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MHG > Prenatal Genetics > Flashcards

Prenatal Genetics Flashcards

1
Q

Define “Screening Test”

A

A test for the general population that you apply to narrow down a group of people at higher risk for a condition. Screening tests are usually non-invasive, cheap and have high sensitivity (high detection rate). Ex) Mammogram

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2
Q

Define “Diagnostic Test”

A

Test aimed at making a diagnosis for a disease. The diagnostic tests are usually invasive, can be painful and have high specificity. Ex) Biopsy

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3
Q

For parents with a previous child with a de novo chromosomal aneuploidy (i.e. DS) what is the risk of recurrence for any chromosomal abnormality?

A

1/100 or 1.0%

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4
Q

What test do doctors rely on to diagnose NTDs and why?

A

Doctors now rely on ultrasounds to diagnose NTD. This is because it has a higher detection rate (95% vs. 80%) and specificity (97% vs. 5%) for prenatal diagnosis of NTD compared to MSAFP.

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5
Q

List the indications for prenatal diagnosis.

A
  1. Maternal Age
  2. Presence of structural chromosome abnormalities in one of the parents (i.e. translocation)
  3. Previous child with de novo chromosomal aneuploidy
  4. Genetic disorder amenable to prenatal diagnosis by biochem or DNA analysis
  5. Sex determination
  6. NTD
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6
Q

List the methods of prenatal DIAGNOSIS in order of increasing risk.

A
  1. PGD (Preimplantation Genetic Diagnosis) (no risk)
  2. Ultrasonography
  3. Amniocentesis (0.2% - 0.3%) (1/300 - 1/500)
  4. CVS (1% - 1.5%)
  5. FBS (2.8%)
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7
Q

What kind of disorders is high AFP seen in?

A
  1. NTD
  2. Fetal Blood Contamination
  3. Fetal abnormalities (e.g. omphalocele)
  4. Placental disorders (e.g. placenta not implanted properly)
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8
Q

How can you diagnose NTD?

A

Screening with maternal serum levels of AFP. If levels of AFP are high, you can do an ultrasound or amniocentesis to confirm. With amniocentesis, you use the fluid supernatant (not the fetal cells!) to test the AFP levels.

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9
Q

What are the complications associated with amniocentesis?

A
  1. Feto-maternal hemorrhage (mixing of maternal and fetal blood
  2. Leakage of amniotic fluid
  3. Infection
  4. Fetal trauma (rare)
  5. Respiratory distress at birth (b/c of removal of amniotic fluid)
  6. Hepatitis B and HIV transfer
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10
Q

What is the time frame for early amniocentesis?

A

10 - 14 weeks

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11
Q

Describe the disadvantages of CVS

A
  1. Cannot be used to measure AFP
  2. There is a 2% discord between the genetic make up of the fetus and the genetic make up of the placenta (chromosomal mosaicism) so not all cases of CVS will accurately be able to diagnose the fetus.
  3. Transvaginal CVS has a higher risk of infection
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12
Q

What are the complications associated with CVS?

A
  1. Bleeding and sub-chorionic hematoma (under placenta) (most common 4%)
  2. PROM (premature rupturing of the membranes)
  3. Rh-sensitization (happens when maternal and fetal blood mix)
  4. Fetal abnormalities (only before 10 weeks when organs are still forming)
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13
Q

Why is there such a large ultrasound detection range for structural anomalies (15%-50%)?

A

Some anomalies are harder to see on ultrasound than others (i.e. cleft lip and palate, skin conditions, missing ears)

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14
Q

Rate of cardiac anomalies detected with US.

A

Tested for 20 - 24 weeks and detection rate is 50% - 80%

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15
Q

What is the most important tool used to detect fetal abnormalities?

A

Ultrasound!

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16
Q

What is the risk of major fetal anomalies? What is the risk of major fetal anomalies after all possible tests have been preformed?

A

3% - 5% (a normal ultrasound reduces this risk by half to 1.5%-2.5%); 1.1% - 2.1%

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17
Q

What is the percentage of major fetal anomalies that cannot be detected with ultrasound or invasive testing?

