Population Genetics

Front 1

Carrier screening is most commonly used for ______ and _______ conditions in couples planning their families. Screening is targeted for specific known mutations based upon the mutation _______ and _________ in a specific POPULATION. (Give an example of a success story. Give an example of a non-success.)

Back 1

Autosomal recessive
X-linked
Spectrum
Frequency

Key example success: Tay-Sach’s disease → now almost completely eliminated in Ashkenazi populations due to the carrier screening practices and prenatal diagnosis.

Non-success: screening for hemoglobinopathies (sickle cell, thalassemia) in the US has not led to a decreased incidence of illness. In Sicily, on the other hand, the same screening has been very effective.

Also → Cystic Fibrosis screening has just started. Jury still out.

Front 2

What are the criteria for carrier screening?

Back 2

• High carrier frequency in a given population
• Availability of an inexpensive test with high specificity/sensitivity
• Infrastructure for genetic counseling
• Availability of prenatal diagnosis
• Acceptance by a population

Front 3

Cystic Fibrosis is seen most in ______ populations with a carrier frequency of _____.

Back 3

Caucasian
1/25

Front 4

Explain why a screen might be more effective for some populations than others. Give an example.

Back 4

For example: CF sensitivity with a standard 30 mutation panel picks up 97% of cases in Ashkenazi Jewish populations. 90% for northern European populations. 70% for African American. And only 30% for Asian populations.

Front 5

What is our current standard of care for prenatal screening practices?

Back 5

Screening for hemoglobinopathis, CF, and a panel of 16 disorders for Jewish people.

Front 6

We can screen for Down syndrome using ________ which will indirectly indicate fetuses with increased risk. Screening is a combined test using _________ as well as sonography to detect ____________.

Back 6

Biomarkers
Multiple serum markers (ex: PAPP-A and HCG)
Nuchal translucency (higher nuchal translucency = greater risk for Down syndrome)

Front 7

What is the “integrated test” for prenatal screening for Down Syndrome.

Back 7

A step beyond the “combined test.” Serum markers using PAPP-A and HCG and sonogram for nuchal translucency are completed in the first trimester → the “combined test” (Sensitivity 85%. False positive 5%). Estriol, HCG, Inhibin-A and AFP are added in the second trimester (Sensitivity 90-95%). Results from the first and second trimester can be integrated to improve the test parameters.

[Don’t need to know the names of all this stuff]

Front 8

What are the WHO criteria for population based newborn screening (ex: phenylketonuria)?

Back 8

1.) Important health problem
2.) Accepted treatment
3.) Diagnosis and treatment facilities available
4.) Recognizable latent or early symptomatic state
5.) Suitable test or examination
6.) Test is acceptable to the population
7.) Natural disease history adequately understood
8.) Agreed policy on whom to treat as patients
9.) Cost balanced relative to possible expense for medical care.
10.) Case finding is a continuous process.

Front 9

What was the first disorder with population based screening? When was it put in place? What test was used? What other diseases have been added, when, and what tests?

Back 9

Phenylketonuria (PKU) was the first disorder with population based screening in 1964. The Guthrie test (microbial inhibition assay) was used. This assay detects very high levels of phenylalanine (the amino acids that PKU babies can’t digest and eventually causes mental retardation).

Hemoglobinopathies were added in the 1980’s after clinical trials showed that penicillin (PCN) prophylaxis was effective.

Front 10

What new technology greatly enhanced newborn screening practices? How does it work?

Back 10

Tandem mass spec allowed for quick and easy testing of many metabolic disorders. With it, you can screen blood spots for many metabolites simultaneously. The spectrometry sorts and quantifies metabolite molecules on the basis of molecular weight and charge. This gives you a distinct fingerprint (metabolic profile) for each baby.

Front 11

What are second tier genetic tests?

Back 11

This is a second test given in order to decrease the number of false positives. These are DNA-based, confirmatory tests. (EX: cystic fibrosis) Used after the tandem mass spec test.

Front 12

What is MCADD?

Back 12

This is the disorder that prompted tandem mass spec testing. Medium chain acyl dehydrogenase deficiency → a fatty acid oxidation disorder. It is common and readily treated by AVOIDING FASTING. 25% die before diagnosis; 25% result in neurological impairment. No deaths or neurological injuries have occurred since screening started.

Front 13

What are the two phases of CF testing?

Back 13

1st tier: Immunoreactive trypsinogen (IRT)
2nd tier: Confirmatory genetic testing