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Reproductive Genetics II

Risk of Down syndrome ACOG 2007: diagnostic testing regardless of age, not based solely on maternal age >35 yrs
Diagnostic options to detect down syndrome 1.CVS 2.Amniocentesis 3.maternal serum screening for aneuploidy
Risk of pregnancy loss assoc w/ CVS 1/2%
Risk of pregnancy loss assoc w/ Amniocentesis 1%
CVS and Amniocentesis can detect trisomy 21, cannot predict individual variation
Maternal Age >35 yrs is a poor screening test because 1.screen positive rate high- 15% of women 2.predictive value low- 1-2% are true trisomy 21 3.detection rate is low - 30% of trisomy 21
Aneuploidy screening tools Maternal serum markers: 2nd trimester (triple test-MSAFP, hCG, estriol; quad test- triple + inhibin); first trimester (PaPP-A, hCG; nuchal translucency); combined 1st and 2nd trimester screening
Screening for Down Syndrome - Quad screen sensitivity: 81%; PPV: 1/40 (2.5%); Screen positive: 5%
Screening for Down Syndrome - Nuchal lucency sensitivity: 81%; PPV: 1/50 (2.0%); screen positive: 4.2%
Screening for Down Syndrome - NL + PAPP-A, hCG (1st) sensitivity: 87%; PPV: 1/25 (4%); screen positive: 5.0%
combined 1st/2nd trimester screening 2 types: 1.nondisclosure ("integrated"), 2.disclosure (sequential, contingent)
nondisclosure combined 1st/2nd trimester screening PaPP-A and NL 1st trimester + Quad 2nd trimester; results released 2nd trimester; 97% detection (4.7% screen +)
disclosure combined 1st/2nd trimester screening NL + PaPP-A +hCG; disclosure of high risk results 1st trimester; all remaining return for quad (sequential)- 95% detection (4.9% screen +); only intermediate risk return for second trimester (contingent) - 93% detection (4.3 screen +)
Nuchal lucency > 4.0 highly unlikely to screen -ve on serum screening; 0.09% of population; 33% of aneuploidy
Nuchal lucency 3-4 8% have -ve serum screen; 0.3% of population; 17% aneuploidy
1st trimester markers of aneuploidy nuchal lucency, nasal bone, ductus venous
Absent NB likelihood of trisomy 21: 7.05
Ductus flow abnormal likelihood of trisomy 21: 6.42
molecular diagnostic modalities 1.Chorionic villus sampling, 2.Amniocentesis, 3.Percutaneous umbilical blood sampling
Risks of invasive fetal diagnostic procedures 1.Miscarriage, 2.fetal morbidity (rupture of membranes, malformations, infectious, isoimmunization), 3.technical (no sample obtained, misdiagnosis).
Fetal Morbidity of Amniocentesis (PPROM) Premature preterm rupture of membrane - 1% (91% survival)
Fetal Morbidity of Amniocentesis direct fetal trauma is rare with ultrasound guidance
Technical risks of Amniocentesis low technical failures for sample retrieval and culture failure; misdiagnosis can occur from maternal cell contamination
Fetal morbidity and CVS 1.limb reduction defect (recommend CVS >9 wks only) 2.Hemangiomas (3X increase over amnio), confined mostly to transcervical, no relationship to sample size, gestation at sampling, bleeding
Misdiagnosis on CVS 1.evaluation of solely direct or culture cells, 2.MCC, 3.confined placental mosaicism (1-2% of CVS samples, 1/3 reflect true fetal mosaicism, 2/3 are confined to placenta, risks of uniparental disomy, risks of fetal growth restrictions), 4.twins
early amniocentesis 9-12.9 wks
routine amniocentesis >15 wks
post procedure loss early amnio 4.2%
post procedure loss CVS 2.3%
risk of talipes (club foot) in early amnio 1.1%
risk of talipes in mid amnio 0.4%
risk of talipes in routine amnio 0.1%
PUBS ultrasound guidance, fetal umbilical vessel w/ 22 gauge needle; adv: full fetal karyo in 48hrs, all fetal hematology and serology, utility in assessing CVS mosaicism; disadv: 1-2% risk of fetal loss, later in gestation (>18 wks)
Amniocentesis Timing: =>15 weeks; risk of loss: 0.5%; fetal risks: Rh-, fetal trauma (rare); technical: easiest to perform
Early amniocentesis timing: 9-12.9 wks; risk of loss: 2-3%; fetal risks: Rh-, fetal trauma(rare), increase club foot; technical: increased culture failure
CVS timing: =>10 wks; risk of loss: 1.0%; fetal risks: Rh-, fetal trauma(rare), hemangioma?; technical: difficult, confined placental mosaicism