A

1.1% - 2.1%

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18
Q

What kind of abnormalities can be tested with ultrasound? (Give examples when available)

A
  1. Isolated
  2. Associated with aneuploidies
  3. Associated with single gene disorders (some skeletal dysplasias, IPKD)
  4. Associated with multifactorial disorders (cardiac anomalies, NTD, CL/P)
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19
Q

Under what conditions can PGD (Preimplantation Genetic Diagnosis) be preformed?

A

PGD can only be preformed with IVF because the procedure requires taking a cell from the blastocyst stage and running all of the tests on that.

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20
Q

What are the drawbacks of PGD?

A
  1. The more probes you apply to the cell, the more false positives and false negatives you will get.
  2. The single cell taken from the blastocyst may not be reflective of the rest of the cells of the embryo (mosaicism can be up to 50%)
  3. Narrow window of testing
  4. Limited sample material
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21
Q

Define “Detection Rate”

A

AKA: Sensitivity; The ratio of affected fetuses detected by the screen over the total of affected fetuses. = (Test abnormal and affected)/(Test normal and affected + test abnormal and affected)

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22
Q

Define “False Positive Rate”

A

Ratio of normal fetuses falsely identified as affected = (test abnormal not affected)/(test abnormal not affected + test normal not affected)

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23
Q

What is the most important factor of the parent’s decision to get screening/diagnostic testing?

A

The attitude of the woman.

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24
Q

Which category of women benefit most from screening tests?

A

Balanaced. These women consider invasive testing if there is an increased risk of something going wrong with the pregnancy, but they would prefer to get the most information without jeopardizing the pregnancy.

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25
Q

For what Mendelian condition does the ACMG recommend screening for all ethnicities and ACOG does not?

A

Spinal Muscular Atrophy

26
Q

For what Mendelian condition is screening recommeneded by both the ACMG and AGOC?

A

Cystic Fibrosis

27
Q

For what ethnicity foes the ACMG and ACOG recommend screening for nearly all Mendelian disorders?

A

Ashkenazi Jewish Population

28
Q

South East Asians have a higher risk for ____________.

A

Alpha-thalassemia.

29
Q

African Americans have a higher risk for ____________.

A

Sickle Cell Anemia.

30
Q

Mediterranian populations have a higher risk for ____________.

A

Beta-thalassemia.

31
Q

How can the risk based on maternal age be modified?

A

By using screening methods:

  1. Maternal serum screening
  2. Ultrasound screening
32
Q

What percentage of individuals test positive for at least one condition in universal screening?

A

23%

33
Q

What fraction of couples are carriers of the same condition?

A

<1%

34
Q

What is the most common genetic condition?

A

Alpha-1-Antitrypsin

35
Q

List the most common genetic conditions in from highest to lowest frequency.

A
  1. Alpha-1-Antitrypsin
  2. GJB2-Related Deafness
  3. Familial Mediterranean
  4. Achromatopsia
  5. Sickle Cell Anemia
36
Q

What is Fragile X?

A

The most common inherited form of mental retardation (1/4000 in males and 1/8000 in females). It is also the most common gene disorder associated with autism.
Carrrier frequency 1/157 women
The condition is caused by a CGG repeat expansion in 5’ non-coding (promoter) region FMR1 gene on X chromosome. At >200 repeats there is a loss of function of the FMR1 gene.

37
Q

What are serum markers?

A

They are proteins produced by the fetus and/or placenta during normal gestation. Pregnancies with aneuploidies have different levels of these proteins, setting the stage for their use as markers.

38
Q

What is the serum marker for DS?

A

Down syndrome fetuses have lower maternal serum alpha-feto-protein than unaffected fetuses. Thus, the lower the level of MSAFP, the higher the risk of DS. (This is opposite from the MSAFP detection of NTD)

39
Q

How can screening tests be used to modify prior risk?

A

Prior risk can be modified by screening tests.

  1. Screening tests can be proposed to women with “low risk” who decides to have invasive testing done because revised risk post-screening increased
  2. Screening tests can be proposed to women at “high risk” and then come back reassuring, decreasing revised risk, and diagnostic testing will be avoided.
40
Q

What conditions increased the risk for NTD?

A
  1. High MSAFP
  2. Teatogen exposure (ev. valproic acid)
  3. History of previous child with NTD
  4. Pt herself with NTD
  5. Uncontrolled diabetes (high glucose)
41
Q

Why screen for NTD?

