Antenatal Diagnosis of Fetal Abnormalities Flashcards
What % of neonates have a significant congenital abnormality?
2-3%
What does the 20 week fetal anomaly scan detect?
- Abnormalities not compatible with life
- Associated with high morbidity or long term disability
- Foetal condition with the potential for intrauterine therapy
- Foetal conditions that will require special postnatal investigations or treatments
What is chorionic villus sampling (CVS)?
Sticking a needle into and taking a biopsy of the placenta
Why can CVS be used to for genetic diagnosis?
- Chronic (placental) villi are fetal in origin derived from the outer layer of the blastocyst (i.e. trophoblast) so share the same chromosomes
- Can also do metabolic investigations
- Can be transabdominal or transvaginal
When can CVS be done?
After 11 weeks (11-14 weeks)
What are the benefits of CVS?
1) Gives good preparations of DNA without culture
2) Chromosome analysis can be done rapidly within 24h however best quality chromosome analysis after culture (2 weeks)
3) Sampling extra-embryonic tissue
4) Earlier sampling and diagnosis than amniocentesis
5) Possibility of surgical termination in first trimester
What are the risks/cons of CVS?
1) Higher risk of miscarriage 1-2%
2) Possibility of confined placental mosaicism - small risk that the cell line in the placental sample does not represent the fetus giving a FP or FN result
3) Sometimes not possible if the placenta is too posterior to access
What is amniocentesis?
Sample from the amniotic fluid
How is amniocentesis carried out?
- 10-20ml of amniotic fluid sampled by needle aspiration transabdominally under US guidance
- Mainly samples fetal epithelial cells
- Cells from amnion, fetal skin, urinary tract pelleted
- Cultured for 2 weeks to get sufficient numbers to analyse
- Longer culture may be needed for DNA or biochemical studies
- Rapid trisomy screen results by PCR bypass this time requirement
Where does the needle go via in CVS and amniocentesis?
Vagina or abdomen
What is the benefit of amniocentesis
Lower risk of miscarriage (0.5-1%)
When is amniocentesis done?
14/15-16 weeks (often performed if fetal abnormality detected at 20 week scan)
What are the cons of amniocentesis?
1) Fetal material
2) Later diagnosis bc have to wait longer to do test
3) Some loss of abnormal pregnancies
4) Occasionally the concentration of DNA present in the sample can be low, compromising the quality of the results
5) Sometimes the sample can be contaminated by maternal blood which can delay results in a small number of cases
How may a post mortem be used to establish likely diagnosis?
- May be essential to establish likely diagnosis - closure, recurrence risk of happening again and offer test to parents
- Full post mortem
- Limited post mortem - photos, external examination, imaging
- Samples for chromosomes and DNA storage
How is pre-implantation genetic diagnosis used?
- Done if know that fetus is at risk bc of parents
- IVF - embryos tested very early on for specific genetic disorder (at 5 days)
- Only unaffected embryos are re-implanted into the woman to try and achieve healthy pregnancy
- Available for serious genetic disorders on NHS - more cost effective than if baby with condition is born
What other genetic diagnostic testing is offered in pregnancy?
1) Testing for single gene disorders (CVS/amniocentesis)
2) Parental chromosome rearrangement
3) Genome testing following detection of fetal abnormality
What are indicating for offering prenatal diagnostic genetic testing (prenatal referrals)?
1) High risk screening result < 1:150
2) Fetal abnormality detected at 12 or 20 weeks scan
3) FH e.g. previous pregnancy/child with T21, carrier of chromosome rearrangement or carrier of single gene disorder
4) High maternal anxiety
When is testing for single gene disorders carried out via CVS/amniocentesis?
1) Families with a child or previous fetus with a genetic diagnosis of a serious known condition e.g. spinal muscular atrophy, CF, DMD, sickle cell disease
2) Parents may be carriers
3) Parents may wish to test due to the gonadal mosaicism risk
4) If e.g. fetus has heart defect and NT but not trisomy can test for other causes
Describe testing when there is a parental chromosome rearrangement
- One of the parents is known to carry a chromosome rearrangement that puts them at risk of having a child with an uxnabalcned chromosome complement e.g. T21 or T13
How is genome testing done following the detection of a fetal abnormality on US?
1) Array CGH testing is carried out to detect the loss or gain of material across the genome
2) Fetal whole exome sequencing reports on pathogenic variants that the likely explanation of the fetal anomalies (not benign or unknown significance variants)
What are the two types of genetic testing done that aren’t CVS or amniocentesis?
1) Antenatal CGH array
2) Fetal whole exome sequencing
What does antenatal CGH array test for?
1) Significant deletions and duplications
2) Parental DNA tested for imbalance
What do all types of genetic diagnostic testing test for?
1) Whole chromosome aneuploidy
2) Chromsome abnormality
3) Genetic imbalance
4) Monogenic disorders
How are samples collected from invasive methods tested?
1) QF-PCR (rapid prenatal diagnosis) for aneuploidy detection ± sexing - microsatellite (repetitive DNA sequences) markers used to identify and count chromosomes 13, 18, 21 and X/Y
2) Array CGH to detect genomic imbalance
3) G-banded chromosome analysis
4) FISH in metaphase for confirmation of CGH
5) FISH in interphase to detect unbalanced products of a known familial balanced rearrangement
6) Mutation testing or sequencing to detect monogenic disorders
