Lecture 25: Genetic Testing

Question 1

What happens in a ‘normal’ pregnancy?

Answer 1

• positive pregnancy test (no longer confirmed at GP)
• book into antenatal care (see midwife)
• nuchal scan, 10-14 weeks gestation, diff tests dependent on trust
• mid-trimester anomaly scan
• ultrasound examination

Question 2

What is the main method for prenatal diagnosis of foetal abnormalities?

Answer 2

ultrasound examination

Question 3

When should pregnant women be offered routine ultrasound scans?

Answer 3

11-14 weeks and again at 20-22 weeks

Question 4

What are the aims of the 12 week scan?

Answer 4

1) to date pregnancy accurately
2) to diagnose multiple pregnancy e.g. twins
3) to diagnose major foetal abnormalities
4) to diagnose early miscarriage
5) to assess risks of Down syndrome and other chromosomal abnormalities

Question 5

What is taken into account in the 12 week scan?

Answer 5

• maternal age
• blood hormone levels
• nuchal translucency thickness
• nasal bone
• blood flow through foetal heart and foetal abnormalities

Question 6

What is nuchal translucency (NT)?

Answer 6

thickness of fluid at back of foetal neck

Question 7

What can increased nuchal translucency over 3mm indicate?

Answer 7

• Chromosome abnormalities e.g. Down’s syndrome, NT + maternal age detects 75% of Down syndrome w/5% false positive rate
• Birth defects e.g. cardiac anomalies, pulmonary defects, renal defects, abdominal wall defects
• Skeletal dysplasias, bones fragile

Question 8

What is important to remember about NT?

Answer 8

It is a screening test and is not diagnostic

Question 9

When is prenatal testing arranged?

Answer 9

• following abnormal findings at nuchal scan or mid-trimester scan
• following results of combined test which give an increased risk of Down syndrome
• if previous pregnancy affected with a condition e.g. DS, CF
• if parent carrier of chromosome rearrangement or genetic condition
• family history of genetic condition

Question 10

What are the aims of prenatal testing?

Answer 10

• to inform + prepare parents for birth of an affected baby
• to allow in utero treatment
• manage remainder of pregnancy
• be prepared for complications at or after birth
• allow termination of an affected foetus

Question 11

What are the 3 types of prenatal tests?

Answer 11

1) Scanning (ultrasound, MRI)
2) Non-invasive (maternal blood test, cell-free foetal DNA)
3) Invasive (chorionic villus sampling, CVS, amniocentesis)

Question 12

When might a foetal MRI take place?

Answer 12

Usually around 20 weeks+

Question 13

What is maternal serum screening?

Answer 13

Tests maternal serum markers in blood to detect increased risk of foetal trisomy 21, trisomy 18, and/or neural tube defect
Certain hormones measured at certain stages of pregnancy

Question 14

When does the 1st trimester maternal serum screening (w/NT measurement) take place?

Answer 14

11-14 weeks

Question 15

When does the 2nd trimester maternal serum screening (triple screen) take place?

Answer 15

16-20 weeks

Question 16

How does cell-free foetal DNA (cffDNA) work?

Answer 16

Some of mother’s blood contains DNA from foetus. Works by analysing the DNA fragments present in the maternal plasma during pregnancy

Question 17

When is cffDNA first detectable?

Answer 17

from about 4-5 weeks gestation

Question 18

When can cffDNA accurately be detected on testing?

Answer 18

Around 9 weeks

Question 19

What happens to the amount of cffDNA in trisomy 21?

Answer 19

amount of cffDNA for chromosome 21 is higher than normal

Question 20

What is NIPD?

Answer 20

Non-invasive prenatal diagnosis - maternal blood test at around 9 weeks of pregnancy

Question 21

For what 3 conditions is NIPD testing free?

Answer 21

• Achondroplasia
• Thanatropic dysplasia
• Apert syndrome

Question 22

When is sexing offered?

