Prenatal Genetics

Question 1

Prenatal Diagnosis

Answer 1

• medical evaluation of a fetus- that provides both physical and genetic information
• genetic testing has the capability to diagnose fetal disease
• prior to testing, parents should be counseled about the reasons to do the test and the possible outcomes
• depending on the type of test, there could be a risk to the mom and to the pregnancy

Question 2

Indications for Prenatal Diagnosis-Inherited

Answer 2

• 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 3

Other Reasons for Prenatal Diagnosis

Answer 3

• ultrasound anomaly
• repeated miscarriages
• Abnormal MSAFP (maternal serum alphafetoprotein)
• anxiety
• environmental exposures
• increased risk of a chromosomal abnormality

Question 4

Relative Frequency of Types of Aberration

Answer 4

• most common live birth anomaly is trisomy 21
• most common aneuploidy is 45,X
• most common autosomal aneuploidy is trisomy 16
• triploidy is the third highest frequency cause of fetal loss

Question 5

Spontaneous termination frequencies

Answer 5

• 95% of 45,X conceptions
• 90% of trisomy 12 conceptions
• 80% of trisomy 18 conceptions
• 65% of trisomy 21 conceptions

Question 6

Tests available

Answer 6

• examination
• ultrasound
• cytogenetics
• biochemical
• molecular studies

Question 7

invasive vs non-invasive tests

Answer 7

• in general, non-invasive is better than invasive- less risk to the fetus
• want the most specific information at the least risk
• types of testing performed depends on clinical indication- and what information needs to be collected

Question 8

Ultrasound

Answer 8

• verify viability
• detect a multiple pregnancy
• determines the gestational age
• determine the sex
• identify possible abnormalities
• may indicate that additional studies are needed
• usually performed around 18 weeks

Question 9

Nuchal translucency

Answer 9

• indicator on ultrasound of a possible abnormality in a fetus like chromosomal
• thickness of 6.0 mm has been associated with Down syndrome

Question 10

Clefting

Answer 10

-unilateral or bilateral cleft lip, cleft palate, or both can be detected on ultrasound and are usually indicators of a genetic defect

Question 11

Neural tube defects

Answer 11

• can be detected on ultrasounds
• like a meningomyelocele
• range of severity
• less severe forms may be corrected surgically, more severe can be debilitating
• closed: skin is intact
• open: rupture in the skin (spinal fluid mix with amniotic fluid)
• severe ones like anencephaly- absence of the brain and is lethal
• encephalocele when the brain is extruded from the skull

Question 12

Maternal Serum Alphafetoprotein

Answer 12

• 15-20 weeks
• high, low, normal
• gestational age
• mother’s weight, race, diabetic status
• produced by fetal liver and crosses the placenta and can be detected in maternal circulation
• AFP is correlated to the stage of gestation
• risk assessment
• low levels: Down syndrome
• high levels: ONTD- open tubular defects

Question 13

Maternal Serum Quad Test

Answer 13

• 4 different substances
• alpha fetoprotein low
• hCG up
• unconjugated estrol low
• dimeric inhibin up
• 80% combined detection for DS
• can be used up to 40 years

Question 14

Integrated Prenatal Testing

Answer 14

• 10-13 weeks gestation:
• PAPP-A (pregnancy-associated plasma protein A, when lower associated with increased risk of DS)
• nuchal translucency
• 15-21 weeks gestation the Quad MSAFP testing is performed

Question 15

Non-invasive Prenatal Screening/Testing

Answer 15

• the newst non-invasive assay is know as NIPS
• cffDNA= cell free fetal/placental DNA
• isolated from maternal blood at 10-22 weeks gestation
• 10-15% of cfDNA in maternal blood is fetal in origin

Question 16

Technology

Answer 16

• 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 and fetus

Question 17

Detection of Aneusomy

Answer 17

• the expected amounts of DNA per chromosome are analyzed, and any increase or decrease in the total value for a particular chromosome would suggest an aneuploidly
• the numbers are very small, so the hardware and software have to be precise
• it is a screening test that gives a risk for a chromosomal abnormality
• if the numbers are out of bounds it has to be confirmed by a diagnostic test which is usually a karyotype analysis and/or FISH

Question 18

NIPS accuracy

Answer 18

• DS (+21) and trisomy 18:99%
• trisomy 13:72-92%
• XX: 98.4%
• XY: 99%
• abnormals should be confirmed
• 0.5-7 failure rate- due to insufficient fetal DNA

Question 19

Amniocentesis

Answer 19

• needle inserted through abdomen into the amniotic cavity
• 14-20 weeks gestation- usually done 16-18 weeks, can be done as late as 35 weeks
• risk at 1/200
• test possible- AFAFP, cytogenetics, metabolic assays, molecular diagnostics

Question 20

Low AFP Levels

Answer 20

• Trisomies 13, 18, 21
• Mosaic Turner syndrome
• Triploidy
• Unbalanced translocations

Question 21

Elevated AFP Levels

Answer 21

• increased risk of ONTD
• acetylcholineesterase is the confirmatory test
• AChE should only be present in amniotic fluid if there is a defect in the neural tube

Question 22

AFP testing is for screening ONLY

Answer 22

• confirmatory tests
• elevated AFP associated with ONTD- elevation in acetylcholinesterase in the amniotic fluid
• low AFP- chromosomal disorders, specifically Down Snydrome, karyote analysis

Question 23

Chorionic Villus Sampling

Answer 23

• 10-14 weeks gestation
• limb reduction when done <10 weeks
• risk 1/100
• cytogenetics, molecular diagnostics, metabolic (cells only)
• usually works because fetus and placenta come from same zygote (unless mosaicism)- abnormal CVS test may merely mean there is a problem with the placenta

Question 24

Localized Mutation- Placental

Answer 24

• -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
• if only part of the placenta has a mutation, it is called confined placental mosaicism
• a mutation in the placenta may or may not affect the development of the fetus
• if the placenta is sufficiently compromised if may not support fetal development
• if a CVS is done and detects a mutation, it could result in a misinterpretation of the fetal status

Question 25

Confined Fetal Mutation

Answer 25

- if the only cells with the mutation occur in the fetus, then the CVS testing will miss that all together - this risk is low since this doesn't occur very often, but whenever CVS testing is done early, it is important to continue to monitor the pregnancy - the fetus may be completely abnormal or only some of the cells may have the mutation

Question 26

Why choose CVS

Answer 26

-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 27

Outcomes of Prenatal Diagnosis

Answer 27

- no anomalies in 98% of cases - termination - fetal treatment in utero - IVF

Question 28

Assisted Reproductive Technologies

Answer 28

- IVF - intracytoplasmic sperm insertion - zygote intrafallopian transfer - donor egg

Question 29

Polar Body Analysis

Answer 29

- polar body can be collected and tested with no ill effects to the oocyte - a polar body can be collected and tested with no ill effects to the oocyte - if the 1st polar body tests positive for the CF mutation known to be carried by the mom than the corresponding egg would be expected to have CF mutation

Question 30

Preimplantation Genetic Diagnosis

Answer 30

- polar body analysis is difficult so prenatal genetic diagnosis was developed - screening technique for embryos - unsatisfactory = destroyed - eggs collected and fertilized in vitro, at 8 cell stage a single cell is separated out and tested by FISH or molecular assay

Question 31

Next generation screeening

Answer 31

- replace PGD because it is a whole genome screen | - 3000-5000 dollars

Question 32

Donor Egg

Answer 32

- one for mitochondria problems, moms nucleus put in donor egg - or can just carry a donated egg