivative chromosome (e.g. from translocation_
+/- is the gain or loss of chromosome
dn - de novo
mat/pat - maternally/paternally inherited

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10
Q

Describe FISH

A

Florescence in situ hybridisation (FISH) is a method whereby we look for specific sequence of DNA on one specific chromosome.

  • It is targeted as a specific DNA probe is made to identify the region of interest.
  • Therefore to use FISH, you need to know what you are looking for.
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11
Q

What is FSH good for identifying?

A
  • Identifying microdeletions and microduplications.

- Looking for aneuploidies.

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12
Q

What is FSH bad for identifying?

A
  • When you don’t know what to look for.
  • Translocations.
  • Very small deletions/duplications.
  • Tandem duplications.
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13
Q

Describe quantitative PCR

A
  • Uses polymerase chain reaction which is a method of amplifying DNA.
  • Count and compare how much product and results are presented as a graph.
  • Currently QF-PCR is first line for women having child with high risk of Down Syndrome. Will only analyse chromosomes 13,18,21 +/- sex chromosomes as the rest are incompatible with life if a trisomy.
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14
Q

Advantages of quantitative PCR

A
  • Quick
  • Cheap
  • Accurate
  • Picks up aneuploidies
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15
Q

Wht is the disadvantage of quantitative PCR?

A

Will miss rearrangements, duplications, deletions etc as it only picks of aneuploidies.

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16
Q

Describe Array-CGH

A
  • Used as a general screening when we don’t know what we are looking for and can’t gt a special probe made.
  • This technique uses probes which are complementary and are run along the entire genome.
  • Chip with many spots of DNA attached which covers most of the genome
    We use 60,000 probes, all of which have a fluorescent tag and will bind to a bit of the genome. This is what is called a hypothesis free test, because we can go in and do it without having to have an idea of where the issue is.
  • Allow test and control DNA (labelled differently e.g. Red and green) to hybridise
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17
Q

How is the florescence compared in array-CGH?

A
  • Equal amounts of test and control DNA will look yellow
  • If more test DNA it will look green - duplication
  • If more control DNA it will look red - deletion
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18
Q

Advantages of Array-CGH

A
  • Can identify small deletions and duplications.
  • Covers most of the genome so you don’t need to know what you are looking for.
  • Uses DNA so no need to grow cells quicker.
  • Much of the analysis is computerised.
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19
Q

Disadvantages of Array-CGH

A
  • Cannot detect balanced rearrangements.
  • Doesn’t tell us where abberation is.
  • Not good at detecting mosaicism.
  • Produces lots of data which is hard to analyse.
  • Finds variants of unknown significance.
  • May give you information you don’t want e.g. deletion of BRCA.
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20
Q

What is aneuploidy?

A

Aneuploidy are syndromes where a person doesn’t have 23 pairs of chromosomes but instead has an abnormal amount of chromosomes.

21
Q

What is polyploidy?

A

Polyploidy is when the number of chromosomes you have is a multiple of 3, e.g. three chromosome one’s two, three etc.

22
Q

How do aneuploidy arise?

A

Aneuploidy arises due to a problem in the mechanisms of cell division! Very few aneuploidies are compatible with life and most result in miscarriage.
- What can happen during cell division is something called non-disjunction, this results in the daughter cells having an incorrect number of genetic material.
However, sex chromosome aneuploidies are compatible with life e.g. XO, XY, XYY, XXXXY etc.
The extra chromosome is usually a maternal age effect.

23
Q

What is mosaicism?

A

Mosaicism is another way a person can get aneuploidy. People may get mosaic trisomy/monosomy including confined to placenta. This is where there is a problem in mitosis, which allows the embryo to grow keeping the same amount of genetic material. However what can happen is the division doesn’t occur properly so there is a population of (some) cells in the body containing an incorrect number of chromosomes.

e. g. If this happened with chromosome 21, they will only have some features of Down’s syndrome.
- Mosaic phenotypes are thought to be less severe but are difficult to assess because we don’t know which cells are expressing the abnormal number of chromosomes and which have the normal ones.

24
Q

Describe Down syndrome (Trisomy 21)

A
  • Most common aneuploidhy
  • 95% people with Down’s have it due to non-disjunction
  • 2% have an issue with mosaicism
  • The rest have it due to a robertsonian chromosome.
  • Down’s syndrome has an association with older age, this is due to the egg’s being older!
  • Pre-natal screening for Down’s syndrome is something that is offered to everyone, to determine a mothers risk of having a pregnancy with a child with Down’s. The screening usually consists of: Nuchal translucency at 11-14 weeks, then a serum screening (from mother) in 1st trimester (double or triple test) these are testing hormones.
25
Q

What is a robertsonian translocation?

A

Robertsonian translocation (ROB) is the most common form of chromosomal rearrangement in humans where the participating chromosomes break at their centromeres and the long arms fuse to form a single, large chromosome with a single centromere.

26
Q

Clinical Features of Trisomy 21

A
  • Most common cause of mental retardation.
  • There is hypotonia (low muscle tone), particularly in newborn period, there is also developmental delay.
  • As well as these issues there are also often various medical issues like cardiac abnormalities, GI abnormalities and have a higher risk of cancers and alzheimers disease.
27
Q

Physical features of trisomy 21

A 
Facial:
- Epicanthic folds
- Flat nasal bridge
Small hands and feet:
- Single palmar crease
- Sandal gap
Other:
- Short stature
- Hypotonia
- Learning Difficulties
- Cardiac problems
- Dementia and Leukaemia in age
28
Q

What is trisomy 18?

