Chromosomal Abnormalities

Question 1

What are the 2 major types of numerical cytogenic abnormalities?

Answer 1

• Aneuploidy

- Polyploidy

Question 2

What is aneuploidy?

Answer 2

Abnormal number of chromosomes in a cell due to loss/gain of whole chromosomes.

Question 3

What are the 2 types of aneuploidy? Give clinical examples of each.

Answer 3

Trisomies

• Down syndrome (21)
• Edwards syndrome (18)
• Patau syndrome (13)

Monosomies
- Turner syndrome (45,X) - only full monosomy syndrome to be viable.

Question 4

What are the effects of meiotic non-disjunction for zygotes?

Answer 4

Non-disjunction in meiosis I (100% screwed)

• 2 trisomic zygotes
• 2 monosomic zygotes

Non-disjunction in meiosis II (50% screwed)

• 2 OK zygotes
• 1 trisomic zygote
• 1 monosomic zygote

Question 5

Suggest a cause for meiotic non-disjunction.

Answer 5

• Anaphase lag = chromosome can be “left-behind” at cell division because of defects in spindle function or attachment to chromosomes.

Question 6

What is the result of mitotic non-disjunction during cell division in the zygote?

Answer 6

Mosaicism

Question 7

What is polyploidy, and what is its most common cause?

Answer 7

• Gain of a whole haploid set of chromosomes, i.e. Triploidy 3n (69,XXX).
• Polyspermy.

Question 8

Name 4 examples of cytogenic structural abnormalities.

Answer 8

1. Translocations
2. Deletions
3. Duplications
4. Inversions

Question 9

What is the cause of chromosomal deletions and duplications?

Answer 9

Arise through uneven pairing and recombination.

• 2 gametes OK
• 1 gamete with duplication
• 1 gamete with deletion

Question 10

What is the difference between balanced and unbalanced chromosomal rearrangements?

Answer 10

• Balanced = no loss of genetic information (e.g. In many inversions)
• Unbalanced = loss of genetic information

Question 11

What are the 2 types of translocation?

Answer 11

1. Reciprocal translocation

2. Robertsonian translocation

Question 12

What are the causes for reciprocal and robertsonian translocations?

Answer 12

Reciprocal
- 2 break rearrangement (involving 2 chromosome ends breaking and switching)

Robertsonian

• q arms of 2 acrocentric chromosomes fuse together (loss of p arms)
• can involve homologous or heterologous fusion

Question 13

What structure do reciprocal translocations form at meiosis 1 metaphase?

Answer 13

Quadrivalent (instead of bivalent)

Question 14

Describe the types of segregation occurring in meiosis 1 of reciprocally translocated chromosomes.

Answer 14

1. Alternate
   - 1 normal balanced gamete
   - 1 translocated balanced gamete
2. Adjacent 1 (non-homologous centromeres)
   - 2 unbalanced gametes
3. Adjacent 2 (homologous centromeres)
   - 2 unbalanced gametes

Question 15

Is adjacent 1 or 2 segregation more likely to occur in reciprocal translocations?

Answer 15

• Adjacent 1.

- Adjacent 2 is very rare - causes large degree of imbalance.

Question 16

What kind of structure is formed in metaphase of meiosis 1 in robertsonian translocations?

Answer 16

Trivalent (instead of divalent)

Question 17

What kind of gametes are formed from a homologous fusion resulting in Robertsonian translocation?

Answer 17

Always results in trisomies as:

• 1 gamete gets the 2 fused homologs
• 1 gamete gets nothing - non-viable

Question 18

What kind of gametes are formed from a heterologous fusion resulting in Robertsonian translocation?

Answer 18

Gametes will either contain

• 2 normal chromosomes: balanced
• fused chromosomes: balanced
• fused chromosome + 1 normal: unbalanced
• just normal chromosome: non-viable

Question 19

What are uniparental disomies?

Answer 19

Presence of chromosomes from 1 parent only.

Question 20

What are the different types of UPDs?

Answer 20

1. Isodisomy: 2 identical chromosomes from 1 parent (error in meiosis II)
2. Heterodisomy: 2 homologous chromosomes from 1 parent (error in meiosis I)
3. Segmental UPD: only part of chromosome involved
4. Acquired UPD: solid tumours and leukaemias

Question 21

Why does UPD matter?

Answer 21

• Because of genomic imprinting: in some genes, only 1 allele is active depending on parent of origin (determined via epigenetics/methylation).
• Most genes aren’t imprinted so most UPDs have no effect. But a person with UPD may lack any active copy of a gene undergoing genomic imprinting - loss of gene function.
• Can lead to delayed development, intellectual disability, etc.

Question 22

Give 3 examples of UPD syndromes.

Answer 22

1. Prader-Willi syndrome
   - uncontrolled eating and obesity
   - UPD on chromosome 15 (loss of paternal chromo)
2. Angelman syndrome
   - intellectual disability and impaired speech
   - UPD on chromosome 15 (loss of maternal chromo)
3. Beckwith-Widemann syndrome
   - accelerated growth and increased risk of cancerous tumours
   - UPD on chromosome 11

Question 23

Which 4 main mechanisms can generate UPD? Which is the most common?

Answer 23

1. Trisomic rescue (most common)
2. Gamete complementation
3. Monosomic rescue (+ endoduplication)
4. Postfertilisation error (+ endoduplication)

Question 24

How likely is trisomic rescue to lead to UPD?

Answer 24

1/3

Question 25

Why are UPDs rare?

Answer 25

Each mechanism generating a UPD requires 2 separate abnormal events.