18. Chromosome Abnormalities

Question 1

How is DNA packaged?

Answer 1

Wrapped round an octamer of histones. 166 base pairs per octamer and histone H1 stabilises. Higher order structures are then stabilised by hanging loops of DNA on a protein scaffold - chromatin.

Question 2

What form of chromatin is active for genes to be expressed?

Answer 2

Euchromatin is the active form.

Question 3

How does chromatin switch between its active and inactive forms?

Answer 3

By epigenetic modification. Activates by methylation and deactivated by demethylation.

Question 4

What does chromosome analysis require?

Answer 4

A source of living cells for in vitro growth. The cells are cultures, accumulated at metaphase and harvested.

Question 5

Which samples are cultures in suspension and which are grown on substrate from the following?

a. Bone marrow
b. Amniotic fluid
c. CVS
d. Solid tissue
e. Blood

Answer 5

a. Suspension
b. Substrate
c. Substrate
d. Substrate
e. Suspension.

Question 6

What is karyotyping?

Answer 6

The systematic sorting of chromosomes.

Question 7

What do the following mean?

a. Metacentric
b. Sub-metacentric
c. Acrocentric.

Answer 7

a. The p and q arms of the chromosome are of equal length and the centromere is in the middle.
b. The p arm is shorter than the q arm as the centromere is nearer the top/ p arm.
c. The p is very short and has no euchromatin material in it so no genes of importance. The q arm is far longer.

Question 8

How are chromosomes grouped?

Answer 8

By size (in increasing size) and groups A-G by shape.

Question 9

How are G-band chromosomes dyed?

Answer 9

Metaphases exposed to trypsin, which digests proteins. Stained with Romanowski type dye. This produces dark G positive bands (AT rich and gene poor) and light G negative bands (GC rich and gene rich).

Question 10

How does automated karyotyping work?

Answer 10

The slides are scanned automatically by a microscope and images are taken. Digital karyotypes are made from the images. The chromosomes are paired up on the screen fro analysis.

Question 11

What is a problem with automated karyotyping?

Answer 11

It is very expensive.

Question 12

What details are given on a chromosome report?

Answer 12

The chromosome number, sex complement and structural changes.

Question 13

How would the following chromosomal information be written in ISCN form?
A normal female with trisomy 21.

Answer 13

47,XX,+21

Question 14

What does the following mean in words from the ISCN form?

46,XY,inv(7),(p11.2q11.23)

Answer 14

A male with a chromosome 7 inversion at the break points 11.2 on the short, p arm and 11.23 on the long, q arm.

Question 15

What are some uses of cytogenic analysis?

Answer 15

For accurate diagnosis/prognosis of clinical problems (identifies the syndrome, accounts for phenotype and pregnancy loss), for better clinical management, to assess future reproductive risks and for prenatal diagnosis.

Question 16

Give brief details of chorionic villus sampling.

Answer 16

11-12 weeks gestation, 1.2% risk of miscarriage, under ultrasound guidance to minimise this risk.

Question 17

Give brief details of amniocentesis.

Answer 17

15 weeks + gestation. 0.8% risk of miscarriage, under ultrasound guidance to minimise this risk.

Question 18

How is Down syndrome screened for prenatally?

Answer 18

Maternal serum screening, first trimester screening, family history abnormality, ultrasound scan and DNA studies.

Question 19

What is Williams syndrome cause by?

Answer 19

Deletion 7q11.23.

Question 20

What does a deletion at 22q11.2 cause?

Answer 20

DiGeorge syndrome - heartflow defects.

Question 21

Define aneuploidy.

Answer 21

Loss or gain of whole chromosomes.

Question 22

What causes aneuploidy?

Answer 22

Errors at cell division in meiosis. Non-disjunction at one of the meiotic cell divisions so forms gametes with a missing chromosome (monosomy) and an extra chromosome (trisomy). Or in mitotic cell division this causes mosaicism, two cell populations in an individual.

