Structural Chromosome Abnormalities

Question 1

Name some types of rearrangements.

Answer 1

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

Question 2

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

Answer 2

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

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

Question 3

Approximately what number of liveborn individuals carry a balanced translocation?

Answer 3

1 in 500

Question 4

What is a robertsonian?

Answer 4

Fusion of 2 acrocentric chromosomes. Usually non-homologous.

Question 5

What is the most common robertsonian? Why?

Answer 5

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.

Question 6

How is a robersonian formed?

Answer 6

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.

Question 7

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

Answer 7

1 in 1000.

Question 8

Can you get a homologous robertsonian?

Answer 8

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.

Question 9

What are the 2 types of inversions?

Answer 9

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.

Question 10

Give an example of a common variant.

Answer 10

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

Question 11

What are the types of deletion?

Answer 11

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

Interstitial - two breaks with loss of material between breaks.

Question 12

What is a marker chromosome?

Answer 12

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

Question 13

What are the 2 most common marker chromosomes seen?

Answer 13

idic(15) or inv dup(15)

idic(22)

Question 14

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

Answer 14

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.

Question 15

What is important about a idic(15)?

Answer 15

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.

Question 16

What is significant about the idic(22)?

Answer 16

It is associated with Cat Eye syndrome.

Question 17

How would you investigate a marker chromosome?

Answer 17

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.

Question 18

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

Answer 18

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.

Question 19

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

Answer 19

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

Question 20

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

Answer 20

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)

Question 21

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

Answer 21

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

Question 22

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

Answer 22

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).

Question 23

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

Answer 23

• 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.

Question 24

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

Answer 24

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.

Question 25

What types of errors can occur during meiosis?

Answer 25

Replication errors
Recombination errors
Segregation errors

Question 26

What can cause non-recurrent genomic rearrangements?

Answer 26

Non-homologous end joining.

Fork stalling and template switching.

Question 27

What is non-homologous end joining?

Answer 27

• 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.

Question 28

What does fork-stalling and template switching refer to?

Answer 28

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.

Question 29

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?

Answer 29

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.

Question 30

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

Answer 30

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

Question 31

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

Answer 31

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

Question 32

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?

Answer 32

1. A duplication or a deletion,
2. An inversion,
3. Translocation.

Question 33

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

Answer 33

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.

Question 34

What are the different kinds of translocations?

Answer 34

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)

Question 35

What is the most usual method of isochromosome formation?

Answer 35

Misdivision at the centromere.

A horizontal rather than a vertical division.

Question 36

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

Answer 36

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)

Question 37

What is a telomere?

Answer 37

End that caps chromosome.

Question 38

What is the function of a telomere?

Answer 38

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