PUBS timing: =>18wks; risk of loss: 1-2%, fetal risks: Rh-, fetal trauma(rare); technical: hardest
Noninvasive molecular approach based cells that pass between mother and fetus- these are scarce (20 fetal cells per 20 ml maternal blood); difficult to extract, difficult to analyze, but persist after delivery
Cell free nucleic acids identified in adult serum, fragments of DNA/RNA w/out cell membrane, assoc w/ inflammatory diseases (pancreatitis, lupus, glomerular nephritis), rapid cell turnover (cancer), tissue injury (trauma, stroke, myocardial infarct)
where does ffDNA/ffRNA originate 1.fetal cells in the maternal circulation, 2.fetal to maternal circulation, 3.placental apoptosis (present in early gestation, specificity for placental gene expression)
fetal cell free DNA 3-5% of total free DNA in maternal circulation (up to 12%); smaller fragment size than maternal free DNA; present at 5-7 wks, cleared w/in hrs; ffDNA and RNA can be isolated with high fidelity
What factors alter ffDNA levels 1.gestational age (positive correlation); 2.BMI (positive correlation)
What factors do not alter ffDNA levels race, parity, smoking, maternal age, mode of conception, placental volume by 3-D ultrasound
Fetal gene is different from mother's gene SRY -fetal sex; paternal genes different from mother's - RH negative
Fetal gene is the same as the mother's gene Aneuploidy; solved w/ NGS sequencing
ffDNA and aneuploidies high sensitivity (78.6-100%) and specficity (>98%)
Detection rate 2nd trim quad- 80%; 1st trim combined- 90%; integrated- 90%; DNA testing- 99%
Screen positive rate 2nd trim quad- 5%; 1st trim combined- 5%; integrated- 2%; DNA testing- 0.2%
Failure rate 2nd trim quad- <<1%; 1st trim combined- <1%; integrated- <1%; DNA testing- 0.3-3%
Chance of true positive 2nd trim quad- 2%; 1st trim combined- 2-3%; integrated- 4%; DNA testing- =>98%
Complexitity 2nd trim quad- 1 blood draw; 1st trim combined- US and 1 draw; integrated- US and 2 draws; DNA testing- 1 blood draw
ffDNA testing ACOG (2012): not to be offered to low-risk women or women with multiple gestations because it has not been sufficiently evaluated in these groups
discordant results between ffDNA and amnio 1.confined placental mosaicism, 1-2% of pregnancies; 2.'vanished' twin with karyo abnormality; 3.mosaicism in mother; 4.maternal cancer
ffDNA testing false negatives role of BMI (impact of plasma dilution, impact of increased proportion of maternal DNA secondary to greater inflammatory state); role of early gestational age; role of fetal fraction
cardiac anomalies (2nd trim US) cardiac anomalies - 15% if NL >5.5 mm; inc venous pressures, mediastinal compression (congen diaphragmatic hernia, narrow thorax skel dysphasia); altered extracellular matrix (col dis- chondrodysplasias); impair mvmt (fetal akenesia syndrome); Noonan, SLO
US in 2nd trimester for structural anomalies, for aneuploidy screening "soft markers"
2nd trim US structural anomalies risk of aneuploidy greatest for multiple anomalies (18.8%); smaller risk for isolated anomalies (9.3%); minor features and dysmorphia difficult to appreciate
2nd trim US "soft markers" isolated increase risk of aneuploidy 1.5 - 3 fold
2nd trim US "soft markers" 2 or more increase risk of of aneuploid 10 fold or more
2nd trim US "soft signs/markers" nuchal fold, echogenic bowel, echogenic cardiac focus, shortened femur/humerus, renal fullness, choroid plexus cysts (trisomy 18)
2nd trim US abnormalities w/ nl karyotype ~5% have microarray abnormalities
microarray testing of SABs additional 9.8% with clinical relevance
microarray testing of stillbirths 13% abnormal in prior normal or unobtainable karyotype
microarray testing in PGD detect aneuploidy
microarray testing routine amnio less amniotic fluid/faster results; does not identify triploidy or balanced translocations; greater disease detection (6% w/ structural/growth abnl, 0.5% known path changes, 1.2% potential for clinical significance).
Created by: amrs
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