A

Edwards syndrome is trisomy 18.

29
Q

What is trisomy 13?

A

Patau Syndrome is trisomy 13.

30
Q

What is 45X0?

A

Turner’s syndrome

31
Q

What is 47XXY?

A

Klinefelter syndrome

32
Q

Describe Turner’s syndrome

A

Girls with Turners syndrome have a very thick layer of skin behind their neck, problems with lymphedema resulting in swelling of hands and feet.
They can also have various other issues like coarction of the aorta and/or renal malformation (can get horseshoe kidney).
Patients often have short stature. Importantly, most women with full Turners will be infertile (with the exception in turner’s mosaicism.
- This issue arises from paternal meiotic errors.

33
Q

Genetic causes of Turner’s

A
  • 50% 45 XO
  • 41% Mosaic
  • 9% abnormal X (translocations, deletions, inversions)
34
Q

Describe Klinefelter syndrome

A

This is when the individual has XXY in their cells, a man should have XY but males with Klinefelter have XXY.

  • The phenotype is also mild and very variable, some cases may be undetected! The reason why people may realise is when they are much older and are having fertility issues. Due to new reproductive technology some patients may now be able to have children.
  • Children with klinefelter syndrome often present with behavioural problems, they can have a tall stature and a lack of secondary sexual characteristics (sex differences made during puberty). However there are no significant medical problems.
  • it is due to paternal meiotic non disjunction.
35
Q

Describe 47 XYY

A
  • 1/1000 livebirths approx.
  • Paternal meiotic non-disjunction
  • Tall (average 6’3”)
  • IQ often in normal range, need learning support
  • No significant medical problems
  • Puberty and fertility normal
  • Behavioural issues
  • Study showed 3% prison population had 47XYY (Jacobs et al 1965)
36
Q

What are chromosomal translocations?

A

There can be an event, where two non-homologous chromosomes get quite close together and end up getting switched over/exchanged. This is called a structural rearrangement/translocation.

37
Q

Types of translocation

A
  1. Reciprocal
  2. Robertsonian - between acrocentric chromosomes

Which can be :

  • Balanced
  • Unbalanced
38
Q

Describe balanced translocation

A

Here there is no net gain or loss of genetic material, e.g. a swapping of genetic material between chromosome 3 and 10, this shouldn’t give any real problems because we still have the same number of genes, just in a different order.
The cell doesn’t care where the gene is located, just that it is there!

39
Q

Describe unbalanced translocation

A

This is when the child may end up with the wrong amount of genetic material, containing too much or too few genetic material. This is unbalanced translocation.
- This occurs when balanced rearrangement in an individual goes on to have children because the very precise process of cell division confuses the cell.
E.g. The cell doesn’t know if the bit of chromosome 10 that is now on chromosome 3, means that it should treat chromosome 3 as chromosome 10 or vice versa!
So the meiosis process can go wrong, the individual may produce normal gametes, but it could be that the gametes contain abnormal amount of genetic material.

40
Q

Describe reciprocal translocations

A
  • Arises because of 2 way exchange of material between non-homologous chromosomes
  • Balanced translocations don’t usually cause a problem but risk pf unbalanced
  • May be inherited or de novo
  • High recurrence risk
    Important to test parents and other family members
41
Q

Describe robertsonian translocations

A

These translocations involve certain chromosomes called acrocentric chromosomes (13,14,15,21,22).
Acrocentric chromosomes have a very short p arm and a very long q arm.
- So overall, two acrocentric chromsomes get close together, there is a breakage and rejoining and the two q arms join together. This is the robertsonian translocation.
- The p-arms are so short they get lost, this isn’t a real issue as the p-arms just code for repetitive sequences.

42
Q

Describe derivative chromosomes

A

Inversions:
- Paracentric - does not include centromere
- Pericentric - includes centromere
Ring chromosomes where ends of abnormal chromosomes fuse.
Isochromosomes with loss of one arm with duplication of other.

43
Q

Describe a deletion

A
  • A deletion is the loss of a segment of a chromosome and results in partial monosomy.
  • There can also be deletions of areas of chromosomes, which can be large and visible or can be very small, so small that you can’t see under the microscope (called microdeletions).
  • These deletions tend to occur due to unequal crossing over during meiosis.
    There is exchange of genetic material and the cell can get confused where there are lots of repetitive regions.
  • This results in bits missing in one chromosome and duplicated amount in the other.
44
Q

Describe a duplication

A

A duplication is the gain of a segment of a chromosome and results in partial trisomy.

45
Q

List types of deletions

A
  • 22q11.2 Deletion
  • 7q11.2 deletion (williams syndrome)
  • 16p11.2 deletion
46
Q

What is imprinting?

A

Imprinting is when only maternal or paternal alleles are expressed.

47
Q

What is uniparental disomy?

A

Two copies of chromosome from one parents and non from the other

48
Q

What could be the cause of angelman syndrome and praderwilli syndrome?

A

UPD or deletion

MCBHD- Molecular and Cellular Basis of Health and Disease (27 decks)

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