Prenatal Genetics - RS

Question 1

What are indications for inherited prenatal diagnosis?

Answer 1

Familial chromosme anomaly. Family history of a genetic disorder for which testing is available. Familial X linked recessive disorder without testing available. Increased risk of open neural tube defect. Carrier of genetic disorder, ethnic risk. Consanguinity.

Question 2

What are indicators for other prenatal diagnosis? (not inherited disorder)

Answer 2

Ultrasound anomaly. Repeated miscarriages. Abnormal maternal serum alphafetoprotein. Anxiety. Environmental exposures. Increased risk for chromosomal abnormality.

Question 3

What happens to the majority of fetuses with chromosomal errors?

Answer 3

They are not viable and are detected and eliminated naturally. This is true for cases of known aneuploidy. ie. 95% in 45,X conceptions.

Question 4

An ultrasound is a non-invasive procedure that can detect many abnormalities, name some of them:

Answer 4

Anomalies; nuchal translucency may be associated with chromosomal anomally. (ie. 6mm thick = down syndrome)
Clefting
Neural tube defects

Question 5

Maternal serum alphafetoprotein (MSAFP) is a non-invasive blood test, what can it test for? What are important factors to consider?

Answer 5

It just identifies a potential problem if it is too high (neural tube defect) or too low (Down Syndrome and other chrom. anomalies). It is simply a screening test for risk assessment NOT diagnosis. Must consider the mothers weight, race and diabetic status. A larger mother will dilute the AFP with her larger volume of blood.

Question 6

What is the maternal serum quad test?

Answer 6

An evaluation of 4 different substances. Leads to better significance of test. Good test for DS. Low AFP, high hCG, low uE3, and high dimeric inhibin-A give 80% prob of DS.

Question 7

What is integrated prenatal testing?

Answer 7

Combining morphological data with biochemical analysis. Gives even better predictive value. Use of pregnancy-associated plasma protein-A (PAPP-A) with quad test.

Question 8

The newest non-invasive test is called non-invasive prenatal screening/ test (NIPS or NIPT)

Answer 8

It uses cell free fetal/ placental DNA found in the mothers blood. It is NOT a diagnostic study, but gives a risk for a chromosomal abnormality. It must be confirmed by a diagnostic test.

Question 9

An invasive test is an amnoicentesis, what is it? What can be tested?

Answer 9

A procedure where a needle is inserted through the abdomen into the amniotic cavity. Amniotic fluid is withdrawn for testing of AFAFP, cytogenetics, metabolic assay, molecular diagnostics.

Question 10

Is amniotic fluid alphafetoprotein (AFAFP) a diagnostic test?

Answer 10

NO, it is a screening test and is analogous to MSAFP test.

Question 11

What abnormalities are associated with AFP levels? How is it confirmed?

Answer 11

Trisomies 13, 18, 21
Mosaic Turner syndrome
Triploidy
Unbalanced translocation.
Confirmatory test is karyotype analysis.

Question 12

What are some causes of elevated AFP that are not related to disease?

Answer 12

Multiple pregnancies, small mother, monozygotic twins.

Question 13

If there is elevated AFP levels what is there an increased risk of? How is it confirmed?

Answer 13

Open neural tube defect. Acetylcholinesterase is the confirmatory test. AChE should only be present in amniotic fluid if there is a defect in the neural tube.

Question 14

Another invasive procedure is chorionic villi sampling (CVS), what studies can use this?

Answer 14

Cytogenetics, molecular diagnostics, metabolic (cells only). can NOT do AFP.

Question 15

What is the major drawback to chorionic villi sampling?

Answer 15

CVS relies on placental and fetal cells being the same, when in reality there could be a placental problem only (due to mosaicism) and thus amniotic fluid is needed for confirmation.

Question 16

How does complete mosaicism arise? What will it tell us?

Answer 16

If a mutation occurs early in development, some cells of all tissues may be affected. Thus sampling the placenta will most likely also reflect the fetal constitution.

Question 17

How does localized mutation (placental) arise? What will it tell us?

Answer 17

If a mutation occurs only in the layer of cells that will become the placenta, the fetus may be perfectly fine. All or part of the placenta may carry the mutation. This could lead to a misinterpretation of a CVS.

Question 18

How does confined fetal mutation arise? What will it tell us?

Answer 18

If the only cells with the mutation occur in the fetus, then CVS testing will miss that altogether.

Question 19

When would you use CVS (since it is risky)?

Answer 19

If a couple wants to know early if there is a problem so that they have the option of termination of pregnancy, this is the testing method of choice.

Question 20

Assisted reproductive technologies (ART) are good for helping infertile couples or couples with known genetic mutations, what are some of the procedures?

Answer 20

In vitro fertilzation
ICSI - intracytoplasmic sperm insertion (males with low sperm count)
ZIFT - zygote intrafallopian transfer (a single male or female can contract to have a biologically related child)
Donor Egg

Question 21

How should counseling be handled?

Answer 21

Supportive, confidential and Non-directive (let the family decide)

Question 22

What is polar body analysis? What is it used for?

Answer 22

Used typically for couples who are both CF carriers. If the polar body tests positive for the CF mutation known to be carried by the mom, then the corresponding egg would not be expected to have it.

Question 23

Preimplantation genetic diagnosis (PGD) can look for what?

Answer 23

General assay for chromosomal aneuploidies. Possible to identify known specific mutations in family history.

Question 24

When is PGD done?

Answer 24

At the 8 cell stage a single cell is removed and tested by FISH or molecular assay.

Question 25

Is karyotyping an option in PGD?

Answer 25

NO it is not an option because the cell will not be in metaphase to evaluate.

Question 26

Next-generation DNA sequencing is now being used to replace PGD, why is it better?

Answer 26

It is a whole genome screen as compared to the limited types of studies for which PGD excels.

Question 27

What can women with mitochondrial mutations do to have a healthy child? How is it done?

Answer 27

Donor egg exchange. A healthy mother donates an egg. The afflicted mother has her nucleus removed her egg and put into the donor egg who’s nucleus has been removed. Then the father’s sperm is used to fertilize it. This baby technically has 3 parents (3 genomes).

Question 28

At what age would an amniocentesis or CVS be warranted?

Answer 28

35 or older.

Question 29

The most frequent aneusomy in spontaneous abortion is?

Answer 29

45, X ~95% abort. This makes up 19-20% of fetal wastage due to chromosomal abnormalities.