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rep_genII
Reproductive Genetics II
| Term | Definition |
|---|---|
| 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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