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cytogenetics > Structural Chromosome Abnormalities > Flashcards

Structural Chromosome Abnormalities Flashcards

1
Q

Name some types of rearrangements.

A 
Translocation (reciprocal, insertional, robertsonian)
Inversion (peri or paracentric)
Deletion
Duplication
Isochromsome
Marker
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2
Q

What is the most common recurrent rearrangement known to man?
What are the 2 others?

A

t(11;22)(q23.3;q11.2) is most common

t(4;8) and t(X:Y)

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3
Q

Approximately what number of liveborn individuals carry a balanced translocation?

A

1 in 500

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4
Q

What is a robertsonian?

A

Fusion of 2 acrocentric chromosomes. Usually non-homologous.

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5
Q

What is the most common robertsonian? Why?

A

The der(13;14) and the der(14;21) are the most common (the 13;14 accounts for ~75% of all rob translocations).

The sequence on 14p is very similar to both 14 and 21, but the sequence is in opposite orientation. This is what underlies the formation of the rob.

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6
Q

How is a robersonian formed?

A

Fusion of 2 acrocentric chromosomes - usually non-homologous.
Break occurs in both short arms of acrocentric’s and a dicentric robersonian is formed. One centromere is commonly suppressed and is not visible by cyto.

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7
Q

Approximately what number of liveborn individuals are born with a robertsonian translocation?

A

1 in 1000.

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8
Q

Can you get a homologous robertsonian?

A

Yes, but would be very rare. Formed from fusion of mat and pat homologues. Formation is typically postmeiotic.
More likely to be an isochromosome - formed from a single chromosome via misdivision of the centromere or U-type exchange.

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9
Q

What are the 2 types of inversions?

A

Pericentric - spans/contains the centromere and can alter shape of the chromosome and easier to spot.

Paracentric - confined to either long or short arm, can be very subtle.

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10
Q

Give an example of a common variant.

A

Inversion of chromosome 9, involves heterochromatic block around centromere.
Will be commented on in analysis but not reported.

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11
Q

What are the types of deletion?

A

Terminal - single break and material after break is lost, telomere must be healed for stability.

Interstitial - two breaks with loss of material between breaks.

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12
Q

What is a marker chromosome?

A

A chromosome of which no part can be identified. Seen at an increased frequency in mental retardation and subfertility.

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13
Q

What are the 2 most common marker chromosomes seen?

A

idic(15) or inv dup(15)

idic(22)

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14
Q

How are the idic(15) and idic(22) typically formed?

A

U-type exchange.
Inverted low copy repeats mediate the looping of one homologue round to join the other, the result is 1 x small dicentric chromosome and 1 x acentric larger fragment.
This can occur between chromatids or between homologous chromosomes.
The size of the fragments vary depending on which LCR is involved, ranging from heterochromatic to euchromatic.
This is FOLLOWED by a non-disjunction event so that the gamete receives 1 normal chr and the small idic.

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15
Q

What is important about a idic(15)?

A

Due to its origin it may contain the AS/PWS critical region.
Trisomies or tetrasomic dosage of this region correlates with abnormality including developmental delay, autism, epilepsy and minor physical defects.

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16
Q

What is significant about the idic(22)?

A

It is associated with Cat Eye syndrome.

17
Q

How would you investigate a marker chromosome?

A

Most commonly originate from chr15 so FISH for the SNRPN, this probe consists of a CEP15 probe as well so will tell you whether it’s derived from 15 and if it contains AS/PWS critical region.

If not, next most likely is chr22 however we don’t have the probe. Would at this point do an array to determine if there is any euchromatic content.

If no euchromatic content then unlikely to be phenotypically relevant.

18
Q

If you saw a heterochromatic marker chromosome in a male patient referred with fertility issues what would you think?

A

Could be contributing to the fertility issues but could be incidental. Marker chromosomes are reported more frequently in those with subfertility than in the general population but not enough to say it definitely causes infertility.

19
Q

If we had a phenotypic patient who had a heterochromatic marker chromosome derived from 15 what could be a possible explanation?

A

That the remaining intact chromosomes are from the same parent and the patient has UPD15.

20
Q

What is the most common cause of RECURRENT chromosome rearrangements? Name the different subtypes.

A

Non-allelic Homologous Recombination
Caused by either:
- Low Copy Repeats (LCR’s)
- Olfactory gene clusters e.g. t(4;8)(p16;p23)
- Palindromic AT-rich sequences e.g. t(11;22)(q23;q11)

21
Q

What is the most common recurrent deletion that is due to LCR’s?

