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
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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
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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
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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
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5
Q

List the types of invasive testing for prenatal diangosis.

A
  • Amniocentesis
  • Chorionic villus sampling
  • Cordocentesis
  • Preimplantation genetic diagnosis
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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
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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
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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
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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
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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)
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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
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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
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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
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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%
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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
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16
Q

What is a good indicator of neural tube defects? When and how is it measured?

A
  • Alpha-fetal protein can be measured in maternal serum at 15-20 weeks
  • Can also be measured directly from amniotic fluid (AF-AFP) as a way to assess risk for open spina bifida or anencephaly
  • Livebirth incidence about 1:1000
    • decreasing because of folate-reinforced foods
17
Q

What are some of the newer array-based testing technologies?

A
  • Array comparative genomic hybridization (aCGH)
    • detects copy number changes at higher resolution than traditional karyotyping
    • genome-wide or cover only selected regions
    • cannot detect ploidy abnormalities, such as triploidy
  • Single nucleotide polymorphism-based arrays (SNP array)
    • detects copy number AND copy neutral changes
      • uniparental disomy
      • consanuinity
    • can detect ploidy abnormalities