Genetic Screening and Risk Assessment

Question 1

What is newborn screening? What is the goal of newborn screening?

Answer 1

Newborn screening: searching for a mutation that can cause the disease in the person carrying the gene (newborn)
- Goal: detect/prevent disease before serious symptoms occur

Question 2

What are the three diseases screened for in newborns in all US states?

Answer 2

• Phenylketonuria
• Galactosemia
• Hypothyroidism

Question 3

What type of disease is Phenylketonuria (PKU) and what gene does it involve?

Answer 3

PKU is an autosomal recessive mutation involving the Phenylalanine Hydroxylase (PAH) gene

Question 4

Describe the function of the PAH gene normally, and what occurs with PKU (pathological state)

Answer 4

Normally, phenylalanine is converted to tyrosine via PAH (tyrosine used to produce dopamine)

With PKU, the PAH enzyme is deficient causing an accumulation of phenylalanine, which is then converted to phenylketones (also accumulates)

Question 5

What are the symptoms of PKU (6), and how does accumulation of phenylalanine/phenylketones affect the brain specifically? (include the mechanism, and how it affects dopamine levels)

Answer 5

PKU symptoms: intellectual disabilities, mental retardation, seizures, tremors, hyperactivity, stunted growth

High levels of phenylalanine and phenylketones may be toxic to the brain

• Excess phenylalanine may saturate large neutral amino acid transporters (LNAATs) located at the BBB, so this leads to excess phenylalanine in the brain AND prevents other large neutral AAs from entering normally
• No tyrosine = no dopamine or adrenaline produced

Question 6

What is the treatment for PKU?

Answer 6

Low-phenylalanine diet (no meat, fish, eggs, dairy, wheat, legumes/nuts)

Question 7

What is maternal PKU? How can high levels of phenylalanine from the mother affect the fetus?

Answer 7

Maternal PKU: women with PKU who are planning to have children must start a low-phenylalanine diet BEFORE conception and THROUGHOUT pregnancy
- Phenylalanine can diffuse across the placenta and cause brain damage to the fetus even if the fetus is heterozygous and would not normally manifest PKU

Question 8

What is heterozygote screening? What is the goal of heterozygote screening?

Answer 8

Heterozygote screening: searching for a mutation that can cause the disease in the descendants of the carrier (parents are tested)
- Goal: detect unaffected carriers (heterozygotes) of gene mutations and prevent genetic diseases in their offspring

Question 9

What is the method for heterozygote screening and to what disease type is this screening often applied to?

Answer 9

Parents are screened via blood testing

- Most heterozygote screening is applied to autosomal recessive disorders (have a silent carrier)

Question 10

What does PGD stand for and to whom is it available to? What is an example of a disease tested through PGD?

Answer 10

Preimplantation Genetic Diagnosis (PGD) is available to couples at high risk for transmitting a harmful allele
- Tay-Sachs screening in Ashkenazi Jews who have a 1/30 heterozygote frequency

Question 11

Explain the process of PGD in 3 steps

Answer 11

1. After IVF, a single cell is removed from the 2-cell blastomere
2. PCR is applied to amplify the DNA obtained from that single cell
3. After testing, those embryos free of mutation can be implanted

Question 12

What is prenatal screening? Give two examples of invasive testing, two examples of non-invasive testing, and one example of new non-invasive testing

Answer 12

Prenatal screening: techniques conducted before birth

Invasive testing:

• Amniocentesis
• Chorionic Villus Sampling (CVS)

Non-invasive testing:

• Nuchal Translucency (NT) and Maternal Serum Screening
• Ultrasonography

New non-invasive testing:
- Cell-Free Fetal DNA

Question 13

What is the optimal time, samples collected (2), tests (3), conditions reflected (3) and risk involved with Amniocentesis?

Answer 13

Amniocentesis:

• Optimal time: 15-20 weeks
• Samples collected: amniotic fluid, amniocytes
• Tests: cytogenic analysis, DNA-based testing, fetal AFP
• Conditions reflected: chromosomal abnormalities, genotype status of selected gene(s), trisomies or neural tube disorders (NTD)
• Risk? 0.5% for fetal loss

Question 14

What is the optimal time, sample collected (1), tests (2), conditions reflected (2) and risk involved with Chorionic Villus Sampling (CVS)?

Answer 14

Chorionic Villus Sampling (CVS)

• Optimal time: 10-12 weeks
• Samples collected: fetal trophoblastic tissue
• Tests: cytogenic analysis, DNA-based testing
• Conditions reflected: chromosomal abnormalities (includes Trisomies), genotype status of selected gene(s)
• Risk? 1.0% for fetal loss

Question 15

What is the optimal time, samples collected (2), tests (2), conditions reflected (3) and risk involved with Nuchal Translucency (NT) and Maternal Serum Screening?

Answer 15

Nuchal Translucency (NT) and Maternal Serum Screening

• Optimal time: 11-14 weeks
• Samples collected: maternal serum, ultrasound
• Tests: NT measure, maternal AFP
• Conditions reflected: trisomies, NTD, chromosomal anomalies
• No risk

Question 16

What is the optimal time, sample collected (1), conditions reflected (2) and risk involved with Ultrasonography?

Answer 16

Ultrasonography

• Optimal time: 16-18 weeks
• Samples collected: visualization
• Conditions reflected: congenital malformation, NTD
• No risk

Question 17

What is the optimal time, sample collected (1), test (1), conditions reflected (2) and risk involved with Cell-Free Fetal DNA?

Answer 17

Cell-Free Fetal DNA

• Optimal time: 10+ weeks
• Sample collected: maternal blood
• Test: chromosome copy number
• Conditions reflected: trisomies, abnormal sex chromosome number
• No risk

Question 18

Why are Cell-Free Fetal DNA Tests often offered to women age 35+?

Answer 18

This test is still fairly expensive so it is typically offered to women age 35+ due to their maternal age and the associated increased risk for producing a child with a trisomy

Question 19

What condition does a low AFP value indicate a high risk for? What condition does a high AFP value indicate a high risk for?

Answer 19

• Low AFP: high risk for Trisomies

- High AFP: high risk for Neural Tube Defects (NTD)

Question 20

What three Trisomies are often tested for?

Answer 20

Trisomies 13, 18 and 21

Question 21

What three proteins are tested in a Triple Screen test? What is the optimal time to do this test, and what is there concern for with this test?

Answer 21

Triple Screen test three proteins, maternal serum AFP (MSAFP), hCG and estriol

• Optimal time: 16-18 weeks
• Concerns for false positives

Question 22

If Triple Screen test results show increased risk for Anencephaly and increased risk for Spina Bifida, what would test results indicate? What is the percentage risk for each condition?

Answer 22

95-98% chance of Anencephaly and 85-90% chance of Spina Bifida would demonstrate:

• Increased MSAFP
• Normal hCG
• Normal Estriol

Question 23

If Triple Screen test results show increased risk for Down Syndrome, what would test results indicate? What is the percentage risk for this condition?

Answer 23

60-65% chance of Down Syndrome would demonstrate:

• Decreased MSAFP
• Increased hCG
• Decreased Estriol