Lecture 25: Genetic Testing Flashcards
What happens in a ‘normal’ pregnancy?
- 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
What is the main method for prenatal diagnosis of foetal abnormalities?
ultrasound examination
When should pregnant women be offered routine ultrasound scans?
11-14 weeks and again at 20-22 weeks
What are the aims of the 12 week scan?
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
What is taken into account in the 12 week scan?
- maternal age
- blood hormone levels
- nuchal translucency thickness
- nasal bone
- blood flow through foetal heart and foetal abnormalities
What is nuchal translucency (NT)?
thickness of fluid at back of foetal neck
What can increased nuchal translucency over 3mm indicate?
- 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
What is important to remember about NT?
It is a screening test and is not diagnostic
When is prenatal testing arranged?
- 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
What are the aims of prenatal testing?
- 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
What are the 3 types of prenatal tests?
1) Scanning (ultrasound, MRI)
2) Non-invasive (maternal blood test, cell-free foetal DNA)
3) Invasive (chorionic villus sampling, CVS, amniocentesis)
When might a foetal MRI take place?
Usually around 20 weeks+
What is maternal serum screening?
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
When does the 1st trimester maternal serum screening (w/NT measurement) take place?
11-14 weeks
When does the 2nd trimester maternal serum screening (triple screen) take place?
16-20 weeks
How does cell-free foetal DNA (cffDNA) work?
Some of mother’s blood contains DNA from foetus. Works by analysing the DNA fragments present in the maternal plasma during pregnancy
When is cffDNA first detectable?
from about 4-5 weeks gestation
When can cffDNA accurately be detected on testing?
Around 9 weeks
What happens to the amount of cffDNA in trisomy 21?
amount of cffDNA for chromosome 21 is higher than normal
What is NIPD?
Non-invasive prenatal diagnosis - maternal blood test at around 9 weeks of pregnancy
For what 3 conditions is NIPD testing free?
- Achondroplasia
- Thanatropic dysplasia
- Apert syndrome
When is sexing offered?
When there is a X-linked condition in the family e.g. DMD
What does a sexing test detect?
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
What are some limitations of NIPD and NIPT?
- 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
What are the benefits if NIPD and NIPT?
- 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
When are invasive tests offered?
If there is a ‘known risk’
What is chorionic villus sampling (CVS)?
Take sample of chorionic villi - part of developing placenta - same DNA as foetus
What 2 ways can CVS samples be taken?
Transabdominal or transvaginal
What can CVS allow?
Earlier result than amniocentesis which is important for many patients re. TOP decision
At what stage is CVS done?
11-14 weeks
What is amniocentesis?
Small needle used to collect amniotic fluid which contains foetal cells
When is amniocentesis done?
From 16 weeks
What risks are there from amniocentesis?
- up to 1% risk of miscarriage
- infection
- Rh sensitisation
What tests are done with the DNA sample from invasive testing?
- 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
What happens if there are concerns on 20 week scan?
CGH array (comparative genomic hybridization)
What does CGH array look for?
Looks for small/large imbalances in chromosomes (picks up microdeletions and duplications)
What happens if something is found on CGH array?
Standardly test parents to see if either is a carrier - this can help with interpretation
What is the exome?
The coding region of the genome
What is trio exome/ whole exome sequencing?
Sequencing all the exons in a person’s genome
When is trio exome used?
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)
When there is a known reproductive risk, what are the options for family planning?
- 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)
What is pre-implantation genetic diagnosis (PGD)?
uses IVF with an additional step to genetically test the embryo before implantation
particularly used by people who don’t want TOP
What is the process of PGD?
1) stimulation of ovaries
2) egg collection
3) insemination
4) fertilisation
5) embryo biopsy
6) embryo testing
7) embryo transfer
8) pregnancy test
What is PGD used for?
Many genetic disorders:
- translocation carriers
- HD
- DMD (only implant female embryos)
- CF
What is the role of a gynaecologist in prenatal testing?
- 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
