Genetic Testing Flashcards
What is the testing timeline in a normal pregnancy?
- Positive pregnancy test – no longer confirmed at GP
- Nuchal scan – 10-14 weeks gestation. Different tests dependent upon NHS Trust e.g. nuchal translucency, combined test etc.
- Mid-trimester anomaly scan
Ultrasound examination is the main method for prenatal diagnosis of foetal abnormalities. All pregnant women should be offered routine ultrasound scans at 11-14 weeks and again at 20-22 weeks.
What are the aims of the nuchal scan?
- To date the pregnancy accurately.
- To diagnose multiple pregnancy.
- To diagnose major foetal abnormalities.
- To diagnose early miscarriage.
- To assess the risks of Down Syndrome and other chromosomal abnormalities.
Test takes into account the maternal age, blood hormone levels, nuchal translucency thickness, nasal bone, blood flow through the fetal heart and fetal abnormalities. Nuchal translucency is a screening test and not diagnostic but an increased NT can indicate many different genetic syndromes.
What an increased nuchal translucency mainly indicate?
More than 3mm can indicate:
- Chromosome abnormalities
(e.g. Downs, Edwards, Patau, Turners)
NT + maternal age detects up to 75% of Down syndrome with 5% false positive rate - Birth defects:
Cardiac anomalies, Pulmonary defects (diaphragmatic hernia), Renal defects, Abdominal wall defects - Skeletal dysplasias
There are many genetic syndromes seen with increased NT
When is a mid-trimester scan 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(s) carrier of chromosome rearrangement/abnormality or genetic condition, e.g. t(13;14), DMD, HD.
- Family history of genetic condition
What are the aims of prenatal testing?
- To inform and prepare parents for the birth of an affected baby/To be prepared for complications at or after birth
- To allow in utero treatment
- Manage the remainder of the pregnancy
- To allow termination of an affected fetus
What are the different prenatal tests?
1) Scanning
Ultrasound / MRI
2) Non-invasive
Maternal blood test
Cell-free fetal DNA
3) Invasive
Chorionic villus sampling (CVS)
Amniocentesis
What are the 5 types of scans during pregnancy?
- Early/Dating scan
- Nuchal translucency and nasal bone - examination of fetal profile increases sensitivity of screening for Down’s syndrome
- High level/anomaly scan - examination of fetal face done at 18-20 weeks
- Fetal MRI - done at 20 weeks+
- Fetal cardiac scan
What is maternal serum screening?
Tests maternal serum markers in the blood to detect increased risk of fetal trisomy 21, trisomy 18 and/or neural tube defects.
1st trimester maternal serum screening (with nuchal translucency measurement) done at 11-14 weeks
Measures: [hCG, PAPP A]
2nd trimester maternal serum screening (triple screen) done at 16-20 weeks
Measures: [AFP, uE3, hCG]
What is non-invasive prenatal diagnosis?
Works by analysing the DNA fragments present in the maternal plasma during pregnancy (cell-free DNA). Most of this DNA comes from the mother but 10%-20% of it comes from the placenta, which is representative of the unborn baby (cell-free fetal DNA).
Cell-free fetal DNA (cffDNA) is first detectable from about 4 -5 weeks’ gestation, but cannot accurately be detected on testing until around 9 weeks. cfDNA are short DNA fragments and in trisomy 21, greater than normal amounts of foetal DNA for chromosome 21 present.
What conditions are tested in a maternal blood test at around 9 weeks?
Achondroplasia, Thanatophoric dysplasia and Apert syndrome
Why is sexing done early on in the pregnancy?
Currently offered when there is a X-linked condition in the family e.g. DMD. Test detects SRY gene on Y chromosome, enabling us to determine if male or female fetus
If male: go on to prenatal test
If female: no invasive test required
What aneuploidy conditions does cffDNA currently test for?
T13, T18, T21 and this identifies:
99% of fetuses with trisomy 21
97% of fetuses with trisomy 18
92% of fetuses with trisomy 13.
