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NIPT N ON – I NVASIVE P RENATAL T ESTING GENDIA Antwerp, Belgium.

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Presentation on theme: "NIPT N ON – I NVASIVE P RENATAL T ESTING GENDIA Antwerp, Belgium."— Presentation transcript:

1 NIPT N ON – I NVASIVE P RENATAL T ESTING GENDIA Antwerp, Belgium

2 NIPT NON – INVASIVE PRENATAL TESTING Testing of cff DNA (cell free fetal DNA) from maternal blood during pregnancy for trisomy 21, 18 and 13

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4 Frequency aneuploidies AneuploidySyndromeFrequency (live births) Trisomy 21Down syndrome1 in 700 Trisomy 18Edwards syndrome1 in 5,000 Trisomy 13Patau syndrome1 in 16,000

5 Trisomy 21, 18, 13 screening Trisomy 21 (Down syndrome) Trisomy 18 (Edwards syndrome) Trisomy 13 (Patau syndrome)

6 History Down syndrome screening 1980 : Amniocentesis (advanced maternal age) 1990 : Triple screening (T21, T18 and T13) 2000 : First trimester screening (T21, T18 and T13) 2012 : First trimester screening + NIPT (T21, T18 and T13) 2015 : NIPT (extensive genetic screening)

7 Risk Down syndrome versus Maternal Age AgeFrequency (live births) < 35< 0.3 % % 40 1 % %

8 Serum Down syndrome screening Triple screening ( > 1990) –Maternal age –Serum : AFP, HCG, free oestriol Combi test ( > 2000) –Maternal age –Nuchal translucency (NT) –Serum : free B-HCG, PAPP-A

9 Classical Down syndrome screening First trimester serum screening (combi test) Risk calculated from : Maternal age : the higher the age, the higher the risk of T21, T18, T13 Nuchal translucency (NT) : the higher the NT, the higher the risk of T21, T18, T13 Serum parameters PAPP-A and free B HCG

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11 NIPT history 1997 : Lo et al. :cff DNA in maternal circulation 2001 : Fetal Rh(D) genotype 2006 : Sexing fetus for : 1.X-linked genetic disorders 2.Sexing (China ) 2011 : Detection trisomy 21/18/ : > patients screened in China / USA 2013 : Daily > 2000 NIPT tests worldwide

12 NIPT essentials 1. DESCRIPTION: NIPT is a DNA test on maternal blood to screen pregnancies for the most common fetal chromosome anomalies : trisomy 21 (Down syndrome), trisomy 18 (Edwards syndrome), and trisomy 13 (Patau syndrome), with optional sexing. 2. SAMPLE: Specific test kits provided by GENDIA are required: 20 ml blood in specific blood tubes is required from the mother. The samples have to be sent by Express mail to GENDIA's lab in Antwerp (Belgium), and arrive there within 2 days of withdrawal. 3. TIMING: From gestation week TURNAROUND TIME: < 2 weeks 5. RELIABILITY: The reliability of NIPT is very high (more than 99% for trisomy 21). 6. INDICATIONS: Although NIPT can be performed in every pregnancy, it is especially indicated: If the triple test or first trimester screening indicates an increased risk for Down syndrome or trisomy 18 Advanced maternal age Anxiety for invasive procedures 7. CONTRAINDICATIONS: NIPT is not the test of choice when there is: Fetal anomalies on ultrasound Known genetic anomalies that cannot be diagnosed by NIPT A triplet pregnancy or vanished twin 8. PRICE: 690 Euro

13 Cell Free Fetal DNA (cff DNA) in Maternal Blood 13

14 NIPT cff DNA < 1 % of total DNA in maternal circulation is fetal 5-30 % of cell-free DNA in maternal circulation is fetal

15 NIPT for trisomy 21 NIPT measures the ratio of chromosome 21 sequence versus control chromosome sequence to exclude trisomy 21

16 NIPT cffDNA < 1 of cffDNA DNA Fetal Maternal Nl T21

17 Importance of fetal fraction Fetal Fraction Expected ratio for Trisomy 4% % % %1.20 Chromosome 21Reference Chromosome Fetal cfDNA Maternal cfDNA 17

