Genetics

Question 1

What are the 3 types of foetal DNA sampling most commonly used in current practise?

Answer 1

• Non-invasive prenatal testing (NIPT)
• Chorionic villus sampling (CVS)
• Amniocentesis

Question 2

What is non-invasive prenatal testing (NIPT)?

Answer 2

Foetal DNA is obtained through a blood sample from the mother

(as cells from the placenta are shed into the mother’s bloodstream)

Question 3

What is chorionic villus sampling?

Answer 3

When chorionic villi are taken from the placenta for analysis of foetal DNA

Question 4

What is amniocentesis?

Answer 4

An invasive procedure where a small sample of amniotic fluid is extracted from the uterus

(as amniotic fluid contains shed foetal cells)

Question 5

At how many weeks gestation can...
- NIPT
- CVS 
- Amniocentesis 
... be carried out?

Answer 5

NIPT: 10 weeks +

CVS: 11.5 weeks +

Amniocentesis: 15 weeks +

Question 6

List these in order of highest to lowest miscarriage risk:

• NIPT
• CVS
• Amniocentesis

Answer 6

CVS > Amniocentesis > NIPT

Question 7

Why does NIPT have the lowest miscarriage risk?

Answer 7

It is non-invasive

Question 8

What are the pros and cons of NIPT?

Answer 8

Pros: Non-invasive so low miscarriage risk

Cons: Only 10% of the DNA comes from the foetus, the rest is maternal

Question 9

What are the pros and cons of CVS?

Answer 9

Pros: Can be carried out earlier than amniocentesis so can detect foetal abnormalities earlier, higher foetal DNA content than NIPT

Con: Invasive + higher miscarriage risk than amniocentesis

Question 10

What are the pros and cons of amniocentesis?

Answer 10

Pro: higher foetal DNA content than NIPT, can be used to confirm NIPT result

Con: invasive so increased miscarriage risk, carried out later than CVS

Question 11

When is NIPT indicated? (2)

Answer 11

Testing for chromosomal abnormalities (e.g., trisomies)

Sex determination (for determining risk of inheriting sex-linked disorder)

Question 12

When using NIPT for investigating a trisomy, what is a common reason for a false negative result?

Answer 12

Inadequate foetal fraction of DNA in the sample

Question 13

When using NIPT for investigating a trisomy, what are 2 common reasons for a false positive result?

Answer 13

Confined placental mosaicism

Maternal malignancy

Question 14

What is confined placental mosaicism?

Answer 14

When some cells in the placenta have a trisomy but the cells making up the foetus have a normal chromosome number

Question 15

List 3 trisomies that may be picked up on foetal DNA sampling

Answer 15

Down’s syndrome (trisomy 21)
Edwards’ syndrome (trisomy 15)
Patau’s syndrome (trisomy 13)

Question 16

If high levels of chromosome 21 are detected in maternal blood in NIPT, what is the risk of foetal Down’s syndrome?

Answer 16

99%+ (high sensitivity)

Question 17

How is diagnosis confirmed once a high risk NIPT result is obtained?

Answer 17

Amniocentesis

Question 18

When are invasive sampling tests (CVS/amniocentesis) indicated? (2)

Answer 18

For detecting chromosome abnormalities

For detecting single gene changes

Question 19

What is chromosome microarray?

Answer 19

A technique which lights up microdeletions or microduplications in chromosomal DNA

aka ArrayCGH

Question 20

What are the pros and cons of chromosome microarray (ArrayCGH)?

Answer 20

Pros: high resolution, quick, technically easier

Cons: also finds polymorphisms, can make incidental findings of other genetic abnormalities

Question 21

When is chromosomal analysis by chromosome microarray (arrayCGH) indicated? (3)

Answer 21

• If NIPT screening is positive (high risk of chromosomal trisomy)
• If there is foetal abnormality on scanning
• If a parent has a balanced chromosomal rearrangement

Question 22

List 3 foetal abnormalities that may be picked up on scanning

Answer 22

• Small size e.g., symmetrical growth failure
• Increased nuchal thickness (tissue at back of foetus’ neck)
• Structural malformation e.g., of brain or heart

Question 23

PCR sequencing can be used to identify…

Answer 23

Specific single gene changes

Question 24

What is a disadvantage of PCR?

Answer 24

You need to know the exact location of the gene you are looking for

Question 25

Next generation sequencing can be used to…

Answer 25

Sequence the entire genome or exome to identify the causative single gene mutation

Question 26

Parents are offered termination of pregnancy if their baby has a serious genetic abnormality. What method of TOP is offered at…

• <13 weeks
• 13 weeks +

Answer 26

• <13 weeks: medication or surgical termination

- 13 weeks +: labour induction TOP

Question 27

TOP of usually not permitted after ? weeks gestation

Answer 27

24

Question 28

In what cases can TOP be offered throughout the whole pregnancy (+24 weeks)? (2)

Answer 28

• If there is risk of serious abnormality in the child

- If there is serious risk to the mother’s health

Question 29

Suggest 3 chromosomal/genetic abnormalities that can cause hypotonia (i.e., a ‘floppy baby’)

Answer 29

• Down’s syndrome
• Prader-Willi syndrome
• Spinal muscular atrophy

Question 30

Hypotonia/floppy baby is caused by a defect in…

Answer 30

The communication pathway between the brain and muscles

so anywhere along the brain -> spinal cord -> nerves -> muscles pathway

Question 31

What other clinical signs may be seen in a baby with hypotonia (a floppy baby?) (4)

Answer 31

• Weakness
• Decreased deep tendon reflexes (DTR’s)
• Fasciculations (muscle twitches) or seizures
• Reduced alertness

Question 32

When would you carry out a creatine kinase test on a baby?

Answer 32

If concerned about a muscular disorder e.g., Duchenne muscular dystrophy

Question 33

Why may a baby with hypotonia need respiratory or feeding support?

Answer 33

Lack of tone means they can struggle to increase work of breathing and to suck to feed