Genetic Testing (pregnancy)

Question 1

What are the testing steps in a normal pregnancy?

Answer 1

Positive pregnancy test

Book into antenatal care

Nuchal scan - 10-14 weeks gestation. Different tests, eg. Nuchal translucency, combined test. Hormone levels tested, nuchal fold (back of neck of baby) is tested. Also risk figure for downs is also calculated (higher than 1/150 is high)

Mid trimester anomaly scan - all women offered one at 11-14 and 20-22 weeks

Question 2

What are the aims of the 12 week scan?

Answer 2

To date the pregnancy accurately

Diagnose multiple pregnancy

Diagnose major foetal abnormalities

Diagnose early miscarriage

Assess the risk of Down syndrome and other chromosomal abnormalities

Question 3

What is the nuchal translucency?

Answer 3

Done at 10-14 weeks

The thickness of fluid at the back of the foetal neck

Less than 3mm is normal, anything higher can indicate: chromosomal abnormalities (downs, patau, turners) Boeth defects (cardiac abnormalities, pulmonary defects, renal and abdominal wall defects) Skeletal dysplasia

Screening, not diagnostic

Question 4

When is prenatal testing arranged?

Answer 4

Following abnormal findings at nuchal or mid trimester scan

Following results of combined test which give an increased risk of downs

If previous pregnancy affected with a condition

If parents carrier of chromosome rearrangement or genetic condition

FH or genetic condition

Question 5

What are the aims of prenatal testing?

Answer 5

To inform and prepare parents for the north of an affected baby

To allow in utero treatment

Manage the remainder of the pregnancy

Be prepared for complications after birth

Allow the termination of an affected foetus

Question 6

What is cell free foetal DNA (cffDNA)?

Answer 6

Non invasive prenatal diagnosis (NIPD) works by analysing the DNA fragments present in the maternal plasma during pregnancy

Most of this DNA comes from the mother (cell free DNA)

10-20% of it comes from the placenta, which is representative of the unborn baby (cell free foetal DNA)

cffDNA is first detectable from about 4-5 weeks gestation but cannot be accirately detected till around 9 weeks.

Question 7

What is the NIPD?

Answer 7

Non invasive prenatal diagnosis

Done at 9 weeks

Can test for some genetic diseases, such as achondroplasia, thanatophoric dysplasia and apert syndrome

Can also be used for sexing. It is offered when there is an X linked condition in the family (eg. Duchenne muscular dystrophy). The test detects the SRY gene on the Y chromosome

Question 8

How is cffDNA testing used to test for aneuploidy?

Answer 8

Tests for T13, T18 and T21

It identifies 92% with triaonomy 13, 97% woth trisonomy 18 and 99% with trisonomy 21

Offered privately or through research studies

Not diagnostic. Just a test so NIPT

Question 9

What are the limitation of NIPD and NIPT?

Answer 9

Multiple pregnancies - not possible to tell which foetus the DNA comes from

The relative proportion of cffDNA is reduced in women with a high BMA as they have more of their own cf DNA

Although it’s just a blood test, women must still consider the magnitude of the results

An invasive test may still be required to confirm an abnormal result

Question 10

What are the benefits of NIPD and NIPT?

Answer 10

The number of invasive tests carried out is likely to reduce

No increased risk of miscariage

Less expertise is required to carry out the test

Can be offered earlier than invasive tests so gives earlier results

Question 11

When are invasive tests offered?

Answer 11

If there is a known risk of a disease

Question 12

What are the two invasive tests?

Answer 12

Chorionic Villus Sampling (CVS) - tests a small bit of tissue from the placent

Amniocentesis - tests the fluid around the developing baby

Molecular, cytogenic and biochemical tests are carried out with both

They are done on an outpatient basis

Both involve ultrasound guidance

Question 13

What is a CVS?

Answer 13

Chorionic villus sample

11-14 weeks

1-2% of miscarriage

Trans abdominal or transvaginal

Takes sample of chorionic villi - part of developing placenta - same DNA as baby

Gives an earlier result than an amino. Important for decisions around termination of pregnancy

Question 14

What is an amniocentesis?

Answer 14

Takes place at 15-16 weeks

Takes sample of amniotic fluid which contains foetal cells

Up to 1% risk of miscarriage

Small risk of infection and Rh sensitisation

Question 15

What tests are done to the DNA sample from an amino or CVS?

Answer 15

Test for the genetic disorder in question

Test for the karyotype if there’s a chromosomal abnormality in the family - takes 2 weeks

QF-PCR for all. Looks for t13,18 and 21 and maybe sex chromosomes - results in 24-48 hours

Question 16

What is a CGH array?

Answer 16

Done if there are concerns on the 20 weeks scan

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

If something is found the parents are tested to see if either is a carrier. This can help to determine phenotype

Question 17

What is trio exome testing?

Answer 17

Very new. Only made available in October 2020

Can try to explain why a baby has developmental defects but doesn’t necessarily always give results

Exome is the coding region of the genome. DNA is taken from foetus/baby and parents

Question 18

What are the reproductive options when there is a known reproductive risk?

Answer 18

Conceive naturally with no prenatal testing

Conceive naturally with prenatal testing

Use an egg and/or sperm donor

Adoption

Choose not to have children

Pre implanatation genetic diagnosis (PGD)

Question 19

What is egg or sperm donation?

Answer 19

In the name

No longer anonymous. Children have a right to contact the donor when they are 18. This has led to a decrease in donors

Best to go through a licensed UK fertility center. But can get a private donor or go abroad

Question 20

What happens in adoption?

Answer 20

1. Registration and checks

Registering interest with agency. Medical and criminal checks, three written references. Usually takes around 2 months

2. Assessment and approval

Home visits by social worker. Report taken to adoption panel. Panel review about suitability to adopt. Takes around 4 months

Question 21

What is pre implantation genetic diagnosis?

Answer 21

PGD

Uses IVF with ana additional step to genetically test the embryo before implantation

Used particularly by people who do not want termination of pregnancy

Question 22

What is the process of PGD?

Answer 22

Stimulation of the ovaries

Egg collection

Insemination (sperm injected into egg (ICSI))

Fertilisation

Embryo biopsy at blastocyst stage

Embryo testing

Embryo transfer

Pregnancy test

Question 23

What is the eligibility criteria for PGD?

Answer 23

Female is under 39 and must have a normal BMI

Both parents non smokers

Living together in a stable relationship

No living unaffected children from the relationship

Known risk of children having a serious genetic condition

Female must have hormone levels suggesting she will respond to treatment

Question 24

What is the role of a genetic counsellor in prenatal testing?

Answer 24

Arrange and explain CVS, amniocentesis, PGD, cffDNA

Facilitate decision making

Give results

See patients in clinic following diagnosis in utero

Arrange termination if necessary

Discuss recurrence risks and plans for future pregnancies