Genetics Exam Iii: Prenatal Diagnosis And Population Screening

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Testing to identify an unrecognized disease and to sort out those who probably have the disease from those who probably do not.

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Population screening

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A search within a population for genotypes associated with a disease.

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Genetic screening

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Measure by the 2 parameters: sensitivity and specificity

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Valdity of tests

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Valdity of screening

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Refers to the ability of that test to separate individuals who have the disease from those who do not.

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The unaffected people who tested negative

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True Negatives

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The affected people who tested positive

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True Positive

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The affected people who tested negative

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False Negatives

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The unaffected people who tested positive

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False Positives

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The proportion of affected individuals who are "screen positive"

The test's ability to correctly identify those WITH the diseaase.

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Sensitivity

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The proportion of unaffected individuals who are "screen negative"

The test's ability to correctly identify those WITHOUT the disease.

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Specificity

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Equation for sensitivity

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(true positives) / (true positives + false negatives)

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Equation for specificity

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(true negatives) / (true negatives + false positives)

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Increasing sensitivity lowers specificity

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Modifying a test to detect all affected individuals (no false negatives) will often increase the number of false positive.

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Increasing specificity lowers sensitivity

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Modifying a test to avoid all false positives

Will increase the number of false negatives

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Tells us the proportion of positive tests that truly detect the disease. This is true positives/all positives which include true positives and false positives.

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Positive predictive value

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Purpose of prenatal screening

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1. Offered to all pregnant women

2. Designed to detect women who are at an increased risk to have a child with certain birth detects, chrom. or genetic conditions.

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What are the methods to screen pregnant women?

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1. Maternal age
2. Family medical history
3. Maternal serum screeing
4. First trimester screening
5. Screen positive rate

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Maternal age

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Women over the age of 35 should be offered diagnostic testing.

They are at an increased risk for non-disjunction events & trisomic chrom. abnormalities.

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Maternal serum screening

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is a blood test on the mom, which tests for substances normally produced during pregnancy.

1. AFP (alpha-fetoprotein)
2. Quadruple Screening

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AFP (alpha-fetoprotein)

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Performed between 15-23 weeks of gestation, not earlier or later since there are no values to compare to.

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Elevated amounts of AFP cause?

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Increase the risk of open neural tube defects (ONTDs) and ventral wall defects.

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Low levels of AFP cause?

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Increase risk of Down syndrome

But this is not a good screen for Down syndrome. Can be used for women who are only concerned about open fetal defects and do not want to know the risk of Down Syndrome.

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Can gastroschisis and omphalocele be detected using AFP maternal serum screening?

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Yes, these are disorders where the abdominal contents protrude.

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Quadruple Screening based on the pattern of 4 substances

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1. AFP
2. Human chorionic gonadotropin
3. unconjugated estriol
4. Inhibin A

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When is the quadruple screening done?

What does it screen for?

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Beginning to middle of the second trimester.

Screens for Down syndrome, trisomy 18, and ONTDs.

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What is the first-trimester screening?

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PAPP-A (pregnancy associated plasma protein A) and hCG and ultrasound measurement of nuchal translucency (NT).

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How is the measurement of the nuchal translucency (NT) taken?

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Measurement of the fluid filled area behind the neck that can be seen in ultrasound.

The wider it is, the more increased the risk of Down syndrome.

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Blood is drawn at what week for PAPP-A?

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10-14 weeks

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What does PAPP-A screen for?

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Down syndrome
Trisomy 18
NOT for neural tube defects (so the mom should have an AFP screening in the 2nd trimester)

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Integrated Screening

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Combines data from the first trimester screening (PAPP-A & NT) and the Quadruple screening in the 2nd trimester.

-Has the highest detection rate (sensitivity) with the lowest screen positive rate.

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Screen positive rate

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How many women will have a positive screen.

This indicates that the pregnancy is at risk, but is never diagnostic, even if it comes back with an extremely high risk.

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For patients with african american, middle eastern, asian, and mediterranean ethnic backgrounds

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Use hemoglobin electrophoreis is used to screen for sickle cell and thalassemias.

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For Ashkenazi Jewish, screening for what disease is recommended?

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1. Cystic Fibrosis
2. Tay Sachs
3. Canavan Disease
4. Familial Dysautonmia

remember, that these are not diagnostic tests

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Cystic fibrosis

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-Everyone is offered screening for 23 of the most common mutations

-Most common in caucasians

-Negative carrier testing reduces carrier risk, but does not eliminate it.

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When should carrier screening be offered?

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-Ideally take place prior to conception. Typically insurance companies will not cover it.

