213. Repro Genetics

Question 1

What are the 9 indications for prenatal Dx by invasive testing?

Answer 1

1. Advanced Maternal Age (>35 yo)
2. Previous child with de novo Ch abnormality
3. Presence of structural Ch abnormality in one parent (balanced)
4. FamHx of genetic disorder that can be dx with DNA analysis (both partners know they are carriers)
5. Risk of NTD (parent or sibling with NTD)
6. Abnormalities in maternal serum screening, cell free DNA, US soft markers
7. Older Paternal Age (no recommended age specifically)
8. Parental Aneuploidy or aneuploidy mosaicism
9. Prior child with structural birth defect

Question 2

Explain the following

• Chorionic Villous Sampling
• Amniocentesis

Answer 2

CVS: 10-13wks ga, transcervical or transabdominal sample of villous tree tissue to detect placental mosaicism (NO AFP analysis)

Amnio: 15-20wks ga, assess karyotype and amniotic AFP, culture amniotic fluid cells to obtain Ch/DNA results
- indications: maternal age, paternal Ch translocations, previously affected offspring, maternal serum screening

Question 3

Maternal Serum Screening

• 2nd trimester: what is checked (4), signs of Down Syndrome, trisomy 18, NTD
• 1st trimester: what is checked

Answer 3

2nd: QUAD SCREEN: AFP, uE3, b-hCG, DIA (inhibin A)
- Down Syndrome: low AFP, low uE3, high hCG, high DIA
- Trisomy 18: low AFP, low uE3, low hCG
- NTD: high AFP

1st: better spec and sens than quad screen, uses US and serum markers
- aneuploidy: less PAPP-A
- b-hCG: low in Trisomy 18, high in Down syndrome
- nuchal translucency (US finding)

Question 4

Explain the following

• cell free DNA screen
• carrier screening for mendelian disorders
• NTD Screening
• sonographic screening
• whole exome studies

Answer 4

Cell Free DNA: cell free DNA circulates in maternal plasma (maternal and fetal) - use parallel sequencing to match fragments to chromosomes, higher total Ch21 material - trisomy 21

Carrier screen: ID couples at risk (carrier freq should be high enough, interventions should be avail), DNA analysis, enzyme assays, RBC parameters

NTD Screen: elevated AFP = NTD

Sonography: higher risk of genetic disorders with structurally abnormal fetus or fetus with severe growth lag; “soft markers” are minor anomalies that assoc with higher risk aneuploidy

Whole exome studies: high dx yield, not commonly done, high numbers incidental findings, potential for positive VUS (variant of uncertain specificity), very expensive, long time for results if planning to terminate