Reproductive Genetics II
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| Risk of Down syndrome | ACOG 2007: diagnostic testing regardless of age, not based solely on maternal age >35 yrs
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| Diagnostic options to detect down syndrome | 1.CVS 2.Amniocentesis 3.maternal serum screening for aneuploidy
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| Risk of pregnancy loss assoc w/ CVS | 1/2%
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| Risk of pregnancy loss assoc w/ Amniocentesis | 1%
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| CVS and Amniocentesis | can detect trisomy 21, cannot predict individual variation
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| 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
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| 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
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| Screening for Down Syndrome - Quad screen | sensitivity: 81%;
PPV: 1/40 (2.5%);
Screen positive: 5%
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| Screening for Down Syndrome - Nuchal lucency | sensitivity: 81%;
PPV: 1/50 (2.0%);
screen positive: 4.2%
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| Screening for Down Syndrome - NL + PAPP-A, hCG (1st) | sensitivity: 87%;
PPV: 1/25 (4%);
screen positive: 5.0%
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| combined 1st/2nd trimester screening | 2 types: 1.nondisclosure ("integrated"), 2.disclosure (sequential, contingent)
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| nondisclosure combined 1st/2nd trimester screening | PaPP-A and NL 1st trimester + Quad 2nd trimester; results released 2nd trimester;
97% detection (4.7% screen +)
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| 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 +)
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| Nuchal lucency > 4.0 | highly unlikely to screen -ve on serum screening;
0.09% of population;
33% of aneuploidy
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| Nuchal lucency 3-4 | 8% have -ve serum screen;
0.3% of population;
17% aneuploidy
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| 1st trimester markers of aneuploidy | nuchal lucency, nasal bone, ductus venous
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| Absent NB | likelihood of trisomy 21: 7.05
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| Ductus flow abnormal | likelihood of trisomy 21: 6.42
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| molecular diagnostic modalities | 1.Chorionic villus sampling, 2.Amniocentesis, 3.Percutaneous umbilical blood sampling
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| Risks of invasive fetal diagnostic procedures | 1.Miscarriage, 2.fetal morbidity (rupture of membranes, malformations, infectious, isoimmunization), 3.technical (no sample obtained, misdiagnosis).
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| Fetal Morbidity of Amniocentesis (PPROM) | Premature preterm rupture of membrane - 1% (91% survival)
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| Fetal Morbidity of Amniocentesis direct fetal trauma | is rare with ultrasound guidance
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| Technical risks of Amniocentesis | low technical failures for sample retrieval and culture failure; misdiagnosis can occur from maternal cell contamination
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| 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
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| 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
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| early amniocentesis | 9-12.9 wks
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| routine amniocentesis | >15 wks
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| post procedure loss early amnio | 4.2%
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| post procedure loss CVS | 2.3%
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| risk of talipes (club foot) in early amnio | 1.1%
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| risk of talipes in mid amnio | 0.4%
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| risk of talipes in routine amnio | 0.1%
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| 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)
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| Amniocentesis | Timing: =>15 weeks; risk of loss: 0.5%; fetal risks: Rh-, fetal trauma (rare); technical: easiest to perform
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| 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
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| CVS | timing: =>10 wks; risk of loss: 1.0%; fetal risks: Rh-, fetal trauma(rare), hemangioma?; technical: difficult, confined placental mosaicism
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| PUBS | timing: =>18wks; risk of loss: 1-2%, fetal risks: Rh-, fetal trauma(rare); technical: hardest
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| 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
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| 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)
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| 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)
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| 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
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| What factors alter ffDNA levels | 1.gestational age (positive correlation); 2.BMI (positive correlation)
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| What factors do not alter ffDNA levels | race, parity, smoking, maternal age, mode of conception, placental volume by 3-D ultrasound
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| Fetal gene is different from mother's gene | SRY -fetal sex; paternal genes different from mother's - RH negative
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| Fetal gene is the same as the mother's gene | Aneuploidy; solved w/ NGS sequencing
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| ffDNA and aneuploidies | high sensitivity (78.6-100%) and specficity (>98%)
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| Detection rate | 2nd trim quad- 80%; 1st trim combined- 90%; integrated- 90%; DNA testing- 99%
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| Screen positive rate | 2nd trim quad- 5%; 1st trim combined- 5%; integrated- 2%; DNA testing- 0.2%
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| Failure rate | 2nd trim quad- <<1%; 1st trim combined- <1%; integrated- <1%; DNA testing- 0.3-3%
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| Chance of true positive | 2nd trim quad- 2%; 1st trim combined- 2-3%; integrated- 4%; DNA testing- =>98%
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| Complexitity | 2nd trim quad- 1 blood draw; 1st trim combined- US and 1 draw; integrated- US and 2 draws; DNA testing- 1 blood draw
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| 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
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| 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
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| 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
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| 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
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| US in 2nd trimester | for structural anomalies, for aneuploidy screening "soft markers"
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| 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
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| 2nd trim US "soft markers" isolated | increase risk of aneuploidy 1.5 - 3 fold
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| 2nd trim US "soft markers" 2 or more | increase risk of of aneuploid 10 fold or more
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| 2nd trim US "soft signs/markers" | nuchal fold, echogenic bowel, echogenic cardiac focus, shortened femur/humerus, renal fullness, choroid plexus cysts (trisomy 18)
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| 2nd trim US abnormalities w/ nl karyotype | ~5% have microarray abnormalities
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| microarray testing of SABs | additional 9.8% with clinical relevance
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| microarray testing of stillbirths | 13% abnormal in prior normal or unobtainable karyotype
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| microarray testing in PGD | detect aneuploidy
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| 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).
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