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Practice bulletins > #162 Prenatal Diagnostic Testing for Genetic Disorders > Flashcards

#162 Prenatal Diagnostic Testing for Genetic Disorders Flashcards

1
Q

How common is some type of chromosomal abnormality in live births?

A

Approximately 1 in 150

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2
Q

What percent of occult spontaneous abortions (ie, early embryonic death in an unrecognized pregnancy), recognized miscarriages in first trimester, and stillbirths are the result of cytogenetic abnormality?

A

2/3 of occult spontaneous abortions
1/2 of recognized 1st trimester miscarriages
5% of stillbirths

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3
Q

What % of infant and childhood deaths are the result of choromosomal abnormalities?

A

5-7%

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4
Q

What is the definition of genetic mosaicism

A

Abnormal number of chromosomes not present in all cell lines

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5
Q

What is the significance of a balanced translocation in an individual?

A

They are typically normal phenotype, especially if inherited. Some can lead to recurrent miscarriage or an increased risk of genetic abnormality in offspring. Some translocations may be missing genetic material that can be clinically significant

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6
Q

What is the inheritance pattern of mitochondria?

A

Maternally inherited from cytoplasm of oocyte

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7
Q

What is typically affected in mitochondrial disease?

A

Tissues with high energy requirements, such as CNS, heart, and muscle

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8
Q

What can you diagnose on prenatal fetal karyotype?

A

All aneuploidies, including trisomies, Turner syndrome, other sex chromosome aneuploidies, and large rearrangements

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9
Q

How long after CVS or amniocentesis sampling are karyotypes available, why?

A

7-14 days after sampling, need metaphase of cultured cells

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10
Q

What is the diagnostic accuracy of karyotype analysis for aneuploidy and chromosomal abnormalities larger than 5-10 megabases?

A

> 99%

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11
Q

What does FISH stand for?

A

Fluorescence in situ hybridization

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12
Q

How shortly after CVS or amniocentesis are FISH results ready, why?

A

Usually within 2 days, do not need to culture cells. Can do it with cultured cells, which takes 7-14 days

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13
Q

Is FISH on CVS or amniocentesis considered diagnostic or screening testing?

A

Screening test. Abnormal FISH should not be considered diagnostic

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14
Q

Clinical decision making based on information on prenatal FISH (from CVS or amnio) should include at least one of the following additional results:

A

confirmatory traditional metaphase chromosome analysis or chromosomal microarray, or consistent clinical information (such as abnormal US findings or positive screening test result for trisomy 21 or 18)

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15
Q

What can a microarray not detect when used for prenatal genetic testing (CVS, amnio)?

A

Balanced translocations and triploidy, some cases of low-level mosaicism

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16
Q

Can microarray for CVS/amnio sample be performed on culture or uncultured cells?

A

both

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17
Q

What is the typical turnaround time for direct chromosomal microarray analysis of uncultured cells from CVS or amnio?

A

3-7 days

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18
Q

What method of genetic analysis is preferred for cases of fetal death or stillborn, why?

A

Microarray, can yield results from nonviable cells that would not grow in culture (would not provide conventional karyotype)

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19
Q

What percent of fetuses with structure abnormalities on prenatal US will have significant chromosomal abnormalities on microarray with a normal karyotype?

A

6%

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20
Q

What is the primary test that should be offered for patients undergoing prenatal diagnosis for indication of a fetal structural abnormality detected by US? What is the exception?

A

Chromosomal microarray analysis. Exception is if structural abnormality is strongly suggestive of a particular aneuploidy, karyotype with or without FISH may be offered before microarray.

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21
Q

Chromosomal microarray finds pathogenic (or likely pathogenic) copy number variants in how many patients with normal ultrasound examination and normal karyotype?

A

Approximately 1.7%

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22
Q

Where do you get genetic material during preimplantation genetic diagnosis?

A

Polar bodies from oocyte and zygote, single bastomere from cleavage-stage embryo, or group of cells from trohpectoderm at blastocyst stage

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23
Q

Between what gestational ages do you perform chorionic villus sampling?

A

10 to 13 weeks

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24
Q

How do you perform chorionic villus sampling?

A

Transabdominally or transcervically. Continuous ultrasonographic guidance, tip of needle or specialized catheter placed in placenta without entering amniotic sac. Aspirate small amount of placental villi.

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25
Q

What is the advantage of CVS over amnio?

A

Can be performed earlier in gestation, shorter specimen processing time (5-7 versus, 7-14 days)

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26
Q

What is the rate of procedure-related pregnancy loss after CVS?

A

0.22% (1 in 455)

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27
Q

What is the risk of limb reduction after chorionic villus sampling? How does this compare to general population?

A

6 per 10,000. Not significantly greater than the incidence in general population. [greater risk appears to be when procedure before 10wks]

28
Q

What is the incidence of culture failure, amniotic fluid leakage, or infection after CVS?

A

Less than 0.5%

29
Q

When is amniocentesis for the purpose of genetic diagnosis usually performed?

A

Between 15 and 20wks, but can be performed at later GA

30
Q

Does chorion and amnion need to be fused before proceeding with amniocentesis?

A

Often postpone procedure if not fused as higher likelihood of failing to obtain amniotic fluid or requiring second puncture.

