20.04.14 Structural abnormalities of X chromosome

Question 1

What are sex chromosome abnormalities

Answer 1

Numeric abnormalities or structural chromosome defects involving the X and Y chromosome

Question 2

How prevalent are congenital sex chromosome abnormalities

Answer 2

1 in 448 births

Question 3

What is an isochromosome Xq

Answer 3

• Isochromosome of the long arm of the X chromosome.
• Unbalanced structural abnormality.
• Short arm (p) is deleted and replaced with an exact copy of the long arm (q)
• created during mitosis and meiosis through a misdivision of the centromere or U-type strand exchange

Question 4

What syndrome is commonly associated with Xq isochromosome

Answer 4

• Turner syndrome.

- Due to loss of SHOX at the pseudoautosomal pairing regions.

Question 5

Is an isochromosome of short arm of X viable

Answer 5

• No

- It contains XIST, which is a major effector of the X-inactivation process.

Question 6

What are ring chromosomes

Answer 6

An aberrant chromosome whose ends have fused together to form a ring.

Question 7

Can ring X chromosomes be inherited

Answer 7

• Yes

- More commonly mosaic.

Question 8

What two types of ring X chromosomes are there

Answer 8

• Rings with XIST

- Rings without XIST

Question 9

Review of ring X chromosomes with XIST

Answer 9

• If XIST is retained then ring will undergo X inactivation.
• Phenotype varies from Turners to normal.
• Cells with the normal X inactivated would be nullisomic.
• Abnormal segregation can lead to multiple copies of rings. Even if in an inactive state, could be deleterious

Question 10

Review of ring X chromosomes without XIST

Answer 10

• Fail to undergo inactivation leading to functional disomy for X-linked genes retained on ring.
• Phenotype may be severe.
• Rings are often small as functional disomy is only likely to be tolerated for small amounts of genetic material.

Question 11

Examples of XY translocations

Answer 11

• t(X;Y)(p22.3;q11). Most common X-Y translocation. Unbalanced phenotypes differ.
• t(X;Y)(p;p). XX Male. Carrier may be male or female. Variable phenotype regarding fertility. Males are infertile but derivative can be passed from mother to daughter.

Question 12

XX translocation

Answer 12

• Translocation between p and q. Xp11.23 and Xq21.3 are favoured as breakpoints.
• Either recombination between the two Xs in the oocyte or within one X (likely paternal origin)

Question 13

Example of an X chromosome deletion

Answer 13

• Xp22.
• SHOX gene deletion.
• Transcription factor involved in skeletal development.
• One copy in PAR1 (pseudoautosomal region 1) of X and Y chromosomes. So males and females have 2 functional copies.
• 60% of SHOX rearrangements are deletions. Deletions cause short stature with or without skeletal abnormalities.

Question 14

Review of X chromosome duplications

Answer 14

• Xp21.22 duplication containing DAX1. Dose dependent sex reversal in XY individuals who develop as females with streak gonads.
• Xq28 duplications of MECP2 cause Rett syndrome and MECP2 duplication syndrome

Question 15

Review of X inversions

Answer 15

Most patients with inv(X) will inactivate the abnormal X and show a normal phenotype, except for increase in gonadal dysfunction

Question 16

What regions in X and Y chromosomes are responsible for allowing them to pair and segregate properly during meiosis in males

Answer 16

Pseudoautosomal regions (PAR1 and PAR2)

Question 17

Review of pseudoautosomal regions

Answer 17

• Short regions of homology at the tips of X and Y chromosomes.
• Escape X inactivation so expressed from both Xs in females.
• e.g SHOX gene. Important transcription factor involved in embryonic development. In PAR1

Question 18

What gene mediates X inactivation

Answer 18

• XIST gene. In X inactivation center (XIC) on Xq13.
• XIST is only required to start process of X inactivation not to maintain it.
• Inactivation spreads cis outwards from XIC

Question 19

What do balanced X-autosomal translocation lead to in males

Answer 19

Infertility due to spermatogenic arrest

Question 20

What causes a greater number of X-autosome conceptuses to be viable that autosome-autosome translocations

Answer 20

X inactivation

Question 21

What happens if PAR regions are absent

Answer 21

Turner syndrome phenotypes as the derivative chromosome can be lost during mitosis.