18 NIPT reliability Test : Trisomy 21, 18, 13 Specificity : > 99 % Sensitivity : T21 > 99 % T18 > 97 % T13 > 80 %

19 NO NIPT for sex aneuploidies 19 Phenotype for sex aneuploidies is highly variable Mosaicism in the fetus is a problem Mosaicism in the mother is a problem NIPT for sex aneuploidies is less accurate

20 NIPT Indications NIPT is the test of choice when there is : Increased maternal age Increased risk on Combination or triple test Anxiety for invasive procedure (AC / CVS)

21 NIPT Contra indications NIPT is NOT the test of choice when there is : Fetal anomalies on ultrasound A triplet pregnancy Vanished twin Known genetic anomalies that cannot be diagnosed by NIPT

22 NIPT Advantages versus combi test with AC / CVS High sensitivity (few false-negatives) High specificity (few false-positives) More than T21 Non-invasive : no fetal risk CVS : Risk of miscarriage : 1-2 % AC : Risk of miscarriage : 0.5 %

23 NIPT Disadvantages Expensive (690 Euro) Combi test : 150 Euro Combitest + AC + karyotype : 1000 Euro? Only testing 5 chromosomes Failure rate : 3 % Specific kits Not available everywhere

24 Companies offering NIPT ARIOSA (US) VERINATA (US) NATERA (US) SEQUENOM (US) BGI (China) LIFE-CODEXX (Germany)

25 GENDIA offers the HARMONY test from ARIOSA ARIOSA (Harmony)

26 NIPT results 1. Normal result : no specific follow up necessary, unless ultrasound examination of the fetus reveals anomalies 2. Test failure : in 3 % pregnancies not enough fetal DNA : NIPT repeated at no extra cost. 3. Abnormal NIPT result : amniocentesis or chorion biopsy

27 NIPT failures If less than 4 % of cf DNA is fetal 1.High amounts of maternal cf DNA : Maternal obesitas 2.Low amounts of fetal cf DNA : Trisomy 18 Triploidy ??

28 NIPT versus classical Down syndrome screening Classical NIPT False negatives %0.3 % False positives5 % (> 95 % of positives) < 0.1 % Result> Week 13> Week 12 Price150 euro690 Euro

29 NIPT versus classical screening in a country with 10 million inhabitants Classical NIPT Number screenings Expected T21200 (1/500) 200 (1/500) Detection rate73 % > 99 % T False negatives54< 1 False positives4990< 100 Iatrogenic miscarriages500

30 NIPT versus CVS / AC CVS / AC High risk : % (Monogenic disorder) Medium risk : 5-10 % (chromosomal anomaly) Ultrasound anomaly (NT) NIPT Low risk < 5 %

31 NIPT : the future 1. Array CGH – All chromosomes – Small deletions - duplications 2. Detection common monogenic mutations - CF 3. Whole exome / genome sequencing

32 Message in a bottle 1. DESCRIPTION: NIPT is a DNA test on maternal blood to screen pregnancies for the most common fetal chromosome anomalies : trisomy 21 (Down syndrome), trisomy 18 (Edwards syndrome), and trisomy 13 (Patau syndrome), with optional sexing. 2. SAMPLE: Specific test kits provided by GENDIA are required: 20 ml blood in specific blood tubes is required from the mother. The samples have to be sent by Express mail to GENDIA's lab in Antwerp (Belgium), and arrive there within 2 days of withdrawal. 3. TIMING: From gestation week TURNAROUND TIME: < 2 weeks 5. RELIABILITY: The reliability of NIPT is very high (more than 99% for trisomy 21). 6. INDICATIONS: Although NIPT can be performed in every pregnancy, it is especially indicated: If the triple test or first trimester screening indicates an increased risk for Down syndrome or trisomy 18 Advanced maternal age Anxiety for invasive procedures 7. CONTRAINDICATIONS: NIPT is not the test of choice when there is: Fetal anomalies on ultrasound Known genetic anomalies that cannot be diagnosed by NIPT A triplet pregnancy or vanished twin 8. PRICE: 690 Euro

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