Reproductive Genetics 1 Flashcards
List indications for prenatal genetic diagnostic testing.
1
Q
What are the goals of prenatal diagnosis?
A
- Provide information, reassurance, and options
- Non-directive counseling
- Pregnancy management options
- ending pregnancy
- treating fetus
- medical and psychosocial preparation
- Management of dlivery/neonatal care
2
Q
What are the major forms of prenatal diagnosis?
A
-
Genomic assessment
- karyotype
- array based
- single gene mutation analysis
-
Analyte detection
- measure AF-AFP and acetylcholinesterase to detect open neural tube defects
-
Structural survey with ultrasonography
- overt anomalies and aneuploidy “markers”
-
Infection evaluation (amniotic fluid)
- culture, PCR
3
Q
What are the indications for prenatal testing?
A
- Maternal age
- age 35 or older
- risk of miscarriage associated with amniocentesis equals risk of fetus with chromosome abnormality at this age
- risk of amniocentesis has gone down so this is no longer a strict age
- Previously affected child
- 1% risk for empiric recurrence of fetal aneuploidy
- Parental chromosome rearrangement
- risk varies from 1-2% for Robertsonian translocations
- 100% for maternal 21;21 translocations
- very low risk for inversions
- neural tube defects also a risk
- Family history of genetic disease
- multifactorial disorders
- NTDs
- congenital heart disease
- some can be ruled out with biochemical or DNA analysis
- Abnormal screening
- ultrasound findings
- bloodwork
- Maternal anxiety
4
Q
What are the advantages of screening tests vs. invasive testing?
A
-
Screening
- no miscarriage risk
- refince chance beyond maternal-age risk
- high sensitivity
- limited to trisomy 21 and 18 detection
-
Invasive testing
- 1/500-1/1000 procedure-associated loss
- definitive diagnosis
- all chromosomes tested
- Mendelian disorders feasible
5
Q
List the types of invasive testing for prenatal diangosis.
A
- Amniocentesis
- Chorionic villus sampling
- Cordocentesis
- Preimplantation genetic diagnosis
6
Q
List the types of noninvasive testing for prenatal diagnosis.
A
- First trimester aneuploidy screening
- Second trimester maternal serum multiple marker screen
- Ultrasonography
- Isolation of fetal DNA from maternal circulation
- Integrated or sequential screening
7
Q
Describe the application, risks, and benefits of amniocentesis.
A
-
Application
- performed at 15-20 weeks gestation
- karyotype and amniotic fluid alpha-fetoprotein routinely assessed
- amniotic fluid cells cultured to obtain chromosome/DNA results
- turnaround time usually 10-14 days
-
Benefits
- well-established diagnostic assays (99.9% accurate)
- readily available
- safety rates generally accepted
- well-tolerated
- good for NTD testing
-
Risks
- 1/1000 risk for miscarriage
8
Q
What are amniotic fluid cells and how are they used for genetic analysis?
A
- Direct fetal sources
- respiratory
- GI
- GU
- epidermis
- Require culturing for most analyses
- Growth and density of AF cells ideal at 16-18 weels gestation
- Potential for in situ hybridization and genomic array analysis
9
Q
Describe the application, risks, and benefits of chorionic villus sampling.
A
-
Application
- performed transabdominally or transcervically at 10-12 weeks
- obtains chorionic tissue for karyotype or DNA analysis
-
Risks
- miscarriage risk of 1/300-500
- less available than amniocentesis
-
Benefits
- detects placental mosaicism
- found in about 1% of patients
- can be used for other genetic defects as well except for NTDs
- detects placental mosaicism
10
Q
What are the indications for invasive prenatal diagnosis?
A
- Advanced maternal age
- Previous child with chromosome abnormality
- Abnormal serum screening
- At risk for single gene disorder
- At risk for NTD
- Abnormal sonogram (fetal anomalies)
11
Q
What components are measured in maternal serum screening? What can they suggest?
A
- Analytes
- alpha-fetoprotein (AFP)
- unconjugated setriol (uE3)
- human chorionic gonadotropin (hCG)
- inhibin A
- Results
-
Down syndrome
- low AFP
- low uE3
- high HCG
- high Inhibin
-
Trisomy 18
- low AFP
- low uE3
- low HCG
-
NTD
- high AFP
-
Down syndrome
12
Q
What are the disadvantages of maternal serum screening?
A
- Less effective in twin gestations
- Less effective in younger maternal age groups
- Being replaced by analyzing fetal DNA in maternal plasma
13
Q
What are the screening methods used in the first trimester?
A
- Ultrasound assessment of nuchal translucency
- presence indicates increased risk for aneuploidy
- Aneuploidy screening - maternal blood screen for:
- PAPP-A
- reduced in aneuploid pregnancies
- hCG
- elevated in pregnancies in Down syndorme, reduced in trisomy 18
- PAPP-A
14
Q
How is massive parallel sequencing used in prenatal screening?
A
- Used to detect levels of fetal DNA in maternal blood
- Small changes in ratio can be greatly amplified and suggest presence of fetal aneuploidy
- Especially useful for trisomy 21 (Down Syndrome)
- detects 99.5%
- Also detects 95-100% of fetuses with trisomy 18 or 13
- False positive rate is <0.1%
15
Q
Describe the process of carrier screening for mendelian disorders. What are some common disorders?
A
- Certain single gene mutations are tested for based on patient history, family history, heterozygote testing, and hich prevalence disorders based on ethnicity
- Performed through DNA analysis (most accurate), enzyme assays, or red blood cell parameters
- Disease tested for:
- African-American: hemoglobinopathies, esp. Hgb S, C, other
- Mediterranean: beta-thalassemia
- SE Asian: alpha-thalassemia
- Caucasian: cystic fibrosis
- Ashkenazi Jews: Tay-Sachs, CF, Canavan, Gaucher, familial dysautonomia