A

The 22q11.2 deletion that results in DiGeorge Syndrome.

22
Q

What is a palindromic AT-rich sequence? What is significant about them?

A

Sequence that reads the same backwards and forwards, appear throughout the genome.
Causes the most common recurrent constitutional translocation in humans, the t(11;22)(q23;q11.2).

23
Q

What are Low Copy Repeats (LCR)? What do they cause?

A
  • Sequences that are similar to each other that are distributed throughout the genome (~10% of genome)
  • They cause/allow erroneous coming together of different chromosome regions
  • Misalignment of these sequences during meiosis sets stage for formation of translocations, deletions and duplications.
24
Q

What are olfactory gene clusters? What in particular do they cause?

A

Repeat units found on different chromosomes across genome - they are associated with smell.
Similar regions that can allow erroneous recombination.
They cause a recurrent constitutional translocation - t(4;8)(p16;p23)
They are also implicated in the deletion polymorphisms seen on 4p and 8p and also recurrent deletion of 4p and 8p.

25
Q

What types of errors can occur during meiosis?

A

Replication errors
Recombination errors
Segregation errors

26
Q

What can cause non-recurrent genomic rearrangements?

A

Non-homologous end joining.

Fork stalling and template switching.

27
Q

What is non-homologous end joining?

A
  • DNA repair process to fix double strand breaks
  • doesn’t require a homologous template
  • double strand breaks can be caused by ionising radiation, chemical agents and reactive oxygen species
  • error prone and can incorrectly join the ends of different chromosomes together e.g. translocation
  • occurs in both constitutional and cancer.
28
Q

What does fork-stalling and template switching refer to?

A

This is an error that can occur during DNA replication:

  • strands separate and act as template
  • as replication proceeds, it can skip over to another strand and continue inappropriately
  • it can then skip back to the other strand
  • this results in a duplicated or a deleted strand depending on where the stall occurs
  • occurs in both constitutional and cancer.
29
Q

NAHR occurs and the result is a deleted and duplicated chromatid……what happens if it occurs at:

  1. Meiosis?
  2. 1st mitosis following conception?
  3. 2nd mitosis and onwards?
A
  1. Resulting del/dup is full blown and in every cell
  2. 1st somatic mitosis = del and dup cell lines represent in embryo
  3. 2nd mitosis onwards = normal cell line, dup cell line, del cell line present. Levels will depend on where it occurs e.g. later on during development of embryo - majority normal, small number of del and dup.
30
Q

What can be the outcome if the t(11;22) translocation segregates inappropriately?

A

3:1 segregation with the derivative supernumerary chr22 in addition to the 11 and 22.
This is Emmanuel syndrome.

31
Q

Does a deletion caused by an LCR always have a reciprocal duplication?

A

No. If the NAHR occurs within a chromatid, it will delete a section but that section will be acentric and will be lost.

32
Q

What is the outcome if their is NAHR between LCR’s on:

  1. The same chromosome with LCRs in the same orientation?
  2. The same chromosomes with LCRs in opposite orientation?
  3. LCRs on different chromosomes?
A
  1. A duplication or a deletion,
  2. An inversion,
  3. Translocation.
33
Q

If a balanced rearrangement is de novo - what do we need to bear in mind?

A

There is a risk that:

  • the breakpoints may have disrupted a crucial gene
  • the breakpoints may have moved a gene away from it’s appropriate control genes
  • or vice versa moved a gene close to an inappropriate control gene.

So there is always a possibility that a balanced rearrangement is having a phenotypic effect.

34
Q

What are the different kinds of translocations?

A

Single segment - only one of the translocated segments contains genetic material e.g. 1 bit very small

Double segment - both parts of substantial size and contain genetic material

Whole arm - breaks in or near centromere (robertsonian)

35
Q

What is the most usual method of isochromosome formation?

A

Misdivision at the centromere.

A horizontal rather than a vertical division.

36
Q

What is thought to be the explanation behind recurrent rearrangements seen in cancer?

A

The positions of the particular chromosomes in particular cell types

Both loci break and because they are positioned near to each other they can be prone to being incorrectly joined together

In certain situations this confers a growth/proliferative advantage to the cell and therefore causes cancer e.g. t(9;22)

37
Q

What is a telomere?

A

End that caps chromosome.

38
Q

What is the function of a telomere?

A

Cell division = shortening of telomere until eventually cell division stops and cell dies.

cytogenetics (44 decks)

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