Chromosome abnormalities, segregation

Question 1

What is a Robertsonian translocation?

How does a Robertsonian karyotype look?

Answer 1

Fusion of the long arms of two acrocentric chromosomes, short arms are lost

Considered balanced - short arms contain repetitive satellite and ribosomal DNA sequences only

Karyotype shows 45 chromosomes

Question 2

What are acrocentric chromosomes?

Which chromosomes are acrocentric?

Answer 2

Chromosomes where the centromere is not central, have a very small p arm

13, 14, 15, 21, 22, Y

Question 3

Name the three common reciprocal translocations

Answer 3

t(11;22)

t(4;8)

t(X;Y)(p22;q11)

Question 4

What is a derivative chromosome?

Answer 4

The translocation product identified according to which centromere it includes

Question 5

What is a double segment exchange?

What is a single segment exchange?

Answer 5

Double segment exchange - both translocated segments are substantial size

Single segment exchange - one translocated segment is very small

Question 6

How does an insertion (insertional translocation) occur?

Answer 6

3 break rearrangement involving 2 chromosomes

1 break in recipient chromosome, 2 breaks in donor

Question 7

What are the risks of Robertsonian translocations to offspring?

Answer 7

Malsegregation of translocation chromosome can lead to Down syndrome, Patau syndrome etc.)

Increased risk of UPD if malsegregation is corrected by trisomy/monosomy rescue - imprinting disorder if 14 and 15 involved

Question 8

What are the most common Robertsonian translocations?

Answer 8

der(13q14q) and der(14q21q)

Question 9

What are inversions?

Answer 9

2 break intrachromosomal structural rearrangement

Question 10

What are the 2 types of inversion?

Answer 10

Paracentric - breakpoints in the same arm

Pericentric - breakpoint in each arm, includes the centromere

Question 11

What are the implications of an inversion?

Answer 11

Carriers usually phenotypically normal as it’s a balanced rearrangement

Risk of phenotype from position effect, disruption of a gene or epigenetic effect

Infertility in males due to failure of synapsis

Risk to offspring due to inversion loop at meiosis resulting in crossover and therefore imbalances

Risk of acentric or dicentric chr from paracentric inversion

Question 12

What is an isochromosome?

Answer 12

Unbalanced rearrangment

‘Mirror image’ chromosome - 2 identical arms of the same chromosome on either side of the centromere

Question 13

What are the implications of an isochromosome

Answer 13

1. Loss of expression of genes on missing arm (e.g. Turner syndrome, SHOX)
2. If present as a supernumary, results in tetrasomy for the arm (e.g. i(12p) Pallister-Killian syndrome)

Question 14

How does a ring chromosome arise?

What are the clinical implications?

Answer 14

Most arise sporadically, involved breakage in both arms with fusion at the breakpoints and loss of distal segments

Variable phenotype, depends on size/content of deleted distal segments

r(20) associated with epilepsy

Question 15

What happens in alternate segregation?

What does it result in?

Answer 15

The two normal homologues segregate together and the two balanced homologues segregate together

Produce balanced gametes

Question 16

What happens in adjacent 1 segregation?

What does it result in?

Answer 16

Adjacent non-homologous centromeres segregate together (one of each centromere)

Produces only unbalanced gametes

Question 17

What happens in adjacent 2 segregation?

What does it result in?

Answer 17

The 2 homologous centromeres segregate together

Produces only unbalanced gametes

Question 18

What is 3:1 segregation? What are the 2 types?

What do they result in?

Answer 18

3 centromeres to one pole, 1 centromere to the other

Tertiary - 2 normal chromosomes and 1 translocated chr

Interchange - 2 translocated chr and 1 normal

Question 19

What are the implications of carrying a balanced translocation?

Answer 19

Carriers usually phenotypically normal unless positional effect, gene disruption, imprinting

Risk of recurrent miscarriage/infertility

Risk of abnormal offspring due to malsegregation –> imbalance or UPD

Question 20

Give 2 examples of diseases involving isochromosomes

Answer 20

Pallister-Killian syndrome - supernumerary i(12p) = tetrasomy

45,X/46,X,i(Xq) = Turner syndrome variant

Question 21

What are the two types of Robertsonian translocation?

Answer 21

1. Non-homologous translocation = two different chr
2. Homologous translocation = the same chr

Question 22

What happens to translocation chromosomes during meiosis I?

Answer 22

Form a quadrivalent

In order to match homologous segments they form a pachytene cross

Chromosomes then distributed to poles of the cell

Question 23

What is the implication of the t(11;22) balanced translocation on offspring?

Answer 23

Carriers phenotypically normal

Prone to 3:1 segregation - one gamete has tertiary trisomy for normal 11, normal 22 + der(22)t(11;22)

If fertilised, results in zygote with 2x normal 11s, 2 normal 22s + der(22)t(11;22) = Emmanuel syndrome

Question 24

What causes a terminal deletion and what mechanisms can occur to stabilise the chromosome?

Answer 24

Caused by DSBs

1. Synthesis of new telomore
2. Telomere capture from another chr
3. Chr circularisation –> ring chr

Question 25

What is the phenotype of Emmanuel syndrome?

Answer 25

Pre- & postnatal growth deficiency, microcephaly, hypotonia, severe developmental delay, cleft palate, congenital heart defects, kidney abnormalities

Question 26

What is the phenotype of Pallister-Killian syndrome?

Answer 26

Multiple congenital anomalies, seizures, severe developmental delay, macrosomia at birth, deafness, distinct dysmorphic features

Question 27

Give an example of a balanced rearrangement impacting imprinting

Answer 27

Maternal t(7;16) associated with maternal heterodisomy (mat UPD) due to 3:1 segregation and trisomy rescue –> RSS