19. Abnormal phenotypes in balanced karyotypes

Question 1

What is the effect of breakpoints disrupting a gene?

Answer 1

Truncated/no protein

AD - usually de novo
AR - unmasks AR disease

Question 2

What is a cryptic imbalance?

Answer 2

Karyotype appears balanced but sub-microscopic deletion/insertion/inversion at translocation breakpoint causes disease

Question 3

When do the majority of de novo rearrangements arise?

Answer 3

Paternal allele

Spermatogenesis more susceptible then oogenesis

Question 4

What is the positional effect? What does it cause?

Answer 4

Balanced rearrangement moves gene away from promoter/enhancer/inhibitor, into region of heterochromatin, or closer to another gene’s regulatory element

Causes deleterious change in gene expression - relevant for dosage sensitive AD genes

Question 5

Give an example of the positional effect in cancer

Answer 5

Burkitt lymphoma - t(8;14)

c-MYC oncogene under control of immunogloblin enhancer

Question 6

What type of chromosome abnormalities increase the risk of UPD and why?

Answer 6

Robertsonian and reciprocal translocations - increase occurrence of non-disjunction –> trisomy rescue and increased risk of UPD in offspring

Question 7

When does UPD become clinically relevant?

Answer 7

1. When genes involved are imprinted in imprinted regions - therefore differentially expressed on maternal or paternal allele
2. When AR disease is unmasked

Question 8

How can balanced rearrangments involving the X chromosome result in disease?

Answer 8

1. inversion or translocation - breakpoints in X critical region can lead to gondal dysfunction and infertility in females
2. t(X;autosome) - male carriers infertile due to spermatogenic arrest due to disruption of X-Y bivalent , females phenotypically heterogeneous

Question 9

How does a t(X;autosome) affect X inactivation?

Answer 9

Normal X usually preferentially inactivated as cells with inactivated abnormal X do not survive because autosomal regions have been inactivated

If some cells with abnormal X remain - phenotype seen due to inactivation of autosomal regions and disomy for some of X chr regions

Question 10

Give an example of how mosaicism may explain the phenotype in an individual with a balanced karyotype

Answer 10

Pallister-Killian syndrome - balanced karyotype in blood, unbalanced in other tissue

Question 11

Why can balanced translocations and inversions cause infertility in males?

Answer 11

Failure to complete synapsis - activates the meiotic pachytene checkpoint causing cell death

Spermatogenic cells are more vulnerable

Question 12

How do balanced rearrangements impact female fertility?

Answer 12

Oocytes bypass pachytene checkpoint –> recurrent miscarriage rather than infertility as gametes are unbalanced and fetus is not viable

Question 13

How might balanced rearrangements cause BWS/RSS?

Answer 13

1. Positional effect: Maternally inherited translocation has 11p15 breakpoint - moves imprinting centre away from imprinted region –> abnormal HGF2 expression –> BWS
2. UPD: Maternal t(7;16) associated with maternal heterodisomy (mat UPD) due to 3:1 segregation and trisomy rescue –> RSS

Question 14

Give an example of the positional effect in rare disease

Answer 14

Balanced t(4;17) in campomelic dysplasia

Moves SOX9 away from enhancer element - reduced expression