A

Because 90% of NTD cases occur in families with no previous history or risk factors

42
Q

What are specific MSAFP levels associated with prenatal genetic conditions

A

0.5 Down Syndrome
1.0 Normal
5.0 Spina Bifida (NTD)
10 Anencephaly (NTD)

43
Q

How reliable is MSAFP testing for NTD?

A

Sensitivity = 80%

False positive rate = 3.5% (thus if you get a high MSAFP, you need to do an US to confirm it is not a false positive)

44
Q

What is Folic Acid’s role in prenatal genetics?

A

Folic Acid decreases the risk for NTD by 50%. It must be taken 3 months before conception and continued 10 weeks after.

45
Q

What are copy number variances?

A

They propose problems for CGH. They are changes in genetic material that can be seen in the CGH but you do not know if the CNV will carry any clinical significance or not. There are people with CNVs that have no clinical manifestations. CNVs are the reason CGH is not recommended before karyotyping

46
Q

How long do genetic diagnostic tests take?

A

US is immediate
3 days for FISH
1 week for CGH
2 weeks for Karyotype

47
Q

How long do genetic diagnostic tests take?

A

US is immediate
3 days for FISH
1 week for CGH
2 weeks for Karyotype

48
Q

What is the old/Thompson & Thompson rationale behind using maternal age as a prenatal screening measure?

A

Eligibility for prenatal diagnosis that that the risk for fetal abnormality is greater than or equal to the risk of miscarriage or complication for the diagnostic test itself. This was changed by ACOG in 2007 to have all women should have the option to be tested independent of age.

49
Q

What are the complications associated with FBS?

A
  1. Fetal paralysis
  2. Hemorrhage/hematoma
  3. Bradycardia
  4. Fetomaternal Hemmorrhage
49
Q

What is a big advantage of FBS?

A

It is a very quick test. If a fetus is on the verge of death, FBS can be used to diagnose the fetus quickly

50
Q

What factor influences detection rate?

A

Frequency of mutation. In some ethnicities, the number of mutations is higher so detection rates for that ethnicity will be higher.

51
Q

What are the indications for offing genetic testing for Fragile X?

A

Screen the woman using history. If there is a history of female infertility, premature ovarian failure, or family history of unexplained mental retardation and develpmental disabilities or autisim.

52
Q

What are the prenatal screening measures used for most common aneuploidies?

A
  1. Serum markers

2. Sonographic markers

53
Q

What are the screening measures for Down Syndrome?

A
  1. Low levels of maternal serum or amniotic fluid AFP

2. Presences of nuchal translucency in ultrasound (collection of lymphatic fluid behind the neck)

54
Q

What is cell-free fetal DNA test?

A

New screening test that detects levels of fetal DNA in maternal blood. Feta DNA is released during pregnancy due to apoptosis of placental cells. These fetal fragments can be analyzed and determine if there is any excess of genetic material from the fetus (i.e. trisomy 21). The test has VERY HIGH specificity.

55
Q

What are the limitations of cell-free fetal DNA test?

A

It currently has not been tested on many twins and it does not pick up any conditions beside the ones that are tested for. Currently, there is only data on the test being done in high risk women.

56
Q

What is the advantage of CGH compared to karyotype?

A

CGH has a much higher resolution that karyotype so it can pick up anomalies that arent found in karyotype. Currently, it’s recommended that fetuses with structural anomalies and normal karyotype be tested with CGH.

57
Q

What are the advantages of using CGH in prenatal testing?

A
  1. Higher resolution than karyotype
  2. Saves time by not having to wait for cell cultures
  3. Does not require dividing cells and thus can be used to diagnose an aborted pregnancy
  4. Automated
  5. Fast turn around time
58
Q

What are disadvantages of using CGH in prenatal testing?

A
  1. CGH cannot detect balanaced translocations.

2. When CNVs are detected there is uncertainty as to its clinical significance

59
Q

What are copy number variants?

A

Small changes in the genome that can be due to de novo mutations or inheritance. They can have clinical effects, or be silent. When they are found on CGH analysis, it is difficult to interpret their significance.

MHG (8 decks)

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