What are the limitations of NIPD?
- Multiple pregnancies - It is not possible to tell which fetus the DNA is from when carrying twins/triplets etc. - so only used with singleton pregnancies
- The relative proportion of cell-free fetal DNA is reduced in women with a high BMI as they have more of their own cell-free DNA.
- Although it is just a blood test, it has the same implications as an invasive test.
Women may prepare themselves more for the implications of an invasive test result
Women must consider the consequences of the results. Do they want this information? - An invasive test may still be required to confirm an abnormal result.
What are the benefits of NIPD and NIPT?
- The number of invasive tests carried out is likely to reduce as a result
- There is no increased risk of miscarriage.
- Less expertise is required to perform a blood test than an invasive test.
- In many cases we can offer NIPD /NIPT earlier than traditional invasive testing, thereby getting a result much earlier.
What is chorionic villus sampling, when is it carried out, how is it carried out and what are the risks?
Carried out at 11-14 weeks. 1-2% risk of miscarriage (lower in specialist centres e.g. UCH, Chelsea and Westminster appx 1 in ) - risk is higher because the foetus is smaller. Carried out transabdominally or transvaginally.
Takes sample of chorionic villi – part of developing placenta – same DNA as fetus
Allows patient to have an earlier result than amnio - important for many patients re. abortion
What is amniocentesis and what are its risks?
Another invasive testing method. Carried out from 16 weeks. Involves taking sample of amniotic fluid which contains fetal cell. Up to 1% risk of miscarriage, risk of infection and Rh sensitisation.
What tests are done with the DNA collected from invasive test methods?
Test for the genetic disorder in question - Timing for results dependent upon condition
1. Karyotype if chromosomal abnormality in family
Results 2 weeks (dependent upon the cells growing)
- QF-PCR for all:
We send samples to Guy’s Hospital laboratory
Looks for t13, 18 & 21 (plus sex chromosomes if sex chromosome disorder suspected)
Result within 24-48 hours
What does a CGH array do?
If there are concerns on 20 week scan the gold standard is to offer CGH array. Looks for small/large imbalances in chromosomes (picks up microdeletions and duplications). If anything found, parents can be tested to check for carrier genes and provide a clearer picture.
What is exome sequencing and when is it used?
Consider where fetus in previous pregnancy had significant anomalies e.g. heart, brain, skeletal or where baby has been born with developmental delay, dysmorphic features (and array normal). Exome is the coding region of the genome. Take DNA from fetus/baby and parents.
What are the different options for family planning where there is a known risk?
- Conceive naturally, no prenatal testing
- Conceive naturally, have prenatal testing
- Use of egg and/or sperm donors
- Adoption
- Choose not to have children
- Pre-implantation genetic diagnosis (PGD)
What are the options for egg and sperm donation?
- No longer anonymous, children conceived have the right to contact donor when 18
- Best to go through a UK HFEA licensed fertility centre – conform to strict medical, ethical and legal standards
- Can privately find own donor
- Some couples may consider going abroad
What are the 2 stages of adoption?
- Registration and checks
Registering interest with adoption agency
Medical and criminal background checks; three written references
Usually takes ~2 months - Assessment and approval
Home visits by social worker
Compilation of ‘prospective adopters report’, taken to adoption panel
Panel review information and make a decision whether a couple is suitable to adopt
Takes ~4 months
When is pre-implantation genetic diagnosis used?
Uses IVF with an additional step to genetically test the embryo before implantation.
PGD is particularly used by people who do not want TOP.
PGD not always an easy option:
1. Emotional and physical implications
2. Can be lengthy process
3. Success rates ~30% per cycle; ~40% per embryo transfer
What is PGD used?
Patients use PGD for many genetic disorders
1. Translocation carriers
2. HD
3. DMD – can only implant female embryos (where mutation in family is unknown)
4. CF
5. BRCA1/2
PGD is now nationally funded and a licence is required from the HFEA for each genetic condition or indication
