Earlier, accurate & non invasive the new trigene test in the clinical context

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Advantages:

Non-Invasive: only 5 mL maternal peripheral blood is needed. Therefore, there is no risk of intrauterine infection and miscarriage.
Highly Accurate: 100% sensitivity and 99.9% specificity.
Early-Test: can be performed at the early pregnancy (~12 weeks), which allows early detection for a better clinical decision.
Report: available within 2 weeks.
Inclusivity: All chromosomal aneuploidies could be detected in one test.

Applications:

Those that wish to have non-invasive fetal aneuploidies test for trisomy21, 18 and 13.
Those whose age is 35 or above and does not choose to receive invasive prenatal tests.
Those whose serum biochemical tests and ultrasound examinations suggest high risk of chromosome aneuploidies at the first and second trimester.
Those that has contraindication of invasive prenatal testing, such as placenta previa, risks of miscarriage, HBV infection and HIV infection, etc.
Those that received IVF, or previously suffered from habitual abortion.

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  • 1. What is Prenatal diagnosis ?It is the method used to detectdiseases/conditions in a fetus or embryo beforebirth.
  • 2.  Maternal age > 35 years at EDC Abnormal maternal serum screening for:1. DS cut off > 1/2702. Increased risk Trisomy 18 or 133. Other genetic abnormalities Previous child with chromosomal abnormality or diagnosable genetic disorder Balanced translocation carrier Ultrasound anomaly (soft sign vs frank anomaly)
  • 3. Baseline Risk for Having a Child With a Serious Birth Defect 3-5%
  • 4. Maternal DS Risk All Chrom Abn DS risk Age Birth Birth Midtrimester 20 1/1231 30 1/185 1/384 1/685 33 1/592 1/285 1/452 34 1/465 1/243 1/352 35 1/385 1/178 1/274 36 1/287 1/149 1/213 37 1/225 1/123 1/166 38 1/177 1/105 1/129 39 1/139 1/80 1/100 40 1/109 1/63 1/80 41 1/85 1/48 1/61
  • 5. Non-disjunction Normal Sex cell production Monosomy
  • 6. ~70% T21 due to an error in maternal meiosis I~ 20% maternal meiosis II~ 5% occur during spermatogenesis (meiosis II)5% of trisomic 21 error in mitosis- no advanced maternal age andthere is no preference for which chromosome 21 is duplicated inthe mitotic errormost common chromosomal abnormalities in live born children
  • 7. ~1/700
  • 8. Moderate mental retardation Facial Characteristics upslanting palpebral fissures epicanthic folds, midface hypoplasia, macroglossiaCongenital malformations heart (30-40%), atrioventricular canal gastrointestinal tract, such as duodenal stenosis or atresia, imperforate anus, and Hirschsprung disease Leukemia (both ALL and AML) 10-20x acute megakaryocytic leukemia occurs 200 to 400 times more frequently in the Down syndrome 90% have significant hearing loss, usually of the conductive type
  • 9. Trisomy 18, Edward syndrome 1/8000
  • 10. Facial Central Nervous System•microcephaly with prominent occiput severe mental retardation•narrow bifrontal diameter hypotonia -> hypertonia•short palpabral fissures neural tube defects•low-set malformed ears poor suck and weak cry•cleft lip +/- palate failure to thrive•narrow palatal arch ocular anomalies•micrognathia RespiratorySkeletal •apnea•neck Cardiovascular( >95%)•webbed •major: VSD, ASD, PDA•chest •minor: transposition, ToF, coarctation, anomalous•short sternum coronary artery, dextrocardia,•widely spaced nipples •aberrant subclavian artery, arteriosclerosis, PS,•hips: bicuspid aortic and/or pulmonic valves•small pelvis, congenital dislocation of the hips, limited hip Gastrointestinalabduction •inguinal, umbilical, and/or•extremities: diaphragmatic hernia•phocomelia •congenital defects:•rockerbottom feet or equinovarus •diastasis recti, heterotopic pancreas, malrotation,short dorsiflexed big toes Meckels, tracheoesophageal fistulafixed flexion deformity of the fingers (overlapping of the Genitourinary2nd and 5th fingers over the 3rd and 4th fingers) •cryptorchidismsimple arch pattern of the fingers and toes •congenital defects:hypoplasia of fingernails double ureter, ectopic kidney,single crease of 5th finger or all fingers (absence of horseshoe kidney, hydronephrosis,interphalangeal flexion creases) polycystic kidneysimian crease
  • 11. •severe mental retardation•coloboma,•(a cleft palate) and/or a cleft lip•hypotonia•skeletal abnormalities (polydactyly)•Renalheart defects•holoprocencephaly 1/5,000
  • 12. Second most common major congenital defect (1-2/1000)Not a chromosome anomalyRoutinely tested and screened for in pregnancyFailure neural tube to close at 28 days gestation20% are closed lesions and difficult to detect prenatally
