What are some indications for prenatal diagnosis of an inherited condition?
- Familial chromosome anomaly
- Family history of a genetic disorder for which testing is available
- Familial X-linked recessive disorder without testing available
- Increased risk of ONTD (recurrence risk 2-5%)
- Carrier of genetic disorder, ethnic risk
What are some indications for prenatal diagnosis of an UNinherited condition?
- Ultrasound anomaly
- Repeated miscarriages
- Abnormal MSAFP
- Environmental exposures (maternal smoking or alcohol consumption, exposure to infection, x-rays, certain medications)
- Increased risk of a chromosomal abnormality
What prenatal information can an ultrasound provide?
- Verify viability
- Detect a multiple pregnancy
- Determine the gestational age
- Determine the sex
- Identify possible abnormalities
- May indicate that additional studies are needed
What prenatal anomalies can ultrasound detect?
- Nuchal translucency is one indicator of a possible abnormality in a fetus. A skilled ultrasonographer can make accurate measurements that can be associated with a disease process. For example, a thickness of 6.0 mm has been associated with Down syndrome.
- Unilateral or bilateral cleft lip, cleft palate, or cleft lip + cleft palate can be detected on ultrasound and are usually indicators of a genetic defect.
- A variety of neural tube defects can be detected. Here, a meningomyelocele was found.
- Closed neural tube defects
- Open neural tube defects (anencephaly, encephalocele)
What is maternal serum alphafetoprotein (MSAFP)?
Non-invasive blood test (mother's blood, not fetus's) that screens for risks (NOT a definitive diagnosis).
- Window between 15-20 weeks' development
- Levels: High, low, normal
- Gestational age
- mother’s weight, race, diabetic status
What is the maternal serum quad test?
4 different substances
human chorionic gonadotropin [hCG]
unconjugated estriol [uE3]
dimeric Inhibin-A (glycoprotein hormone secreted by the ovary)
~80% combined detection for DS Range 60% < 25 yrs old to 90% > 40 yrs old
What is "integrated" prenatal testing?
10-13 weeks gestation:
PAPP-A (pregnancy-associated plasma protein-A; when , associated with increased risk of DS)
15-21 weeks gestation the Quad MSAFP testing is performed
Embryo mosaicism digression
What is non-invasive prenatal screening/testing (NIPS/NIPT)?
Cell-free placental DNA (cfpDNA) isolated from maternal blood (non-invasive) at 10-22 weeks gestation
10-15% of cfpDNA in maternal blood is placental in origin
Genome sequencing to identify DNA fragments
Determine chromosomal source of each fragment
Statistically analyze the number of fragments per chromosome compared to expected number for mother + fetus
Look for trisomy 13, 18, 21; X and Y chromosome abnormalities
Counting method to detect aneusomy
Trisomy is about 0.05% of the total DNA
What are some problems with the counting method (NIPS/NIPT)?
- Some problems can arise because the technique looks at totals and not the source of the DNAs
- Cannot differentiate between maternal and placental abnormalities
- In the case of a failed twin pregnancy (vanishing twin), it cannot determine if mutations detected are from the demise or the remaining twin.
- Cannot detect triploidy
What is SNP haplotype analysis?
What is SNP-based NIPS?
Isolate maternal DNA and identify those haplotypes
Subtract extra maternal haplotypes to identify the fetal haplotypes
improved detection for several of the categories, including a 99% detection rate for trisomy 13 and triploidy.
Identify maternal duplications
Identify “vanishing twin”
Adding markers to know syndromes yields additional data
Velocardiofacial syndrome (22q11.2) 1p36 deletion syndrome
What is amniocentesis?
14-20 weeks gestation
Usually done 16-18 weeks
Can be done as late as 35 weeks
Risk @ 1/300-1/500
Results in collection of cells and fluid for testing
Tests possible – AFAFP (corollary to MSAFP)
– Metabolic assays
– Molecular diagnostics
What are some potential causes for elevated AFP levels?
What is chorionic villus sampling (CVS)?
10-14 weeks gestation
Limb reduction when done
<10 weeks gestation
– Molecular diagnostics – Metabolic (cells only)
CVS samples the placenta so it has some of the same problems as NIPS
False positive for a confined placental mosaic
False negative for a confined fetal mosaicism
All abnormalities detected must be confirmed on fetal tissue.
Why might a couple choose to undergo CVS?
Examples of situations where the option of early termination may be desired.
If the family has a known mutation that puts the child at risk of a genetic disorder (e.g., CF).
If the mother is a DMD mutation carrier, and a male fetus is at risk of inheriting DMD.
If one parent is a translocation or inversion carrier and the couple has lost previous
pregnancies due to chromosome imbalances.
The mother is older and at risk of having a child with aneuploidy.