31
Q

What is the rate of procedure-related pregnancy loss that is attributable to amniocentesis?

A

Approximately 0.1-0.3% (1 in 370 to 1 in 900)

32
Q

What is the risk of amniotic fluid leakage after amniocentesis?

A

1-2%

33
Q

What is the perinatal survival rate in cases of amniotic fluid leakage after midtrimester amniocentesis?

A

> 90%

34
Q

What is the rate of amniotic fluid cell culture failure after amniocentesis?

A

0.1% of samples

35
Q

Do structural chromosomal abnormalities, such as microdeletions and duplications, increase in frequency with maternal age?

A

No

36
Q

What is the definition of advanced paternal age?

A

No consensus, most studies suggest age 40-50yo

37
Q

Are there additional recommended screening for pregnancies fathered by father with advanced paternal age?

A

No, routine care

38
Q

What does advanced paternal age increase the risk of? Why?

A

Single-gene disorders (eg, achondroplasia, Apert syndrome, Crouzon syndrome). Increased incidence of gene mutations that occur during spermatogenesis

39
Q

What is the % risk of having future offspring with unbalanced chromosomes if the parents are identified as carriers of chromosomal rearrangements after the birth of a child with abnormality?

A

5-30%

40
Q

What is the chance of parents having an offspring with unbalanced chromosomes if parents are found to be carriers of chromosomal rearrangements during an infertility workup?

A

0-5%

41
Q

Do women with Trisomy 21 have an increased risk of having an offspring with a trisomy?

A

Yes

42
Q

Do women with 47XXX have increased risk of offspring with trisomy?

A

No, but data limited

43
Q

Do men with 47XYY have increased risk of offspring with trisomy?

A

No, but data limited

44
Q

Do men with Klinefelter syndrome (47XXY) whose partners conceive by IVF with ICSI have an increased risk of aneuploidy in offspring?

A

No

45
Q

What is the general risk of having another child with an isolated structural abnormality that is not associated with recognized genetic syndrome?

A

Varies by anomaly and often by the sex of the affected child, but generally 2-3%, may be higher depending on number of affected individuals

46
Q

What is the recurrence risk after one affected pregnancy with autosomal trisomy or sex chromosome aneuploidy?

A

1.6x8.2 times the maternal age risk of autosomal trisomies

47
Q

What is FISH used for regarding prenatal genetic testing?

A

Can be used for rapid assessment of major aneuploidies (13,18,21, X and Y). On cultured cells can be used to detect microdeletions and duplications

48
Q

With IUFD, if fetal death recent, what is the best option to obtain fetal cells that are most likely to grow in culture and yield a karyotype?

A

Amniocentesis.

49
Q

Can amniocentesis lead to vertical transmission of hepatitis B?

A

Yes

50
Q

What increases the risk of vertical transmission of hepatitis B at the time of amniocentesis?

A

High viral load (21-fold higher rate of newborn infection compared to low viral load) and positive for hepatitis B e antigen

51
Q

What is the risk of vertical transmission of Hepatitis C with amniocentesis?

A

Appears to be low

52
Q

Can amniocentesis lead to vertical transmission of HIV?

A

Yes, prior to current retroviral regimens. With current regimens with no viral load no increased risk of transmission.

53
Q

What are the options for pregnancy management with twin gestation where only one fetus has aneuploidy?

A

Continuation of pregnancy, terminating entire pregnancy, selective 2nd tri termination of affected fetus

54
Q

What is the attributable loss rate of amniocentesis performed in twins?

A

1-2%

55
Q

What is the procedure-related loss rate for CVS?

A

1%

56
Q

What is one of potential complication from CVS in twin gestation that might give misleading results? What is the risk of this complication?

A

Cross contamination, or inadvertent sampling of both fetuses. Approximately 1%

57
Q

How often does chromosomal mosaicism occur in amniocentesis specimens?

A

0.25%

58
Q

How often does chromosomal mosaicism occur in CVS specimens?

A

1%

59
Q

What can cause a false-positive mosaic result on amnio or CVS?

A

If there is maternal cell contamination

60
Q

How can you technically reduce the rate of false-positive results of mosaicism for amniocentesis and CVS?

A

Discard first 1-2mL of amniocentesis specimen. Carful dissection of CVS from maternal decidua

61
Q

Is mosaicism higher in CVS samples that are tested directly or cultured trophoblasts?

A

Tested directly

62
Q

What is the next step in management if CVS results mosaicism?

A

Offer amniocentesis. In approximately 90% of cases amnio is normal and mosaicism is assumed to be confined to trophoblast (placental mosaicism)

63
Q

What is placental mosaicism?

A

Mosaicism confined to trophoblast

64
Q

What is the obstetric implication of placental mosaicism?

A

Increased risk of third-trimester growth restriction. Unlikely to cause defects in fetus

65
Q

What is trisomy rescue?

A

Conception originally was trisomy, which is seen in placenta, but fetus with euploid karyotype

66
Q

What is uniparental disomy and what implications does it have?

A

Condition in which both chromosomes were inherited from the same parent, can involve any chromosome. If imprinted genes are present on the chromosome involved, this may have consequences for the fetus (eg, Prader-Wili or Angelman syndromes)

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