Question 23

What three trisomies are viable?

Answer 23

Down syndrome +21, Patau syndrome +13 and Edwards +18.

Question 24

What monosomy is viable?

Answer 24

Turner syndrome, 45X.

Question 25

What is polyploidy?

Answer 25

The gain of a whole haploid set of chromosomes. Triploidy 3n, 69XXX.

Question 26

What causes polyploidy?

Answer 26

Polyspermy most commonly, the egg is fertilised by more than one sperm.

Question 27

What is anaphase lag?

Answer 27

Chromosomes are left behind at cell division because of defects in spindle function or attachment to chromosomes. The chromosome may be lost entirely in mitosis or meiosis.

Question 28

What are the clinical features of Down syndrome (trisomy 21)?

Answer 28

Hypotonia (floppy baby - low muscle tone), characteristic facial features, heart defects, intellectual disability.

Question 29

What is the frequency of Down syndrome?

Answer 29

1:650-1000

Question 30

What are the clinical features of Edwards syndrome (trisomy 18)?

Answer 30

Small lower jaw, prominent occiput, low-set ears, rocker bottom feet, overlapping fingers.

Question 31

What is the frequency of Edwards syndrome?

Answer 31

1:6000, with female predominance.

Question 32

What is the modal lifespan of Edwards syndrome?

Answer 32

5-15 days.

Question 33

What are the clinical features of Patau syndrome (trisomy 13)

Answer 33

Multiple congenital abnormalities, polydactyl, holoprosencephaly.

Question 34

What is the incidence of Patau syndrome?

Answer 34

1:12000

Question 35

What is the lifespan of Patau syndrome?

Answer 35

Majority die in neonatal period (first four weeks after delivery).

Question 36

What are the clinical features of Turner syndrome (45,X)?

Answer 36

Short stature, heart defects, mild learning difficulties, infertility, puffy feet and redundant skin at the back of the neck.

Question 37

What causes Turner syndrome?

Answer 37

Absent paternal X.

Question 38

What is the incidence of Turner syndrome?

Answer 38

1:2500

Question 39

What is X inactivation?

Answer 39

Only one X chromosome is ever active in a human cell, in a female, they have two X chromosomes. X inactivation ensures individual have the same X chromosome complement that is active.

Question 40

Why is single X activation a problem?

Answer 40

Males only have one X chromosome but the X and Y chromosomes have short regions in common at the tips of the p and q arms. The PAR1 and PAR2 regions are essential for meiosis pairing.

Question 41

What is mosaicism?

Answer 41

Presence of two or more cell lines in an individual, normally from mitotic non-disjunction.

Question 42

What is uniparental disomy?

Answer 42

The presence of homologous chromosomes from one parent.

Question 43

Define isodisomy.

Answer 43

2 identical chromosomes from one parent.

Question 44

Define heterodisomy.

Answer 44

2 homologous chromosomes from one parent.

Question 45

What is segmental uniparental disomy?

Answer 45

Only part of the chromosome is involved.

Question 46

Why is uniparental disomy a problem?

Answer 46

When it comes to imprinting. Imprinted chromosomes show differential expression of specific genes depending on their parental origin.

Question 47

What are two UPD syndromes?

Answer 47

Prader-Willi/Angelman syndrome (15) and Russell-Silver/Beckwith-Wiedemann (11).

Question 48

What are the four origins of UPD?

Answer 48

Trisomy rescue (commonest), monosomy rescue, gamete complementation and mitotic error.

Question 49

Explain how trisomy rescue can lead to UPD.

Answer 49

A disomic and monosomic gamete form a trisomic conceptus. In postzygotic mitosis, a mitotic error means the monosomic gamete part is removed, leaving all the genetic material from the disomic gamete, hence the UPD embryo.

Question 50

How can UPD be tested for?

Answer 50

Molecular genetic testing, see whether inheritance is biparental - if not UPD is confirmed.