5.7 - Genetic Testing Flashcards
1
Q
What happens in a normal pregnancy?
A
- positive pregnancy test - no longer confirmed at GP
- book into antenatal care - see midwife
- nuchal scan at 10-14 weeks gestation - different tests depending on NHS Trust e.g. nuchal translucency, combined test etc
- maternal age taken into account and risk of Down’s syndrome given - anything more than 1/150 considered high risk, anything below is low risk and no further testing done
- mid-trimester anomaly scan - 20-22 weeks gestation
- ultrasound examination is the main method for prenatal diagnosis of foetal abnormalities
2
Q
What are the aims of the nuchal scan (12 weeks)?
A
- to date the pregnancy accurately
- to diagnose multiple pregnancy
- to diagnose major foetal abnormalities
- to diagnose early miscarriage
- to assess the chance of Down’s syndrome and other chromosomal abnormalities
- takes into account maternal age, blood hormone levels, nuchal translucency thickness, nasal bone, blood flow through the foetal heart and foetal abnormalities
3
Q
What is nuchal translucency (NT)?
A
- done at 10-14 weeks
- it is the thickness of fluid at back of foetal neck
- screening test and not diagnostic
- can indicate a range of genetic syndromes
- combined with maternal blood markers and maternal age
4
Q
What can a NT increased >3mm indicate?
A
- chromosome abnormalities e.g. Down’s, Edwards, Patau, Turners –> NT and maternal age detects up to 75% of Downs syndrome with 5% false positive rate
- birth defects e.g. cardiac anomalies, pulmonary defects (diaphragmatic hernia), renal defects, abdominal wall defects
- skeletal dysplasias
5
Q
What is the aim of anomaly scan?
A
Look for structural abnormalities specifically in the heart, brain, spinal cord, face, kidney and abdomen to measure the lengths of the bones
6
Q
What other scans are available?
A
- foetal MRI if more detailed scan needed
- foetal cardiac scan offered to look at blood flow through baby heart to diagnose cardiac conditions
7
Q
When is prenatal testing offered?
A
- following abnormal findings at nuchal scan or mid-trimester scan
- following results of combined test which give an increased risk of chromosomal abnormality
- if previous pregnancy/child was affected with a condition e.g. Down’s syndrome, CF
- if parent(s) is a carrier of chromosome rearrangement or genetic condition e.g. t(13;14), DMD, Huntington’s
- if there is a family history of a genetic condition
8
Q
What are the aims of prenatal testing?
A
- to inform and prepare parents for the birth of an affected baby
- to manage the remainder of the pregnancy
- to be prepared for complications at or after birth
- to allow termination of an affected foetus - this can be after 24 weeks
- to allow in utero treatment
9
Q
How does non-invasive prenatal diagnosis (NIPD) work?
A
- non-invasive prenatal diagnosis (NIPD) works by analysing DNA fragments present in the maternal plasma during pregnancy (cell-free DNA)
- most of this DNA comes from the mother - 10-20% comes from the placenta, which is representative of the baby (cffDNA)
- cffDNA first detectable from around 4-5 weeks gestation but cannot be accurately detected on testing until around 9 weeks
- maternal blood test of 20ml of her blood (large amount)
- achondroplasia, thanatophoric dysplasia and apert syndrome can be detected from cffDNA in this blood
10
Q
How can NIPD detect dominant and recessive disorders?
A
- detects autosomal dominant single gene disorders inherited from the father e.g. NF1
- NIPD is also possible to alter management of pregnancies at risk of recessive conditions when the mother and father carry different mutations in the same gene
- if the paternal mutation has been inherited by the foetus, invasive prenatal testing can be offered to look for maternal mutation - if baby not inherited paternal mutation then we know baby won’t be affected so further tests unnecessary
- e.g. for CF - haplotyping (RHDO) can test for both maternal and paternal mutation
11
Q
How is NIPD used for foetal sexing?
A
- currently offered when there is an X-linked condition in the family e.g. DMD
- the test detects SRY gene on Y chromosome, enabling us to determine if male or female foetus
- if male, we go on to prenatal test (as they more commonly get DMD)
- if female, then no invasive test required
12
Q
What is cffDNA testing for aneuploidy (NIPT)?
A
- offered after high-risk combined screen / privately (Harmony) / via research studies
- currently tests for trisomy 13, 18 & 21 which identifies 92%, 97% & 99% of foetuses with those trisomies respectively
- done using non-invasive prenatal test (NIPT) which is not diagnostic - invasive test recommended if issue identified
13
Q
What are the limitations of NIPD and NIPT?
A
- multiple pregnancies - not possible to tell which foetus the DNA is from when carrying twins etc
- women with high BMI - relative proportion of cffDNA is reduced as they have more cell-free DNA = may need a second sample after 9 weeks
- women not prepared for implications - despite only blood test, same implications as invasive test e.g. can identify genetic problem in baby - do they want this info?
