Chromosomal Abnormalities II

Question 1

Types of chromosomal changes

Answer 1

Numerical: can be detected through Karyotyping and FISH, QF-PCR and NGS
Structural: can be detected through karyotyping, FISH and arrayCGH

Question 2

What are some structural abnormalities that can occur in chromosomes?

Answer 2

• Translocations: Reciprocal and Robertsonian
• Inversion
• Deletion
• Duplication
• Rings
• Isochromosomes
• Microdeletions/Microduplications

Question 3

Why and how do structural abnormalities occur in chromosomes?

Answer 3

They occur due to double-strand DNA breaks and also occur within the cell cycle.
They generally are repaired through DNA repair pathways. The mis-repair leads to structural abnormalities.

Question 4

What are reciprocal translocations and the mechanism behind how they occur?

Answer 4

Reciprocal translocations are the physical exchange of a section of chromosome between non-homologous chromosomes. This occurs by Non-Homologous End Joining (NHEJ).

Question 5

What type of chromosomes are formed after NHEJ occurs?

Answer 5

Derivative chromosomes which are a mixture of two different chromosomes. There are no deletions, just the chromosome ends are in the wrong place.

Question 6

What is the difference between balanced and unbalanced translocations?

Answer 6

Balanced translocations have the right amount of each chromosome just maybe not in the expected place.
Unbalanced translocations have too much or too little of a particular chromosome.

Question 7

What condition(s) can carriers of balanced translocations acquire?

Answer 7

It can cause chronic myeloid leukemia. This is caused by the presence of the Philadelphia chromosome (ABL-BCR). There is a fusion gene formed between BCR and ABL that triggers the ABL gene part.

Question 8

Summarise reciprocal translocations

Answer 8

• It is the exchange of two segments between non-homologous chromosomes
• Balanced translocation - there is no net gain or loss of material.
• Usually, no deleterious phenotype unless the breakpoint affects the regulation of a gene.
• The carrier of balanced translocation is at risk of producing unbalanced offspring.
• The unbalanced individuals at significant risk of chromosomal disorders.

Question 9

How are unbalanced individuals produced?

Answer 9

1. At meiosis, in the presence of a balanced carrier, rather than aligning two homologous chromosomes (this is not present as the sections are different on each chromosome), a quadrivalent is formed.
2. These sections are pulled apart during anaphase and can result in different gametes being formed.
3. There are three possible combinations: normal/balanced, unbalanced - missing a gene or unbalanced - extra gene. It is possible to have an unbalanced trisomy with respect to a specific region.

Question 10

What are the clinical implications of unbalanced reciprocal translocation?

Answer 10

• It can lead to miscarriage in women (women who have had high numbers of unexplained miscarriages are screened for having a balanced translocation).
• Learning difficulties and physical difficulties
• However, it is catered to the specific individual so the exact risks and clinical features vary.

Question 11

Describe the formation of a robertsonian translocation

Answer 11

1. This is when 2 acrocentric chromosomes break at or near the centromeres and there is a loss of the P arms.
2. The 2 sets of the Q arms then join together.
3. This leads to the loss of one chromosome and therefore you end up with 45 chromosomes instead of 46.
4. However, if there are 46 chromosomes including a Robertsonian then must be imbalanced.

Question 12

What are the acrocentric chromosomes that are formed when the Q arms join?

Answer 12

13, 14, 15, 21 and 22

Question 13

Why is it possible for a cell to survive when a chromosome doesn’t have a P arm?

Answer 13

The P arm only contains satellites which encode rRNA molecules and the cell can survive without that.

Question 14

Which robertsonian translocations are common?

Answer 14

13:14 and 14:21 are common

Question 15

What does a 21:21 robertsonian translocation lead to?

Answer 15

100% risk of down syndrome

Question 16

Using chromosome 14 and 21 as an example, explain the consequences of a robertsonian translocation

Answer 16

• Upon fertilisation, if the mum has normal gametes only certain combinations will survive: the only viable trisomies are 13, 18 and 21. To be viable, it needs to have two 14q arms and two 21q arms. If there is less or more then, the offspring will not be viable or may have abnormal defects.

