Genetics Testing Flashcards
Prenatal Tests
- Scanning - Ultrasound, MRI
- Non-invasive
- Invasive - Chorionic villus sampling (CVS), Amnioncentesis
- Scanning - Ultrasound , MRI
· Ultrasound is the main method of diagnosing foetal abnormalities -
All pregnant women should be offered routine ultrasound scans at 11-14 weeks and again at 20-22 weeks.
Nuchal scan – 10-14 weeks gestation. Different tests dependent upon NHS Trust e.g. nuchal translucency, combined test etc.
Mid-trimester anomaly scan
Foetal MRI
Foetal cardia scan
- Non-invasive
- Maternal blood test
2. cffDNA - cell free foetal DNA
- Invasive
Offered if there is a ‘known risk’
- Chorionic villus sampling (CVS)
- Amniocentesis
- Molecular, cytogenetic and biochemical tests
- Ultrasound guidance
- Outpatient basis
Progression of a normal pregnancy
Positive pregnancy test – no longer confirmed at GP
Book into antenatal care – see midwife
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 12 weeks 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.
Taking into account the maternal age, blood hormone levels, nuchal translucency thickness*, nasal bone, blood flow through the fetal heart and fetal abnormalities.
Nuchal Translucency test
10-14 weeks
Thickness of fluid at back of fetal neck
Increased > 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:
1. Cardiac anomalies
2. Pulmonary defects (diaphragmatic hernia) 3. Renal defects
4. Abdominal wall defects - Skeletal dysplasias
There are many genetic syndromes seen with increased NT
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(s) carrier of chromosome rearrangement/abnormality or genetic condition, e.g. t(13;14), DMD, HD.
- Family history of genetic condition
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 foetus
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): 11-14 weeks [hCG, PAPP A]
- 2nd trimester maternal serum screening (triple screen): 16-20 weeks [AFP, uE3, hCG]
- Nuchal translucency measurement: 11-14 weeks
- Other variations combining 1st and 2nd trimester screening results available privately
Cell-free foetal DNA (cffDNA)
Non-invasive prenatal diagnosis (NIPD) works by analysing the DNA fragments present in the maternal plasma during pregnancy (cell-free DNA).
Most of this DNA comes from the mother
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
Non Invasive Prenatal Diagnosis (NIPD) in the NHS
Maternal blood test at around 9 weeks of pregnancy :
- Achondroplasia - testing is free
- Thanatophoric dysplasia - testing is free
- Apert syndrome - testing is free
SEXING:
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 then go on to prenatal test
If female, no invasive test required
NIPD offered privately in NHS
Autosomal dominant single gene disorders inherited from the father or arise de novo
NF1
NIPD is also possible to alter management of pregnancies at risk of recessive conditions when the mother and father carry different altered genes.
- If the paternal alteration has been inherited by the foetus, invasive prenatal testing can be offered to find the maternal gene
- Cystic fibrosis – haplotyping (RHDO) can test for both maternal and paternal mutation
cffDNA testing for aneuploidy (NIPT)
Offered privately (Harmony) or via research studies
Harmony 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.
Is this accurate enough to make a decision?
Limitations of NIPD and NIPT
- 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.
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.
Chorionic Villus Sampling
- Done between 11-14 weeks
- 1-2% risk of miscarriage (lower in specialist centres e.g. UCH, Chelsea and Westminster) - risk is higher because the foetus is smaller
- Transabdominal or transvaginal
- 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. TOP decision (termination of pregnancy)
Amniocentesis
- From 16 weeks
- Takes sample of amniotic fluid which contains fetal cell
Risks
- Up to 1% risk of miscarriage
- Infection
- Rh sensitisation
What tests are done with the DNA sample?
- Test for the genetic disorder in question:
- Timing for results dependent upon condition - 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 - CGH Array
CGH Array
- 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 something found on array we standardly test parents to see if either is a carrier. This can help with interpretation
- Neurosusceptibility loci: 1q21.1 dup, 16.11.2 dup, 15q11.2 del etc etc. Uncertainty regarding penetrance. Be wary about discussing PND/PGD
Trio Exome
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
Trio refers to the parents and the baby
Good pick up (40%+) where referrals are appropriate
Started with Deciphering Developmental Disorders (DDD) study
Whole genome sequencing is coming!
Reproductive options
Where there is a known reproductive risk, the options for family planning include:
- 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)
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
Process of adoption
Two stages:
First Stage :
- Registration and checks
- Registering interest with adoption agency
- Medical and criminal background checks; three written references
- Usually takes ~2 months
Second Stage : 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
Pre-implantation genetic diagnosis
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:
- Emotional and physical implications
- Can be lengthy process
- Success rates ~30% per cycle; ~40% per embryo transfer
Our patients use PGD for many genetic disorders :
- Translocation carriers
- Huntington’s Disease
- DMD – can only implant female embryos (where mutation in family is unknown)
- Cystic Fibrosis
- BRCA1/2
PGD is now nationally funded
A licence is required from the HFEA for each genetic condition or indication
Process of PGD
- Stimulation of the ovaries
- Egg collection
- Insemination
- Fertilisation
- Embryo biopsy
- Embryo testing
- Embryo transfer
- Pregnancy test
Eligibility for PDG
- Female partner is suitable age, BMI and hormone levels
- Female partner is under age 39
- Female partner has a BMI of 19-30
- Female partner has hormone levels that suggest she will respond to treatment - The couple are non-smokers in an appropriate situation (stable and no concerns)
- Both partners are non-smokers
- Couple are living together in a stable relationship
- No welfare concerns for the unborn child - No other unaffected children
- No living unaffected children from the relationship - Genetic problems (accurate test with at least 10% risk of serious condition)
- Known risk of having a child affected by a ‘serious’ genetic condition (at least 10%)
- An accurate genetic test is available
What is the role of a Genetic Counsellor (GC) in prenatal testing
- Arrange & explain CVS, amniocentesis, PGD, cffDNA
- Facilitate decision-making
- Give results
- See patients in clinic following a diagnosis in utero
- Arrange termination if necessary
- Discuss recurrence risks and plans for future pregnancies
How does a GC facilitate decision making
In the context of:
- Previous experience
- Family situation
- Dealing with indecision
- Couples do not always agree
- Religion
- Personal beliefs
- Psychosocial situation
- Balancing miscarriage risk with genetic risk
