Genetic Testing

Question 1

• What is the main method for prenatal diagnosis of foetal abnormalities?
• Why might a Normal Nuchal scan be taken and when are they taken?

Answer 1

Ultrasound, one scan at 11-14 weeks and one at 20-22 weeks

To read the thickness of the fluid at the back of the neck

At 12 weeks and 20 weeks

Question 2

• What is the aim of the 12 week scan?

Answer 2

To date the pregnancy accurately

To diagnose multiple pregnancies

To diagnose major foetal abnormalities

To diagnose early miscarriage

To assess the risk of Down Syndrome and other chromosomal abnormalities

Question 3

• A thickness of fluid at the back of fetal neck of above 3mm can indicate what?

Answer 3

Chromosome abnormalities eg downs, turners

Birth defects

- Cardiac anomalies
- Pulmonary defects
- Renal defects
- Abdominal wall defects

Skeletal dysplasias

Question 4

• Is Nuchal Translucency a screening test or a diagnostic?

- When is prenatal testing arranged?

Answer 4

Screening test

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
If parent is a carrier of chromosome rearrangement or genetic condition
Family history of genetic condition

Question 5

• What are the aims of prenatal testing?

Answer 5

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

To allow in utero treatment

Manage remainder of pregnancy

To be prepared for complication at or after birth

To allow termination of  an affected fetus

Question 6

• Why is a Fetal MRI needed?

- Why is a fetal cardiac scan needed?

Answer 6

For more detailed scan to see organs more clearly

To look at flow of blood through body's heart to diagnose cardiac conditions

Question 7

• What is cffDNA?

- When can cffDNA be detected?

Answer 7

Cell-free fetal DNA
Short DNA fragments of baby
Floats around in mother’s blood from placenta & composed of baby’s DNA

First 4-5 weeks of gestation but cannot accurately be detected on testing until 9 weeks

Question 8

• What is NIPD?

- For which genetic conditions is NIPD free for?

Answer 8

Non-invasive prenatal diagnosis, analyses fragments of DNA present in maternal plasma during pregnancy (cell free DNA)
Maternal blood test at around 9 weeks of pregnancy

Achondroplasia
Thanatophoric dysplasia
Apert syndrome

Question 9

• What gene is detected to determine the sex of the fetus?

- How does this diagnose an X linked condition in the family?

Answer 9

SRY gene on the Y chromosome

If male - go on to prenatal test

If female- no invasive testing is required

Question 10

• For Cystic Fibrosis, what test is used to detect both maternal and paternal mutation in the fetal DNA?

Answer 10

Haplotyping

Question 11

• What are the limitations of NIPD and NIPT?

Answer 11

Not possible in multiple pregnancies to tell which DNA came from which fetus

Relative proportion of cffDNA is reduced in women with high BMI so 2nd sample may be needed after 9 weeks

Women may not be as prepared for the result as they would be for an invasive test

Invasive test may still be required to confirm an abnormal result

Question 12

• What are the benefits of NIPT and NIPD?

Answer 12

Number of invasive tests carried out is likely to reduce as a result

No increased risk of miscarriage

Less expertise required to perform blood test than invasive test

NIPD/NIPT can be offered earlier than traditional invasive testing, so result given earlier

Question 13

• What is CVS?

- How long until CVS can be carried out?

Answer 13

Sample of chorionic villi (part of developing placenta with same DNA as fetus) is taken transabdominally or transvaginally

Allowing patient to have result earlier than amniocentesis

11-14 weeks

Question 14

• How long until Amniocentesis can be carried out?
• What is Amniocentesis?
• What are the risks of Amniocentesis?

Answer 14

16 weeks

Sample of amniotic fluid which contains fetal cells is taken

Up to 1% risk of miscarriage

Infection

Rh Sensitisation

Question 15

• What tests are done with a DNA sample?

Answer 15

Test for genetic disorder in question

Karyotype if chromosome abnormality is present in the family history

QF-PCR for all

- Looks for trisomy 13, 18 and 21

Question 16

• What is CGH array?

- If something is found on the array, what happens next?

Answer 16

If there are concerns on 20 week scan, the gold standard is to offer CGH array

Look for small/large imbalances in chromosomes (microdeletions and duplications)

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

Question 17

• What are the 4 steps in carrying out a CGH array?

Answer 17

Extract DNA from test and from control sample and Label one with a red dye and the other with a green dye

Mix and Hybridise (bind) to a microassay with thousands of oligonucleotide probes, then wash

detect red and green signals with a fluorescent scanner  

    Analyse Data- compute and report gains/ losses of test DNA using software

Question 18

• What does a Trio Exome allow?
• What is an Exome?
• What is a Trio Exome?

Answer 18

Efficient diagnosis of genetic condition in utero

The coded region of DNA

Exome is taken from the baby and parents

full genetic sequencing. offered where previous pregnancies have had significant anomalies

Question 19

• What is a reason why are there fewer egg and sperm donors?

- What are the 2 stages that must be gone through when a couple want to adopt?

Answer 19

Donations are no longer anonymous and children conceived have the right to contact the donor when 18

Registration and checks- references, criminal checks

Assessment and approval- social worker visits home, a panel review couple

Question 20

• What is Pre-implantation Genetic Diagnosis?

- Who is PGD particularly used by?

Answer 20

PGD uses IVF with an additional step to genetically test the embryo before implantation

People who do not want TOP (termination of pregnancy)

Question 21

• Describe the process of PGD?

Answer 21

Stimulation of ovaries- hyperstimulation so many eggs removed

Egg collection

Insemination - intracytoplasmic sperm injection (ICSI) of only a single sperm to reduce contamination from more sperm cells

Fertilisation

Embryo biopsy- at the 8 cell stage 

Embryo testing - at blastocyst stage

Embryo transfer - of those that did not inherit the genetic condition into the womb

Pregnancy test

Question 22

• For which disorders is PGD used for?

Answer 22

Used for conditions caused by single faulty gene to reduce the amount of non embryo DNA (incl sperm DNA) which could make the risk of a wrong diagnosis higher

Translocation carriers
Huntingdons disease
Duchenne Muscular Dystrophy - only implant female embryos
Cystic Fibrosis