Genetic Diagnosis

Question 1

What terms apply to the following definitions?

1. Testing DNA, RNA, proteins for abnormalities
2. Test population for unrecognized conditions
   
   • sort those probably affected form probably not
3. Test populatin for specific genotypes
   
   • may affect them or future generations

Answer 1

1. Genetic Testing
2. Population screening
3. Genetic screening

Question 2

What characteristics should be considered befrore screening for a disease?

Answer 2

1. Disease characteristics
   
   1. common and serious conditions
   2. natual history should be known
   3. need a treatment option or prenatal diagnosis
2. Test characteristics
   
   1. acceptable to population
   2. easy, inexpensive, valid, relaible
3. System characterisics
   
   1. accessible resources for diagnosis and treatment
   2. efficient method of communicating results

Question 3

Describe how neonatal PKU meets the criteria for genetic screening.

Disease?

Test?

System?

Answer 3

• Disease?
  
  • 1/10-15,000 newborns affected
  • >95% untreated cases suffer severe developmental delay
  • dietary management is possible
• Test?
  
  • (older version) blood drop form heel stick – simple and inexpensive
  • (new version) mass spectrometry of many metabolites
• System?
  
  • rescreen 2-4 weeks if positive

Question 4

Identify the type of result that falls into each box.

What is the ability to correctly identify affected individuals? How is this calculated?

Whta is the ability to correctly identify unaffected individuals? How is this calculated?

Answer 4

sensitivity = a/(a+c)

specificity = d/(d+b)

Question 5

Setting a cutoff point is a balance between which two concepts?

What is the cutoff for creatine kinase level screening for female carriers of muscular dystrophy? Is this a perfect cutoff?

Answer 5

specificity and sensitivity

the cutoff is 95% for notmal females. This means 5% normal females are false positives, but also that a good number of heterozygous females are being detected as false negatives

Question 6

What is the accuracy of a positive test?

What is the accuracy of a negative test?

What are these numbers most dependent on?

Answer 6

accuracy of positive test: positive predictive value = a/(a+b)

accuracy of negative test: negative predictive value = d/(d+c)

dependent on prevalence in population

Question 7

What is the impact of prevalence on predictive value?

Answer 7

a higher prevalence increases predictive value (accuracy of a positive predictive test)

Question 8

What are comon newborn screenings?

Why is newborn screening performed?

Answer 8

• PKU
• galactosemia
• hypothyroidism
• hemoglobin disorder (HbS)
• muscular dystrophy

can be used to inform future reproductive decisions

Question 9

What is the purpose of heterozygote screening?

Answer 9

find carriers in population at risk

aid in reproductive decisions, prenatal diagnosis

Question 10

What type of screening is applied to presons at risk for certain disorders? What are exaples of diseases that are screened for like this?

Why are these types of screenings performed?

Answer 10

presymptomatic diagnosis

• diseases that appear late in life: huntington’s, familial breast cancer, polycystic kidney disease
• ease mind of non-carriers; aid in reproductive decisions; decide about medical options

Question 11

What are some limits of genetic testing?

Answer 11

• no test is 100% accurate
  
  • genotyping errors can occur
  • mosaicism
• tests find mutatinos, not disease
  
  • penetrance varies as does age of onset
• not all mutations are known and/or have tests
  
  • CF, most common is only 70%
• complex ethical and social considerations
  
  • stigma, no treatment, affects family members

Question 12

What are the 7 methods used to perform prenatal diagnosis of genetic disorders?

Answer 12

• ultrasound
  
  • noninvasice, no known risks to fetus
  • not very sensitive, but very specific
    
    • may not find everything, but when you do, you know what it is
    • meningomyelocele (irregular development spinal column)
    • nucal translucency (measure width of fluid accumulation near cervical spine– Turner’s syndrome)
• Amniocentesis
  
  • 15-17 weeks
  • 10-12 day for cytogenetic test results
    
    • may change during culture
    • must be assessed to differentiate mosaicism from pseudomosaicism
  • biochemical/karyotype measurment on amniotic fluid
  • 0.5% pregnancy loss
• Chorionic Villus sampling
  
  • 10-11 weeks
  • 2 approaches
    
    • transcervical (no needle)
    • with needle through absomen
  • samples placental tissue
  • can be complicated by confined placental mosaicism
    
    • follow-up with amniocentesis
• Fetal blood sampling
  
  • PUBS
  • blood from umbilical
  • hematologic disorder – rapid cytogenetic results
  • way to distinguish between fetal mosaicism and other types in vitro
• Maternal Serum AFP
  
  • less invasive than amniocentesis
  • ranges normal and abnormal overlap
  • after 15 weeks
  • low in Down’s and other conditions
  • also measure ungonjugated estriol and human chroionic gonadotropin, inhibin A for quadruple
• Measuring Metabolites
  
  • tandem mass spectrometry
  • compare to “normal”
• Cell-free DNA
  
  • some form fetus, mainly placenta
  • increases with time
  • need to look for paternal marker
  • detect sex, Rh status, aneuploidies