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

Unmask AR disease

FISH to determine if locus is disrupted, NGS to map breakpoints

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 to 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

Give an examples of how a balanced karyotype can disrupt imprinting

Answer 6

BWS - maternally inherited translocation has 11p15 breakpoint - moves imprinting centre away from imprinted region –> abnormal H19 expression

Question 7

What type of chromosome abnormalities increase the risk of UPD

Answer 7

Robertsonian and reciprocal translocations - increase occurrence of non-disjunction –> increased risk of UPD

Carriers of Robertsonian and reciprocal translocations may have offspring with UPD

Question 8

When does UPD become clinically relevant?

Answer 8

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

Question 9

Give an example of when UPD disrupts imprinting

Answer 9

Maternal t(7;16) associated with maternal heterodisomy (mat UPD7) in Russel Silver syndrome

Question 10

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

Answer 10

1. inv(X) - breakpoints in X critical region can lead to gondal dysfunction and infertility
2. t(X;autosome) - male carriers infertile due to spermatogenic arrest , females phenotypically heterogeneous

Question 11

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

Answer 11

If XIC is on der(X) - abnormal X is inactivated + autosomal material on der(X). Translocated section of X is not inactivated

If XIC is on der(A) - part of autosome is inactivated and der(X) is functional –> functional disomy of for some of X chr and loss of autosome function

Question 12

Give an example of how mosaicism may explain the phenotype

Answer 12

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

Caused by 3:1 segregation at meiosis

Question 13

How can balanced rearrangements affect fertility?

Answer 13

Disturb process of gamete formation, especially in males - causes miscarriages and infertility

Homologous regions fail to pair