14. Structural abnormalities of X chromosome

Question 1

What is isochromosome X?

Answer 1

2 copies of the long arm of the X chr - unbalanced rearrangement

Question 2

What is i(Xq) associated with?

Answer 2

Turner syndrome due to loss of SHOX at PAR

Also in patients with variant of Klinefelter syndrome - 47,X,i(Xq),Y

Question 3

Why is an isochromosome for Xp not viable?

Answer 3

XIST would be absent - disomy for genes on Xp

Question 4

What is a ring chromosome?

Answer 4

Chr whose ends have fused together - range in size depending on amount of material lost from p and q arms

Question 5

What phenotype is associated with rX that includes XIST?

Answer 5

Phenotype varies from Turner syndrome to normal depending on amount of X chr lost

Selective X-inactivation

Cells with normal X inactivated are nullsomic for parts of X chr that are missing from rX

Question 6

What phenotype is associated with rX without XIST? Why?

Answer 6

Severe phenotype

Fail to undergo X inactivation - functional disomy for genes retained on ring

Often small rings as functional disomy only tolerated for small number of genes

Question 7

What are the PARs?

What is their function?

Answer 7

Short regions of homology between X & Y - contain genes present on both

Allow X & Y to pair & segregate during meiosis in males

Escape inactivation as dosage compensation not required

Question 8

What key gene is located in the PAR? What is its role?

Answer 8

SHOX - important TF involved in formation of body structure in early embryonic development

Question 9

Why are PARs expressed from both Xs in females?

Answer 9

PARs escape X inactivation

Question 10

What is the most common X/Y translocation?

Answer 10

t(X;Y)(p22;q11)

Question 11

What phenotype is associated with deletions in the Xp22.3 region?

Answer 11

Icthyosis (STS)
Hypogonadism, ID (KAL1)
Short stature (SHOX)

Question 12

What phenotype is associated with deletions in the Xp11.22 region?

Answer 12

HUWE1, CLCN5 - associated with ID

Question 13

What phenotype is associated with MECP2 duplication syndrome?

Answer 13

Moderate/severe ID

Immune abnormalities if IRAK1 is duplicated

Seen exclusively in males, females unaffected due to selective X inactivation

Question 14

What is the result of translocations with breakpoints in Xq13-22?

Answer 14

Ovarian disorders ranging from premature ovarian insufficiency to primary amenorrhea.

Question 15

What is the effect of a balanced X-autosome translocation in females?

Answer 15

Preferential (skewed) inactivation of normal X

Functional balance achieved using both parts of the X in the translocated chromosome as the active X

Breakpoints in Xq13-22 cause ovarian disorders

Question 16

What is the effect of a balanced X:autosome translocation in males?

Answer 16

Disruption of the X-Y bivalent at meiosis –> Spermatogenic arrest and infertility

Question 17

What are the potential consequences of skewed X inactivation in patient with a balanced X;autosome translocation?

Answer 17

Normal X not preferentially silenced

Monosomy of some autosomal genes (due to the spread of X inactivation)

Functional disomy of other X chromosome genes

XLR disorder (e.g. DMD) may manifest due to skewing

Question 18

What phenotype is associated with balanced X-autosome translocations in females?

Answer 18

Usually normal

Ovarian dysfunction if breakpoints are in critical region - Xq13-22

Question 19

What is the purpose of X-inactivation?

How does it occur?

Answer 19

Mechanism for gene dosage compensation

Equalises X chromosome gene expression between males and females

Random transcriptional silencing of either maternal or paternal X chromosome

Question 20

When does X inactivation occur?

Answer 20

As cells differentiate in late blastula stage

Pattern of X inactivation inherited stably in daughter cells

Question 21

Describe the structure of the inactive X

Answer 21

Highly condensed, heterochromatic state

Visualised as a Barr body

Question 22

Describe the mechanism of X inactivation

Answer 22

Initiated at XIC

XIST is a lncRNA transcribed from inactive X only - acts in cis

XIST spreads from XIC, recruits polycomb proteins, coats X chr –> DNA methylation and histone acetylation

Question 23

What is the role of Tsix?

Answer 23

Transcribed from antisense strand of XIST - represses XIST expression through DNA methylation and histone acetylation

Question 24

How do XIST and Tsix regulate inactivation?

Answer 24

Prior to inactivation, both Xs weakly express XIST and Tsix

At inactivation, future inactive X ceases to produce Tsix and XIST expression increases

XIST is repressed on active X by methylation of promoter

Question 25

What is the effect of random X inactivation on XLD disorders?

Answer 25

Trait is less severe in females as 50% of cells with pathogenic X are inactivated

Female more severely affected due to non-random/skewed X inactivation due to variants in Xist or Tsix

Question 26

How can skewed X inactivation be tested for?

Answer 26

Most commonly HUMARA assay

gDNA digested with methylation-specific enzyme - digests unmethylated allele only

Amplification of CAG STR in AR gene - only methylated allele is amplified