Wk6 Chromosome Abnormalities

Question 1

What is a chromosome?

Answer 1

A chromosome is made of a single molecule of DNA

Each chromosome has hundreds of genes along its length

Question 2

What is a gene?

Answer 2

• A specific stretch of DNA where the sequence contains genetic instructions is a gene
• Genes are arranged one after the other along the DNA of a chromosome, with stretches of non- coding DNA between them

Question 3

Structure - telomere

Answer 3

DNA and protein cap
Ensures replication to tip
Tether to nuclear membrane

Question 4

Structure - light bands

Answer 4

Replicate early in S phase
Less condensed chromatin
Transcriptionally active
Gene and GC rich

Question 5

Structure - centromere

Answer 5

Joins sister chromatids
Essential for chromosome segregation at cell division
100s kilobases of repetitive DNA: some non-specific, some chromosome specific

Question 6

Structure - dark G bands

Answer 6

Replicate late
Contain condensed chromatin
AT rich

Question 7

How do we examine chromosomes?

Answer 7

• Karyotype from peripheral lymphocytes
• Fluorescent in situ Hybridisation (FISH)
• Array CGH - comparative genomic hybridisation -

Question 8

What type of chromosome abnormalities are there?

Answer 8

• abnormalities of chromosome number
• abnormalities of chromosome structure
• chromosome abnormalities are also classified according to which cells of the body they are distributed in
  Constitutional = all cells of the body
  Somatic = only in certain cells/tissues of the body

Question 9

How do abnormalities of chromosome number occur?

Answer 9

Aneuploidy

• trisomy
• monosomy

Polyploidy

• triploidy
• tetraploidy

Question 10

Why is there an increased risk of meiotic error leading to trisomies in geriatric pregnancies?

Answer 10

• the stock of oocytes is ready by 5 months gestation. Each remains in maturation arrest at the crossing-over stage until ovulation
• there may be a lengthy interval between onset and completion of meiosis (up to 50 years later)
• accumulating effects on the primary oocyte during this phase may damage the cell’s spindle formation and repair mechanisms predisposing to non-disjunction

Question 11

Clinical consequences of chromosomal abnormalities

Answer 11

• abnormalities of chromosome number have significant often lethal consequences
• significant development abnormalities occur due to the imbalance of gene products
• the effect of reducing the gene copy usually has more severe consequences than increasing the gene copy

Question 12

What are the most frequent numerical anomalies?

Answer 12

Autosomes
Down syndrome - trisomy 21: 47, XX, +21
Edwards syndrome - trisomy 18: 47, XX, +18
Patau syndrome - trisomy 13: 47, XX, +13

Sex chromosomes
Turner syndrome - 45, X
Klinefelter syndrome - 47, XXY

All chromosomes
Triploidy - 69 chromosomes

Question 13

What is the genetic basis of Down syndrome?

Answer 13

• 95% people have 3 separate copies of chromosome 21: trisomy 21
• 4% have the extra copy of C21 because of a robertsonian translocation
• 1% have mosaicism with normal and trisomy 21 cell lines (and usually have much milder features because of the presence of the normal cells)

Question 14

How does having 3 copies of gene cause DS?

Answer 14

• “ gene dosage effect” - features of syndrome caused by 1.5x amount of specific gene products from chromosome 21
• “amplified developmental instability” - features of syndrome caused by overall effect of imbalance on development

Question 15

What are the implications for genetic counselling?

Answer 15

• aneuploidy is usually the results of meiotic non disjunction related to maternal age
• the risk of recurrence is therefore low and will be related to age of the mother

Question 16

What is a robertsonian mutation?

Answer 16

Breakage of 2 acrocentric chromosomes (13, 14, 15, 21, 22) at or close to their centromeres with subsequence fusion of their long arms - short arms are lost

Balanced = no effect on phenotype as no gene imbalance 
Unbalanced = e.g. Down syndrome

Question 17

What is the probability of recurrence for robertsonian translocations?

Answer 17

• carrier for 14:21 has a high theoretical probability of having a child affected with DS
• but the observed figure is less than predicted
• also compared with low recurrence in regular trisomy DS due to error in cell division
• this is why it is importance to karyotype a person with DS - to determine chromosomal cause

Question 18

What is a reciprocal translocation?

Answer 18

Breakage of 2 non-homologous chromosomes with exchange of the fragments
Any chromosomes can be involved

Question 19

Outcome of normal zygote

Answer 19

Normal

Question 20

Outcome - normal but unbalanced translocation but balanced carrier

Answer 20

Risk to children

Question 21

Outcome of partial trisomy + partial monosomy

Answer 21

Miscarriage, congenital malformation, developmental delay, mental abnormality

Question 22

Outcome of Partial monosomy + partial trisomy

Answer 22

Miscarriage, congenital malformation, developmental delay, mental abnormality

Question 23

What are the probabilités of recurrence for reciprocal translocations?

Answer 23

The size and position of the chromosome segments involved in the translocation may have an effect on:

• the pairing of the chromosomes at meiosis
• Frequency of different forms of translocation in the gametes
• the likelihood of the concept us with that abnormality developing to thermal

Question 24

What are large chromosome délitions/duplications?

Answer 24

Can occur because of unequal crossing-over in meiosis following mis pairing (often at the sites of repeated sequences)

Question 25

What is mosaicism?

Answer 25

Two populations of cells with different genetic constitutions usually as a result of an error in mitosis

Question 26

What is somatic mosaicism?

Answer 26

Two populations of cells in body

Question 27

What is somatic mosaicism?

Answer 27

Two populations of cells only in the gonads