2-33 Prenatal Genetics

Question 1

What are some indications for prenatal diagnosis of an inherited condition?

Answer 1

• 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
• Consanguinity

Question 2

What are some indications for prenatal diagnosis of an UNinherited condition?

Answer 2

• Ultrasound anomaly
• Repeated miscarriages
• Abnormal MSAFP
• Anxiety
• Environmental exposures (maternal smoking or alcohol consumption, exposure to infection, x-rays, certain medications)
• Increased risk of a chromosomal abnormality

Question 3

What prenatal information can an ultrasound provide?

Answer 3

• Verify viability
• Detect a multiple pregnancy
• Determine the gestational age
• Determine the sex
• Identify possible abnormalities
• May indicate that additional studies are needed

Question 4

What prenatal anomalies can ultrasound detect?

Answer 4

• 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)

Question 5

What is maternal serum alphafetoprotein (MSAFP)?

Answer 5

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

Question 6

What is the maternal serum quad test?

Answer 6

4 different substances

α-fetoprotein [AFP]

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

Question 7

What is “integrated” prenatal testing?

Answer 7

10-13 weeks gestation:

PAPP-A (pregnancy-associated plasma protein-A; when , associated with increased risk of DS)

Nuchal translucency

15-21 weeks gestation the Quad MSAFP testing is performed

Question 8

Embryo mosaicism digression

Question 9

What is non-invasive prenatal screening/testing (NIPS/NIPT)?

Answer 9

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

Question 10

What are some problems with the counting method (NIPS/NIPT)?

Answer 10

• 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

Question 11

What is SNP haplotype analysis?

Question 12

What is SNP-based NIPS?

Answer 12

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
Prader Willi-Angelman
Cri-du-chat

Question 13

What is amniocentesis?

Answer 13

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)

– Cytogenetics
– Metabolic assays
– Molecular diagnostics

Question 14

What are some potential causes for elevated AFP levels?

Answer 14

Question 15

What is chorionic villus sampling (CVS)?

Answer 15

10-14 weeks gestation

Limb reduction when done

<10 weeks gestation

Risk 1/100

Tests

– Cytogenetics
– 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.

Question 16

Why might a couple choose to undergo CVS?

Answer 16

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.