Question 17

Genetics of offsping from a mum with normal (14 and 21) chromosomes and dad with healthy 14, healthy 21 and robertsonian chromosome.

Answer 17

Potential Offspring 1: can inherit healthy 14 and healthy 21 so normal chromosomes = two 14 and 21 arms.

Potential Offspring 2: can inherit Robertsonian chromosome + normal 14 and 21 chromosome = viable healthy carrier offspring. The child will have two 14 but three 12 arms

Potential Offspring 3: can inherit Healthy 21 and Robertsonian chromosomes + normal 14 and 21 = Down’s syndrome offspring. The child will have trisomy 21 which is viable but Down’s child.

Potential Offspring 4: Healthy 14 + normal 14 and 21 = non-viable/lethal. The child will have two 14 arms but one 21 arm. Monosomy 21 is not viable.

Potential Offspring 5: Healthy 21 + normal 14 and 21 = non-viable/lethal as the child has two 21 arms but only one 14 arm. Monosomy 14 is not viable.

Potential Offspring 6: Healthy 14 and Robertsonian Chromsoms + normal 14 and 21 = non-viable/lethal. The child will have two 21 arms but three 14 arms. Trisomy 14 is not viable. Therefore, overall the chances of the parents having a viable child are 1/2.. The chances of the child having down’s syndrome out of the viable children is 1/3.

Question 18

How can trisomy 21 be acquired?

Answer 18

• Happen due to non-disjunction (NDJ): due to abnormal chromosome division and therefore you end up with 3 full copies of chromosome 21, this is meiotic non-disjunction therefore the problem is with the gametes.
• Can also happen in mitotic non-disjunction which occurs post fertilisation and is one of the reasons there is mosaicism in Down’s syndrome.
• Due to robertsonian translocation: due to an additional chunk of 21 chromosome on the 14 chromosome making it 3 copies of chromosome 21.

Question 19

What are the outcome effects of translocations?

Answer 19

• Difficult to predict: only have approximate probability of producing possible gametes.
• Some unbalanced outcomes may lead to spontaneous abortion of conceptus so early that it is not seen as a problem.
• Some unbalanced outcomes may lead to miscarriage later on and present clinically.
• Some may carry to term and result with live born babies with various problems.

Question 20

What are terminal deletions?

Answer 20

There is a deletion at the end of the chromosomes and you get a new ending which acts as the telomere.

Question 21

What is an inversion?

Answer 21

When a chunk of the chromosome will get changed upside down and re-joined.

Question 22

What is a duplication?

Answer 22

When a section of the chromosome is duplicated which cause misalignment of the chromosomes when they line up.

Question 23

What is a ring chromosome?

Answer 23

When both terminal ends of the chromosome which are the telomers are lost and therefore the chromosome winds up around itself.

Question 24

What are the most common structural changes?

Answer 24

Deletions and duplications

Question 25

Where can deletions occur?

Answer 25

May be terminal (at the end) or interstitial (in the middle) of the chromosome

Question 26

What is the consequence of a deletion?

Answer 26

• Can cause a region of monosomy.
• Haploinsufficiency of some genes (do not have enough copies of the genes)
• Monosomic region has phenotypic consequences.
• Phenotype is specific for size and place on deletion.

Question 27

How are microdeletions/microduplications identified?

Answer 27

• Many patients have no abnormality visible on metaphase spread.
• High resolution banding, FISH and now CGH showed ‘micro’ deletions
• Only a few genes may be lost or gained - contiguous gene syndrome.

Question 28

How do deletions and duplications occur?

Answer 28

1. There is unequal crossing over during meiosis 1.

2. Then, the misalignment of the chromosomes leads to some chromosomes having extra and some having less genes.

Question 29

Why is having less genes in a cell more detrimental than have more genes?

Answer 29

Microdeletions are more common with abnormal phenotype which relates to less genes in the cell being more detrimental than a lot of genes.