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Various strategies for carrier screening

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1. Test one partner (often female). Only test 2nd partner if positive

2. Test both partners and give independent results

3 Test both partners and only report if the pregnancy is at risk, not who the carrier is.

3.

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Ultrasound

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-Performed around 20-22 weeks gestatin
-Evaluates anatomical structure of the fetus, amniotic fluid levels, and placenta

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Ultrasound can also screen for soft signs, which are?

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1 Nuchal translucency (can inc. risk for down syndrome)

2. Choroid plexus cysts: benign cysts on the brain that usually resolve on their own and are related to inc. development of trisomy 18

3. An intracardiac echogenic foci: bright spot on the heart, which increases risk of chrom. abnormalities

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When is prenatal diagnosis used?

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Offered to women at an inc. risk due to risks associated with prenatal diagnostic procedures:

1. advanced maternal age
2. abnormal serum screening
3. known carrier status in parents
4. abnormal ultrasound findings

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Examples of prenatal diagnosis

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1. Amniocentesis
2. Early Amniocentesis
3. Chorionic Villus sampling (SVS)
4. Cordocentesis or Percutaneous Umbilical Blood Sampling (PUBS)

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Amniocentesis performed when?

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Typically done 15 and 22 weeks, but can be doen any time after 15 weeks.

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How is amniocentesis done?

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Use ultrasound guidance to find the placenta and withdraw cells, which are sloughed off. Then, the chrom. are analayzed and tested for genetic disorders.

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What else can amniocentesis be used for besides chrom. abnormalities?

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Can measure amniotic fluid AFP and acteylcholinesterase to screen for ONTDs.

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Are there risks for amniocentesis?

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Yes, there is a miscarriage risk of 1/200-1/300, maybe as low as 1/1600.

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Early amniocentesis occurs when?

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Between 11 and 14 weeks, hence "early."

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What can early amniocentesis NOT screen for?

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Cannot screen for ONTDs, so you still need AFP screen later.

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Is there any risk in early amniocentesis?

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Yes, there is a 1% miscarrage risk, risk for club foot because baby has less space to move, and risk for pulmonary development

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Chorionic Villus Sampling (CVS) is performed when?

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Between 10 and 12 weeks

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How is CVS performed?

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Obtains a sample of chorionic villi (membrane around the amniotic sac derived from the placenta).

Can enter stomach transcervically or transabdominally

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What can CVS screen for?

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1. Chromos & genetic testing
2. NOT screen for ONTDs
3. Detect mosaicism

Mosaicism is generally confined to the placenta, so there is a second cell line present in the placenta, but not the fetus.

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When should amniocentesis be done to determine if the baby has true mosaicism or confined placental mosaicism?

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In the second trimester because these cells come directly from the baby, not the placenta.

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When is cordocentesis or Percutaneous Umbilical Blood Sampling (PUBS) done?

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Performed after 16 weeks of gestation

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How is Cordocentesis or PUBS conducted?

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Involves puncturing the umbilical cord and drawing a small amount of blood

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What are the benefits of prenatal diagnosis?

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1. Prepare for the birth of a child with special needs
2. Option of terminating an affected fetus
3. Possible fetal treatment

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Fetal treatment

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When intervention during pregnancy is more beneficial that postnatal treatment.

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What are the examples of surgical treatments available?

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1. Fetal shunts for hydrocephalus (fluid buildup on the brain), which relieves the pressure on the brain so it can grown normally.

2. Cystic Hygromas

3. Open fetal surgery for spina bifida: spinal problems repaired are perfo

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Preimplantation genetics diagnosis

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Diagnosis of the embryo prior to implantation. Has to be utilized with in vitro fertilization.

For genetic disorders, must know specific mutations in the family.

1. Embryo biopsy
2. Polar body diagnosis

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What technology is used for preimplantation genetics diagnosis?

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FISH since there is not enough time for full karyotpe.

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Embryo Biopsy

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Around day 3, at the 6-10 cell stage, 1-2 blastomeres are removed. PCR and FISH performed on day 4, and normal embryos are implanted onday 5

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Polar Body Diagnosis

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Used to test heterozygote carriers for a defective gene or to screen for aneuploidy.

Ovum's composition can be inferred from polar body analysis.

ONLY looks at maternal contribution

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Neonatal Screening Program

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Detects genetic diseases in the newborn populatlion pior to damage caused by disease.

Often detects metabolic conditions

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Example of a disease that caused the creationof neonatal screening program

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Phenylketonuria where infants cannot process phenylalanine. If not avoided, can develop mental retardation.

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Neonatal screening program-MI

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Each state decides what tests they will include.

Michigan state law requires that all newborns be screened between 24 and 36 hours after birth.