Prenatal Testing

Question 1

What is the most common autosomal chromosome defect at birth?

Answer 1

Trisomy 21

Question 2

Before genetic carrier screening, what is important to ask?

Answer 2

Family history

With recessive conditions, often no family history

Question 3

When is carrier screening best performed?

Answer 3

Pre-conception

Question 4

When is carrier screening often performed?

Answer 4

During pregnancy

Question 5

What is the relationship between maternal age and risk of Down syndrome?

Answer 5

Risk of having affected baby increases with maternal age

However, young maternal age also carries risk

Question 6

How can the majority of neural tube defects be prevented?

Answer 6

Taking folate supplements before and during pregnancy

Question 7

To whom are screening tests offered?

Answer 7

All pregnant women

Question 8

To whom are diagnostic tests offered?

Answer 8

Women who are at increased risk of having child with birth defect

Question 9

What does prenatal screening identify?

Answer 9

Subset of women, from general population, at increased risk of having child with birth defect

Question 10

Are prenatal screening tests definitive?

Answer 10

No, need to be followed up be followed up by specific diagnostic procedure

Question 11

What is first trimester combined screening?

Answer 11

Non-invasive prenatal testing/screening (NIPT/S)
Test for
- Trisomy 21
- Trisomy 18

Question 12

What is second trimester screening?

Answer 12

Test for

• Trisomy 21
• Trisomy 18
• Neural tube defects

Question 13

What happens in first trimester combined screening?

Answer 13

Blood taken at 9-13 weeks
- 2 biochemical analytes measured
Ultrasound performed at 11-13 weeks
- Nuchal translucency measured
- Crown rump length
Other factors; eg: maternal age
Algorithm calculates risk figure

Question 14

What is nuchal translucency?

Answer 14

Increased width of nuchal translucency associated with chromosomal abnormalities
- Especially trisomy 21
All babies have certain amount
Many resolve over time

Question 15

What are the risk cut-offs in first trimester combined screening?

Answer 15

Trisomy 21: 1 in 300

Trisomy 18: 1 in 175

Question 16

What happens in second trimester maternal serum screening?

Answer 16

Blood taken at 14-20 weeks
- 4 biochemical analytes measured
Other factors; eg: maternal age

Question 17

What are the risk cut-offs in second trimester maternal serum screening?

Answer 17

Trisomy 21: 1 in 250

Trisomy 18: 1 in 200

Question 18

How is NIPT/S done?

Answer 18

Uses cell-free foetal DNA in maternal blood
Massively parallel sequencing
Compare individual sequenced chromosome against reference for analysis
Detection of aneuploidy; eg: trisomy 21

Question 19

What are the two foetal sampling procedures used?

Answer 19

Chorionic villus sampling (CVS)

Amniocentesis

Question 20

Describe CVS

Answer 20

From 11 weeks gestation usually
Placental tissue
Ultrasound
Invasive
Risk of miscarriage 1% above background risk
If termination of pregnancy requested, dilatation and curettage under general anaesthetic (<16 weeks)

Question 21

Describe amniocentesis

Answer 21

15-16 weeks gestation usually
20mL of amniotic fluid containing sloughed off foetal cells removed
Ultrasound
Invasive
Risk of miscarriage 0.5% above background risk
If termination of pregnancy requested, by prostaglandin induction of labour (>16 weeks)

Question 22

what is fluorescence in situ hybridisation (FISH)?

Answer 22

DNA probe specific for something; eg: chromosome 21
Put probe on
Measure fluorescence
Count number of chromosomes
Increasingly used
Turn around time of 24-48 hours

Question 23

What is FISH used to test for?

Answer 23

Trisomy
- 13
- 18
- 21
XX and XY testing

Question 24

What is the gold standard for detecting chromosomal abnormalities?

Answer 24

Karyotyping

Question 25

What is karyotyping?

Answer 25

Looking in more detail at chromosomes | Take dividing cells > burst cells > stain > line up chromosome pairs > count them

Question 26

What is a balanced translocation?

Answer 26

Reciprocal translocation between 2 chromosomes No net gain/loss of function May not result in abnormal phenotype

Question 27

What is a Robertsonian translocation?

Answer 27

Translocation between 2 acrocentric chromosomes - 13 - 14 - 15 - 21 - 22

Question 28

How can an unbalanced translocation lead to trisomy 21 and therefore Down syndrome?

Answer 28

Balanced translocation between chromosomes 14 and 21 > carrier status Unbalanced translocation between chromosomes 14 and 21 > trisomy 21 - Extra 21 on a copy of chromosome 14

Question 29

How can Down syndrome be inherited?

Answer 29

Chromosomes in 1 possible gamete who is carrier of balanced translocation translocation + chromosomes in gamete from non-carrier parent Embryo is trisomic for chromosome 21: Down syndrome

Question 30

What are microarrays or DNA chips, and what can they be used for?

Answer 30

Can look at single nucleotide polymorphisms (SNPs) | Can look at larger changes - number of chromosomes and copy number variations (CNVs)

Question 31

How do chromosomal microarrays (CMAs) work?

Answer 31

``` Patient sample labelled with red fluorescent dye + normal control sample labelled with green fluorescent dye Mix together and apply to slide Hybridisation Microarray scanner Can measure deletion and duplications ```

Question 32

When should prenatal molecular karyotyping be performed?

Answer 32

Foetal abnormality identified on ultrasound scan Nuchal translucency measurement >3.5 mm Banded (classical cytogenetic) karyotype identifies complex change Family member has microdeletion syndrome and pregnancy at risk

Question 33

What is pre-implantation genetic diagnosis (PGD)?

Answer 33

Requires IVF 1-2 cells from dividing zygote at 8 cell stage Can do DNA testing if parents known carriers, FISH, and chromosomal microarrays Unaffected embryos implanted