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NIPTNON – INVASIVE PRENATAL TESTING
GENDIA
Antwerp, Belgium
NIPT
NON – INVASIVE PRENATAL TESTING
Testing of cff DNA (cell free fetal DNA)
from maternal blood during pregnancy
for trisomy 21, 18 and 13
www.DOWNsyndromeNIPT.info
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Frequency aneuploidies
Aneuploidy Syndrome Frequency (live births)
Trisomy 21 Down syndrome 1 in 700
Trisomy 18 Edwards syndrome 1 in 5,000
Trisomy 13 Patau syndrome 1 in 16,000
Trisomy 21, 18, 13 screening
Trisomy 21 (Down syndrome)
Trisomy 18 (Edwards syndrome)
Trisomy 13 (Patau syndrome)
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)
Risk Down syndrome versus Maternal Age
Age Frequency (live births)
< 35 < 0.3 %
37 0.5 %
40 1 %
50 10 %
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
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
Classical Down syndrome screening
NT (mm)
Normal : 2.0
T21 : 3.4
T18 : 5.5
T13 : 4.0
B-HCG (MoM)
Normal : 1.0
T21 : 2.0
T18 : 0.2
T13 : 0.5
PAPP-A (MoM)
Normal : 1.0
T21 : 0.5
T18 : 0.2
T13 : 0.3
Nicolaides et al 2008
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 21/18/13
• 2012 : > 100.000 patients screened in China / USA
• 2013 : Daily > 2000 NIPT tests worldwide
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 10
4. 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
Cell Free Fetal DNA (cff DNA) in Maternal Blood
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NIPT cff DNA
• < 1 % of total DNA in maternal circulation is fetal
• 5-30 % of cell-free DNA in maternal circulation is fetal
NIPT for trisomy 21
NIPT measures the ratio
of chromosome 21 sequence
versus control chromosome sequence
to exclude trisomy 21
NIPT cffDNA
• < 1 of
cffDNA DNA
Fetal
Maternal
Nl NlT21 T21
Importance of fetal fraction
Fetal Fraction
Expected ratio for Trisomy
4% 1.02
10% 1.05
20% 1.10
40% 1.20
Chromosome 21Reference
Chromosome
Fetal cfDNA
Maternal
cfDNA
•17
NIPT reliability
• Test : Trisomy 21, 18, 13
• Specificity : > 99 %
• Sensitivity :
T21 > 99 %
T18 > 97 %
T13 > 80 %
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
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)
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
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 %
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
Companies offering NIPT
• ARIOSA (US)
• VERINATA (US)
• NATERA (US)
• SEQUENOM (US)
• BGI (China)
• LIFE-CODEXX (Germany)
GENDIA offers the HARMONY test from ARIOSA
• ARIOSA (Harmony)
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
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 ??
NIPT versus classical Down syndrome screening
Classical NIPT
False negatives 30 - 40 % 0.3 %
False positives 5 % (> 95 % of positives) < 0.1 %
Result > Week 13 > Week 12
Price 150 euro 690 Euro
NIPT versus classical screening in a country with 10 million inhabitants
Classical NIPT
Number screenings 100.000 100.000
Expected T21 200 (1/500) 200 (1/500)
Detection rate 73 % > 99 %
T21 146 198
False negatives 54 < 1
False positives 4990 < 100
Iatrogenic miscarriages 50 0
NIPT versus CVS / AC
CVS / AC
• High risk : 25-50 %(Monogenic disorder)
• Medium risk : 5-10 %
(chromosomal anomaly)
• Ultrasound anomaly (NT)
NIPT
• Low risk < 5 %
NIPT : the future
1. Array CGH – All chromosomes– Small deletions - duplications
2. Detection common monogenic mutations
- CF
3. Whole exome / genome sequencing
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 10
4. 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
www.DOWNsyndromeNIPT.info