  • 13. Marker Down Syndrome Edward Patau Syndrome (T21) Syndrome (T18) (T13)AFP Lower- 25% Lower- 35-55% Slightly raiseduE3 Lower- 30% Lower- 35-55% Lower- 30%Free HCGβ Raised - 2X Lower- 50% Lower- 50%PAPP-A Lower- 50% Lower- 50% Lower -50%Inhibin-A Raised – 2X No value Raised - 2X
  • 14. Test When What Performance* Diagnostic test T21 30-40% 1.CVS or amniocentesis Maternal Age > 35 y.o. Age alone T18 30-40% 2. higher miscarriage rate with T18 NTD no relation Ultrasound 10-12 Age + NT T21 75-80% CVS or amniocentesis T21 60% Amniocentesis Ultrasound 18-20 Age + T18 85% sonogram NTD 70-98% E3 T21 60-70% Amniocentesis Triple Screen 16-20 (15- msAFP T18 60% 21) BHCG NTD 75-80% E3 T21 75-80% Amniocentesis Quad Screen 16-20 (15- msAFP T18 60% BHCG 21) NTD 75-80% Inhibin-A FTS: First PAPP-A T21 83-90% 1.CVS or amniocentesis Trimester 11-12 (10- Free BHCG T18 80% 2.Need msAFP Screen, 3. detection of 14) NT NTD ----- miscarriages Ultrascreen Integrated 10-14 PAPP-A T21 92% Amniocentesis Screen 16-20 (15- NT T18 90% Quad Screen 21) NTD 80%First trimester serum, stepwise sequential screen, contingency sequential screen *SPR 5%
  • 15. Fetal Anomaly Detection RateNTD- AFP alone 75-80%Trisomy 21- Triple test 70%- Down syndromeTrisomy 18- Triple test 80%- Edward’s syndrome *SP = screen positive rate 5%
  • 16.  AMNIOCENTESIS CHORIONIC VILLUS SAMPLING PERCUTANEOUS UMBILICAL CORD SAMPLING
  • 17. PERFORMED ROUTINELY 16-20 WEEKS
  • 18. Chromosome analysisAF-AFP levels ONTDAcetylcholinesteraseRisk of miscarriage associated with procedure 1/100-1/400 Advantage Disadvantage Late in gestationHighly reliable results 99+%Familiar oDecision makingLong standing reputation oPrivacy oMom feels movementNTD detection Fear of needles Needle invades the sac
  • 19. Performed>10 wks-13 weeksChromosome analysisRisk 1/100-1/200
  • 20. DisadvantageHigher loss rateLess access to procedureHigher chance of insufficient sampleEarly test=risk of sampling a fetus potentiallydestined to miscarryNo ONTD testingMore risk of vaginal bleeding/infection.
  • 21. Disadvantage~2% risk of lossTechnically difficult prior to 20 weeks AdvantagesBlood disorders such as hemophilia and anemiaUseful for detection of Rh isoimmunization of the fetus (blood cellcount and oxygen level)→erythroblastosis fetalis (HDN) Fetal karyotype is available in 48 hours to study ChromosomalabnormalitiesInfections such as toxoplasmosis and rubella.The procedure is also used to perform blood transfusions to thefetus and to administer medication directly into the fetal bloodsupply.
  • 22. RISK ProcedureFetal Aneuploidy Related RISK
  • 23. Non-invasive prenatal screening will be based on bloodcollection from pregnant women and investigation of thefetal DNA present in maternal circulation Advantage Do not put the fetus at risk for spontaneous abortion Can be offered to all pregnancies Provide a more effective prevention Done at early pregnancy High accuracy
  • 24. What is already Known Non-invasive prenatal detection of fetal trisomy 21 is achievable by Next Generation Sequencing (NGS) of maternal plasma DNAWhat are the Benefits of NGS Among high risk pregnancies clinically indicated for invasive prenatal diagnosis, noninvasive Detection of fetal trisomy 21 can be achieved with the use of multiplexed massively Parallel sequencing of maternal plasma DNA with 100%sensitivity and 99.9% specificity, Giving a 99% positive predictive value and 100% negative predictive value The sequencing test could be used to rule out trisomy 21 among high risk pregnancies before proceeding to invasive diagnostic testing .This will reduce the number of cases requiring Amniocentesis or chorionic villus sampling
  • 25.  Multiplexed maternal plasma sequencing / Next Generation Sequencing has overcome the difficulty that poses the small proportion of fetal DNA in maternal circulation Large-scale validity study used multiplexed maternal plasma DNA sequencing analysis in pregnant women at high risk for fetal trisomy 21 to compare the conventional screening who underwent invasive procedures for full karyotyping Research suggested that the invasive diagnostic procedures could be avoided in about 98% of the cases in a high-risk population It is cost-effective and NOW easily obtained from diagnostic laboratories
  • 26.  Those whose age is 35 or above and do not choose to receive invasive prenataltests Those whose serum biochemical tests and ultrasound examinations suggesthigh risk of chromosome aneuploidies at the first and second trimester Those that wish to have non-invasive fetal aneuploidies test for trisomy21, 18and 13 Those that received IVF, or previously suffered from habitual abortion Those that have contraindication of invasive prenatal testing, such as placentaprevia, risk of miscarriage or infections (HIV, HBV etc)
  • 27. Thank you