Chromosomal abnormalities II

Question 1

give some examples of structural abnormalities

Answer 1

Translocations (Reciprocal or Robertsonian)
Inversion
Deletion
Duplication
Rings
Isochromosomes
Microdeletions/Microduplications

Question 2

how do structural abnormalities arise?

Answer 2

Double strand DNA breaks

Occur throughout cell cycle

Generally repaired through DNA repair pathways

Mis-repair leads to structural abnormalities

Question 3

when do balanced translocations form?

Answer 3

spontaneously during meiosis, relatively common

Question 4

translocation mechanism?

Answer 4

2 two double strands breaks, each on a different chromosome

DNA mechanisms within the cell will monitor genome integrity and repair faults

What can happen is instead of joining together the correct two bits, the DNA repair mechanism happens to stitch together the chromosome in incorrect pairs - most of one chromosome, with the end of another chromosome attached

Non-Homologous End Joining (NHEJ) is the mechanism

Question 5

what is meant by unbalanced translocations?

Answer 5

too much or too little of a particular chromosome

Carriers of balanced translocation are at risk of producing unbalanced offspring

Question 6

examples of balanced chromosomes going wrong?

Answer 6

Philadelphia chr
short arm of ch 9 and long arm of chr 22

formation of BCRABL fusion protein, forms an activated oncogene

Question 7

what are reciprocal Translocations?

Answer 7

Exchange of two segments between non-homologous chromosomes

Usually no deleterious phenotype unless breakpoint affects regulation of a gene

Question 8

unbalanced translocation individuals are…

Answer 8

….at significant risk of chromosomal disorder

Question 9

key characteristic of balanced translocations?

Answer 9

no net gain or loss of genetic material – it’s all there, just in a different place

Question 10

how might a balanced translocation carrier produce an unbalanced zygote?

Answer 10

the chromosomes pair up before separating and form a structure called a pachytene quadrivalent

could result in an unbalance arrangement where in each daughter cell there is loss of one end of a chromosome and gain of the end of the other chromosome.

Question 11

clinical result of unbalanced reciprocal translocation

Answer 11

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 and clinical features vary

Question 12

Robertsonian Translocations

Answer 12

2 acrocentric chromosomes break at or near their centromeres

the two sets of long arms join together, loss of the satellites (p arms).

The only genetic material we’ve lost are the satellites and the cell can do without those and so this isn’t a problem for the cell - p arms encode rRNA (multiple copies so not deleterious to lose some)

The resultant chromosome usually contains the long arms of different chromosomes

The cell will now have 45 chromosomes

Question 13

most common Robertsonian translocation?

Answer 13

involves chromosomes 13 and 14, which accounts for approximately 1/3 of all Robertsonian translocations

also 14 and 21

Question 14

terms given to chromosomes depending on where the centromere is?

Answer 14

metacentric if it’s in the middle

submetacentric if it’s displaced from the middle

acrocentric if it’s essentially at the end of the chromosome, such that the p arm is just this little stubby satellite structure.

Question 15

balanced carrier of a Robertsonian Translocation has how many chromosomes?

Answer 15

45 chromosomes

If there are 46 chromosomes present including Robertsonian, then must be unbalanced

Question 16

risks with robertsonian translocations

Answer 16

carriers of Robertsonian translocations can be phenotypically normal - it is possible for them to have a child with a normal chromosomal complement, or even a normal carrier of the same Robertsonian chromosome

However, couples where one partner is a carrier of a Robertsonian translocation can experience multiple miscarriages because of the way the chromosomes segregate, leading to loss of a chromosome or a trisomy which is incompatible with life

Question 17

causes of downs syndrome?

Answer 17

4% of Down’s due to Robertsonian translocations

95% due to non-disjunction

Question 18

are translocations difficult to predict?

Answer 18

Very difficult to predict

Question 19

Other Structural Changes

Answer 19

Terminal deletion

Interstitial deletion (DiGeorge Syndrome)

Inversion

Duplication

Ring chromosome - 2 breaks in the same chromosome, results in a ring

Question 20

Deletions

Answer 20

Deletion may be terminal or interstitial

Causes a region of monosomy

Gross deletions seen on metaphase spread on G-banded karyotype

Question 21

Cri-du-chat

Answer 21

5p minus syndrome

chromosomal condition that results when a piece of chromosome 5 is missing.

developmental delay, microcephaly

Question 22

Microdeletions/Microduplications

Answer 22

Many patients had no abnormality visible on metaphase spread, so they had to use a different method to work out the genetic cause to their condition

High resolution banding, FISH and now CGH showed ‘micro’ deletions

Only a few genes may be lost or gained – contiguous gene syndrome