- an invasive test may still be required to confirm an abnormal result
14
Q
What are the benefits of NIPD and NIPT?
A
- the number of invasive tests carried out is likely to reduce as a result
- no increased risk of miscarriage (unlike invasive)
- 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
15
Q
What is invasive testing?
A
- offered if there is a ‘known risk’
- two types: chorionic villus sampling (CVS) where placenta tissue is taken, and amniocentesis where fluid from around developing baby is taken
- molecular, cytogenetic and biochemical tests done on these samples and ultrasound guidance used with both
- offered on an outpatient basis - come in for appointment, do test and go home same day
16
Q
What is CVS?
A
- chorionic villus sampling
- done at 11-14 weeks
- transabdominal or transvaginal (usually former)
- takes sample of chorionic villi - part of developing placenta, same DNA as foetus
- allows patient to have an earlier result than amniocentesis - important for many patients e.g. for abortion decisions
- risks: 1-2% risk of miscarriage, infection, Resus (Rh) sensitisation
17
Q
What is amniocentesis?
A
- happens from 16 weeks
- takes sample of amniotic fluid which contains foetal cells
- risks: up to 1% risk of miscarriage, infection, Rh sensitisation
18
Q
What tests are done with the DNA sample?
A
- test for the genetic disorder in question - timing for results depends on condition
- karyotype if chromosomal abnormality in family - results in two weeks (dependent on cells growing)
- QF-PCR looking for t13, 18 & 21 (plus sex chromosomes if sex chromosome disorder suspected) - results within 24-48 hours
19
Q
What is a CGH array?
A
- 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 - can help with interpretation (change is inherited or new?)
- neuro-susceptibility loci (changes in chromosomes that can cause developmental delay and other features in some but not all with changes) e.g. 1q21.1 dup –> uncertainty regarding penetrance
20
Q
What is prenatal exome?
A
- consider where foetus has significant abnormalities e.g. heart, brain, skeletal, dysmorphic features = trio-exome testing done
- exome is coding region of genome - take DNA from foetus and parents to confirm where issue came from e.g. if baby has genetic condition and both parents found to be carriers
- urgent test - results approx 1 week
- allows efficient diagnosis of genetic condition in utero
- does not always give full answers if results too complicated to interpret / diagnosis isn’t made - important when counselling
21
Q
What options are there for family planning if there is known reproductive risk?
A
- conceive naturally, no prenatal testing
- conceive naturally, have prenatal testing
- use of egg and/or sperm donors - helps reduce risk e.g. if both parents are carriers then using a donor means only one parent is a carrier
- adoption
- choose not to have children
- pre-implantation genetic diagnosis (PGD) - uses IVF with an additional step to genetically test embryo before implantation, particularly used by people who do not want termination of pregnancy (TOP)
22
Q
What are the rules against egg and sperm donation?
A
- 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 to find donor
23
Q
What is the process of pre-implantation genetic diagnosis?
A
- stimulation of ovaries - women take medicine to produce many eggs
- egg collection
- insemination - using intracytoplasmic sperm injection (single sperm injected into centre of each egg, used for conditions caused by a single faulty gene to reduce amount of non-embryo DNA that could increase risk of wrong diagnosis)
- fertilisation
- embryo biopsy - at blastocyst stage
- embryo testing - on one cell
- embryo transfer - of those that have not inherited genetic condition
- pregnancy test
24
Q
What disorders is PGD used to test for?
A
- translocation carriers
- Huntington’s disorder (HD)
- DMD - only implant female embryos where mutation in family is unknown
- CF
25
Q
What are the eligibility criteria for PGD?
A
- female partner under age 39
- female partner has a BMI of 19-30
- both partners are non-smokers
- couple are living together in a stable relationship (longer than a year)
- no living unaffected children from the relationship
- known risk of having a child affected by a ‘serious’ genetic condition (at least 10%)
- female partner has hormone levels that suggest she will respond to treatment
- accurate genetic test available
- no welfare concerns for unborn child
- license required from the HFEA for each genetic condition / indication
- eligible couples usually funded for three rounds of PGD
26
Q
What is the role of a genetic counsellor in prenatal testing?
A
- arrange & explain CVS, amniocentesis, PGD, cffDNA
- facilitate decision-making
- give results
- see patients in clinic following a diagnosis
- arrange termination if necessary
- discuss recurrence risks and plans for future pregnancies
27
Q
What facilitates decision making?
A
- previous experience
- family situation
- religion
- personal beliefs
- psychosocial situation
- balancing miscarriage risk with genetic risk
- dealing with indecision
- couples do not always agree
