Prenatal Genetic Screening: An Update
/One of our very first podcasts covered prenatal genetic screening and testing. Since then, ACOG has updated the former PB 163 to the new PB 226. For today, we’ll cover some changes/updates and get more into diagnostic testing, which we didn’t cover in depth on our previous episode. Diagnostic testing info remains well-covered by PB 162.
How do you provide genetic counseling to a patient?
Every pregnancy has a risk for genetic abnormality and review that this risk increases with increasing age
Average rate is 1/150 live births. There is also risk based on family history.
Review family history of birth defects, genetic diagnoses in the family, etc. prior to discussion
Risk of abnormalities based on age:
Review options for genetic screening for patients.
All types of genetic screening is limited, and all genetic screening tests detect fewer abnormalities than diagnostic tests with microarray. Diagnostic tests include CVS and amniocentesis.
Screening and diagnostic testing should be discussed and offered to all patients early in pregnancy regardless of maternal age or baseline risk
What are the available tests?
Preimplantation genetic testing/screening
PGT-A (also called PGS previously) - preimplantation genetic testing for aneuploidies
Biopsy of an embryo at the blastocyst stage, usually around day 5-6 of development
Cells are taken from the outer layer of cells (trophectoderm) that will eventually become the placenta
PGT-A just screens for aneuploidy, and the idea is to increase the chances of live birth by screening for embryos that have aneuploidy.
PGT-M - preimplantation genetic testing for monogenetic/single gene mutations
Same as above in terms of how the cells are gotten, but in this case, tests are done for monogenic disease or single gene mutations
Can be used to choose embryos that do not have a genetic disease, like screening for embryos that do not have Huntington’s or cystic fibrosis
Disease and mutation must be known beforehand — this is a highly targeted screening.
PGT-SR - preimplantation genetic testing for structural rearrangements
Useful when there are parental structural chromosomal abnormalities.
Detects things like translocation, inversion, deletions, insertions, etc.
With PGT, because the cells biopsied are destined to become placenta, other forms of pregnancy genetic screening should still be offered due to risk of mosiacism - that is, different genetic material in different cell lines.
Screening and Testing During Pregnancy
Discuss that many screening tests are sensitive for T21, but may have less sensitivity for other chromosomal disorders.
Review these tests cannot detect other genetic abnormalities like point mutations, deletions, translocations, etc.
Types of screening tests:
NIPT (cell free DNA) – test any time around 9-10 weeks to term. 99% detection rate for trisomy 21. It has the highest DR of all tests and lowest false positive rate, but also may detect maternal aneuploidy or disease. Highest sensitivity and specificity. Does NOT test for open neural tube defects.
Someone with a screen positive serum analyte test may choose cfDNA for follow up if they want to avoid a diagnostic test, but they should be informed that it is still a screening test, meaning it can still fail to identify some chromosomal abnormalities and may delay definitive testing if positive.
Integrated screen – two tests. First is at 10w-13w6d. Then 15-22w. DR for T21 is 96%, but you need two samples and no first trimester results. Method: NT + PAPP-A in first trimester, then quad screen (hCG, AFP, uE3, inhibin A)
Sequential – 10w-13w6d, then 15-22 w. 95% DR for T21. Still need two samples, with first trimester NT + BHCG, PAPP-A and +/- AFP. Then quad screen.
Quad screen – 15w-22w. 81% DR for T21. It’s a one-time test, but also has lower DR than integrated
Other options with lower detection rates: first trimester screen (NT+PAPP-A, bHCG, AFP), Serum integrated (Integrated just without NT), NT alone
ACOG PB 226
Diagnostic Testing
The gold standard for detecting genetic abnormalities and should be offered after abnormal genetic screening tests.
Chorionic villi sampling – done between 10-13 weeks.
Get placental villi transabdominally or transcervically.
Pregnancy loss rate 1/500. Limb reduction defect is super low, around 6/10,000.
Can cause spotting/bleeding. Also the tissue is placental, so there is still possibility of mosaicism (ie. placenta doesn’t have abnormalities, but fetus does).
Because of this, sometimes after CVS can still recommend amnio.
Amniocentesis – done between 15-20 weeks usually, but can be done any time later too.
Reason not to do too early: amnion and chorion not fused, increasing anomalies/loss rate.
Rate of loss is about 1:300 – 1:750 depending on studies.
Other complications include spotting or loss of fluid.
Cells are from sloughed off fetal skin cells, so can actually get fetal DNA.
Type of tests that can be sent from diagnostic testing - a question you might get: what are you sending it for?
Karyotype
Detects aneuploidies, like trisomies, 45X, 47 XXY.
Need culturable cells, so takes longer (7-10 days).
Cannot usually be done on dead tissue (ie. stillbirth), because the cells likely won’t grow
Microarray
Can find major aneuploidies and submicroscopic changes that you can’t see just with karyotype.
Can’t detect balanced translocations and triploidy.
Can be done on cultured cells or uncultured tissue.
Can also be done on copy number variants If done on uncultured cells.
Can be fast turn-around (3-7 days).
FISH
Uses probes for specific chromosomes or chromosomal regions (ie, can detect T21 but also can detect 22q11.2 deletion).
Can be done on uncultured cells, so can get results in as few as 2 days.
Good to use if someone screens positive for T21 or other aneuploidy on serum analytes or cfDNA and you want a quick results before you get the full karyotype/microarray results
Often start with FISH, then reflex to microarray if normal, or karyotype if abnormal (to confirm).