Structural Chromosomal Abnormalities

Question 1

What is a translocation?

Answer 1

Exchange of two segments between non-homologous chromosomes
Reciprocal or Robertsonian
One of the most common ways in which translocation occurs is due to Non-homologous end joining

Question 2

What is non homologous end joining?

Answer 2

Hay 2 double strands breaks, each on a dif chromosome. Sometimes, instead of joining the correct bits, the DNA repair mechanism joins the chromosome in incorrect pairs

NHEJ is aka balanced translocations. They form spontaneously during meiosis
No hay gain/loss of genetic material – it’s all there, just in a dif place.
They can involve any chromosome and the fragments can be of any size
Occur in~1 in 930 people

Question 3

How are unbalanced individuals produced?

Answer 3

•A reciprocal translocation=no loss/gain of material. But, chromosomes can separate so that a cell has a gain in yellow chromosome and a loss of the end of the purple chromosome.

The other daughter cell has a loss of the end of the yellow chromosome and gain of the purple chromosome. This is an unbalanced arrangement

Question 4

What is the result of unbalanced reciprocal translocation?

Answer 4

Many lead to miscarriage (hence why a woman with a high number of unexplained miscarriages should be screened for a balanced translocation)

Learning difficulties, physical disabilities

Tend to be specific to each individual so exact risks + clinical features vary

Question 5

What is a Robertsonian translocation?

Answer 5

Only affect acrocentric chromosomes (those w the centromere near the chromosome tip). These are chromosomes 13, 14, 15, 21 & 22

If 2 acrocentric chromosomes break at their centromeres, when fragments rejon it’s possible for just long arms to be brought juntos y hay loss of the satellites

The only lost genetic material=unecessary satellites so this isn’t a problem for the cell.

Question 6

How many chromosomes will an individual w a robertsonian translocation have?

Answer 6

Balanced carrier has 45 chromosomes. If 46 chromosomes present including Robertsonian then the individual must be unbalanced

p arms encode rRNA (multiple copies so not deleterious to lose some)

Robertsonian translocations 13;14 and 14;21 relatively common. 21;21 translocation leads to 100% risk of Down syndrome in fetus

Question 7

This shows a robertsonian translocation between chromosomes 14 and 21. Explain all of the different gamete possibilities and the clinical outcome

Answer 7

a) daughter cell has the normal copy of chromosome 14 + 21 (normal).
b) daughter cell just has the translocated chromosome (carrier)
c) daughter cell has the normal chromosome 21 + translocated chromosome. After fertilisation, these r joined by otra chromosome 14 + 21. So hay normal number of chromosomes 14, but 21 triploidy= Down’s

Hay 3 other ways these chromosomes can segregate but these will either result in monosomy 14/21 or trisomy 14 – which are incompatible w life.

Question 8

Describe chromosomal deletions

Answer 8

Deletions are either from the end of the chromosome (terminal) or from within a chromosome (interstitial)

If the end of the chromosome is lost then the only way the chromosome can be made stable is if a new telomere is added; without the telomere the cell will die

Question 9

What are chromosome inversions and duplications?

Answer 9

• Inversion: hay 2 breakpoints within the same chromosome and when these are repaired the middle section is “upside down”
• Duplication: hay a region of the chromosome repeated
• A ring chromosome is 2 breaks in the same chromosome. Non-homologous end joining joins the 2 ends of the large chunk together, forming a ring.

Question 10

Describe the clinical outcome of deletions

Answer 10

• Deletion may be terminal or interstitial
• Causes a region of monosomy
• Haploinsufficiency of some genes
• Contiguous gene syndrome (=multiple, unrelated clinical features)
• Phenotype is specific for size and place on deletion
• Gross deletions seen on metaphase spread on G-banded karyotype

Question 11

Describe the clinical outcome of micro deletions

Answer 11

• Many patients had 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
• Velocardiofacial (DiGeorge), 22q11
• Wolf-Hirschhorn, 4p16
• Williams, 7q11

Question 12

Most deletion duplication events occur due to…

Answer 12

Most deletion duplication events occur due to unequal crossing over

This is when you get exchange of genetic material between homologous pairs of chromosomes, but they’ve not aligned appropriately.

If they have misaligned then you can get simultaneous deletions and duplications on the individual chromatids.