Chromosomal abnormalities

Question 1

What is a karyotype?

Answer 1

A persons collection of chromosomes

Shows us condensed chromosomal DNA- chromatin

Question 2

How do you prepare a karyotype?

Answer 2

1. Collect about 5ml of heparinised venous blood (Can use amniotic cells from CVS)
2. Isolate white cells
3. Culture in presence of phytohemagglutinin - stimulates T cell growth and differentiation
4. After 48 hours add colchicine- causes mitotic arrest
5. Place in hypotonic saline
6. Place on slide
7. Fix and stain
8. Cut out chromosomes and arrange them in a karyograph

Question 3

What is an ideogram?

Answer 3

Each chromosome has a distinct pattern- can be represented as an ideogram
Gisema stain leaves a recognisable pattern of bands

Question 4

What are common features of chromosomes?

Answer 4

Have centromere between P arm (small arm) and q arm (long)

Question 5

What do band numbers mean?

Answer 5

Bands caused by staining
Originally these bands were identified with low level resolution- only a few bands per chromosome
Improved technology means more visible bands- sub-bands and sub-sub-bands
E.g. 3p22.1

Question 6

What do different bands show?

Answer 6

Bphs= bands per haploid set
Bands do not represent genes
Dark bands = heterochromatin- more compact, fewer genes
Light bands = euchromatin- less compact, more genes
Chromosomes from prophase often used because they’re less compact so you get more detail

Question 7

What is aneuploidy?

Answer 7

Abnormal number of chromosomes

Question 8

How does aneuploidy occur?

Answer 8

Meiosis allows random assortment of homologues and recombination
Non- disjunction (faring to separate correctly) results in uneven number of chromosomes in daughter cells
This can occur is meiosis I or meiosis II:
Meiosis I = all daughter cells affected
Meiosis II = half of daughter cells affected
Always results in +1 or -1 chromosome: trisomy or monosomy when fertilised

Question 9

Why is sex chromosome imbalance tolerated?

Answer 9

X- inactivation of excess X chromosome

Low gene content of Y chromosome

Question 10

Why does an abnormal number of X chromosomes have an affect?

Answer 10

Both X and Y chromosomes have PAR (pseudo- autosomal region)

This is a region on the X chromosome which is not inactivated along with the rest of the chromosome

Question 11

What is trisomy 21?

Answer 11

Aka. Downs syndrome
3 copies of chromosome 21
Most trisomy 21 is maternal non-disjunction

Question 12

How does age affect maternal disjunction?

Answer 12

Risk of maternal disjunction increases with maternal age
This happens because of inherent vulnerability in oogenesis
This means with increased ages, the egg stays in meiosis for increased time.
This likely leads to degradation of factors which hold homologous chromatids together so so risk of non-disjunction increases

Question 13

What is the affect of paternal age on non-disjunction?

Answer 13

Primary spermocytes undergo about 23 mitotic divisions per year and potentially accumulate defects
Paternal age is not a risk factor for increased aneuploidy but does increase risk of gene disorders by point mutations

Question 14

What is a risk factor that increases paternal involvement in aneuploidy?

Answer 14

Smoking

Question 15

What is the risk of aneuploidy in pregnancy?

Answer 15

Leads to approx. 5% still births and 50% spontaneous abortions
Trisomy can be detected prenatally
Most trisomy not compatible with life

Question 16

When do most chromosomal abnormalities occur?

Answer 16

Occur during crossing-over
Crossing over:
- occurs in prophase I
- increases genetic diversity

Question 17

What is the result of unequal crossing-over?

Answer 17

Duplication: extra material
Deletion: loss of material

Question 18

What causes duplication?

Answer 18

Uneven crossing-over
Breaks in chromosome during meiosis
Can occur at ends and middle of chromosome

Question 19

What causes deletion?

Answer 19

Crossing-over

Question 20

What is paracentric inversion?

Answer 20

Theres a break in the chromosome and this broken piece is inverted
Occurs in middle of chromosome

Question 21

How can 2 chromosomal abnormalities occur?

Answer 21

Caused by a mutual exchange of information between non-homologous pairs
If this is balanced, it does not affect the carrier but may affect all offspring

Question 22

What are 2 types of chromosomal deletions?

Answer 22

Microscopic- easily detected by microscope
e.g. Cri-du-chat syndrome 46,X,Y,del

Microdeletion- seen in high resolution banding
e.g. velocardiofacial/ Digeorge syndrome 22q11.2 del

Question 23

What is Williams syndrome?

Answer 23

7q11.23 deletion
Long philtrum
Short, upturned nose
Supravascular aortic stenosis
Friendly personality, absence of social anxiety
Phenotypes caused by imbalance of genes which are unrelated apart from their location
Deletion is it too small to detect using standard karyotyping
Can be detected using large FISH (fluorescent in situ hybridisation)
Lack of elastin on all affected chromosomes

Question 24

What is duplication syndrome?

Answer 24

7q11.23 duplication
Delayed speech development
Autistic behaviours that affect social interactions
Dilation of aorta
Flat eyebrows
Broad nose and short philtrum
Duplications usually have milder phenotype that reciprocal deletion

Question 25

What are the classes of chromosomes?

Answer 25

Metacentric
Submetacentric
Acrocentric (chromosomes 13, 14, 15, 21 and 22)

Question 26

What is Robertsonian translation?

Answer 26

Occurs between acrocentric chromosomes
Can be homologous or non-homologous
Most common 13 and 14, 14 and 15, 14 and 21
Most people unaffected
Can cause problem in offspring

Question 27

What is mosaicism?

Answer 27

Presence of 2 or more populations of cells with different genotypes
X-inactivation results in mosaic expression

Question 28

What 2 mechanisms can cause mosaicism?

Answer 28

Non-disjunction in early development

Loss of extra chromosome in early development