Answer 22

When there is a X-linked condition in the family e.g. DMD

Question 23

What does a sexing test detect?

Answer 23

Test detects SRY gene on Y chromosome, enabling us to determine if male of female foetus:

• MALE –> go on to prenatal test
• FEMALE –> no invasive test required

Question 24

What are some limitations of NIPD and NIPT?

Answer 24

• multiple pregnancies - not possible to tell which foetus the DNA is from if twins or triplets
• relative proportion of cffDNA reduced in women with high BMI as have more own cffDNA
• same implications as invasive test
• invasive test may still be required to confirm abnormal result

Question 25

What are the benefits if NIPD and NIPT?

Answer 25

• no. invasive tests carried out is likely to reduce as result
• no increased risk of miscarriage
• less expertise required
• in many cases we can offer NIPD/NIPT earlier than traditional invasive testing, so get earlier result

Question 26

When are invasive tests offered?

Answer 26

If there is a ‘known risk’

Question 27

What is chorionic villus sampling (CVS)?

Answer 27

Take sample of chorionic villi - part of developing placenta - same DNA as foetus

Question 28

What 2 ways can CVS samples be taken?

Answer 28

Transabdominal or transvaginal

Question 29

What can CVS allow?

Answer 29

Earlier result than amniocentesis which is important for many patients re. TOP decision

Question 30

At what stage is CVS done?

Answer 30

11-14 weeks

Question 31

What is amniocentesis?

Answer 31

Small needle used to collect amniotic fluid which contains foetal cells

Question 32

When is amniocentesis done?

Answer 32

From 16 weeks

Question 33

What risks are there from amniocentesis?

Answer 33

• up to 1% risk of miscarriage
• infection
• Rh sensitisation

Question 34

What tests are done with the DNA sample from invasive testing?

Answer 34

• test for genetic disorder in question
• karyotype if chromosomal abnormality in family (results 2 weeks dependent on cells growing)
• QF-PCR for all (looks for t13, 18 and 21 + sex chromosomes if chromosome disorder suspected) - result within 24-48 hours

Question 35

What happens if there are concerns on 20 week scan?

Answer 35

CGH array (comparative genomic hybridization)

Question 36

What does CGH array look for?

Answer 36

Looks for small/large imbalances in chromosomes (picks up microdeletions and duplications)

Question 37

What happens if something is found on CGH array?

Answer 37

Standardly test parents to see if either is a carrier - this can help with interpretation

Question 38

What is the exome?

Answer 38

The coding region of the genome

Question 39

What is trio exome/ whole exome sequencing?

Answer 39

Sequencing all the exons in a person’s genome

Question 40

When is trio exome used?

Answer 40

Considered where foetus in previous pregnancy had significant abnormalities e.g. heart, brain, skeletal or where baby has been born with developmental delay, dysmorphic features (and array normal)

Question 41

When there is a known reproductive risk, what are the options for family planning?

Answer 41

• conceive naturally, no prenatal testing
• conceive naturally, have prenatal testing
• use of egg/sperm donors
• adoption
• choose not to have children
• pre-implantation genetic diagnosis (PGD)

Question 42

What is pre-implantation genetic diagnosis (PGD)?

Answer 42

uses IVF with an additional step to genetically test the embryo before implantation
particularly used by people who don’t want TOP

Question 43

What is the process of PGD?

Answer 43

1) stimulation of ovaries
2) egg collection
3) insemination
4) fertilisation
5) embryo biopsy
6) embryo testing
7) embryo transfer
8) pregnancy test

Question 44

What is PGD used for?

Answer 44

Many genetic disorders:

• translocation carriers
• HD
• DMD (only implant female embryos)
• CF

Question 45

What is the role of a gynaecologist in prenatal testing?

Answer 45

• arrange and explain CVS, amniocentesis, PGD and cffDNA
• facilitate decision-making
• give results
• see patients in clinic following a diagnosis in utero
• arrange termination if necessary
• discuss recurrence risk and plans for future pregnancies