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PrenatalSAFE® Karyo test is the most technologically advanced genome-wide NIPT
Through cfDNA analysis from maternal plasma, PrenatalSAFE®Karyo detects:
Aneuploidies
structural chromosomal aberrations(deletions or duplications) across the fetal genome
providing karyotype-level insight.
What is
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PrenatalSafe® Karyo analyzes every chromosome in the genome.
Unlike any other noninvasive prenatal test available to date, it offers a level of information previously only available from a fetal karyotype analysis, performed with invasive prenatal diagnosis procedures (amniocentesis and CVS)
the next level in noninvasive prenatal testing
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Maternal blood sample
Maternal cfDNA Fetal cfDNA
NIPT uses cell-free DNA (cfDNA)
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Whole-genome sequencingtechnology
Fetal FractiondeterminationcfDNA
extraction
DNA Sequencescounting
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2 levels of genome-wide screening
It can also test for 9 common microdeletion syndromes
Microdeletion Syndrome Prevalence
DiGeorge syndrome (22q11.2) 1 in 4,0001p36 deletion syndrome 1 in 4,000 to 1 in 10,000Angelman syndrome (15q11.2) 1 in 12,000Prader-Willi syndrome (15q11.2) 1 in 10,000 to 1 in 25,000Cri du Chat syndrome (5p15.3) 1 in 20,000 to 1 in 50,000Wolf-Hirschhorn syndrome (4p16.3) 1 in 50,000Langer-Giedion syndrome (8q24) 1/200.000Jacobsen syndrome (11q23) 1/100.000Smith-Magenis syndrome (17p11.2) 1/15.000 - 1/25.000
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Detection rate
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Detection rate
PrenatalSAFE® Karyo Plus test identifies 95.5% of chromosomal anomalies prenatally detected and 99.1% of those anomalies observed at birth, achieving a level of detection rate very closed to the traditional fetal karyotyping (96.9%), obtained with invasive, prenatal diagnostic techniques.
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Conventional Prenatal Screening vsDetection Rates for Trisomy 21
ACOG Practice Bulletin No. 77, January 2007
False Positive Rate (FPR): 5%
Integrated Screen
Quadruple Screen
1st Trimester Blood Screen
+ NTSerum
Integrated
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Fetal Karyotyping vs Traditional Karyotyping
Analyzes every chromosome
Detects chromosomalgains or losses >7 Mb
Detects chromosomegains or losses >10 Mb
Requires an invasive procedure
Detects unbalanced translocations
Detects segmental deletions/duplications
Detects mosaic trisomies
Detects marker chromosomes
Detects microdeletion syndromes
Detects triploidy
Considered diagnostic
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Pre-clinical Validation performance
Fiorentino et al., EJHG conference 2016; ISPD conference 2016
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Performance Clinical Cases
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Performance Standard protocol
PPV: Positive Predictive Value; NPV: Negative Predictive Value; SCA: Sex Chromosomes Aneuploidy
Follow-up March 2016
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Performance FAST protocol
PPV: Positive Predictive Value; NPV: Negative Predictive Value; SCA: Sex Chromosomes Aneuploidy
Follow-up March 2016
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Published validation studies
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Which Patients Should Be Offered?
This test is intended for patients at 10 weeks or greater gestation who meet any of the following criteria:
Maternal age-related risks (e35 years)
Positive results on maternal serum screening
Abnormal ultrasound finding(s)
Prior pregnancy with aneuploidy
Parental translocation
Low risk pregnancies
Patients wanting early, accurate testing and are at average risk of aneuploidy
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The test is suitable for both singleand twin pregnancies.
It can be performed in patients whose pregnancies have been achieved by IVF techniques, including pregnancies with egg donation.
pregnancy characteristics
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Free services supplied
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Case study
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Case Study 1
31 y.o. patient
5
Negative Result
Fetal abnormal ultrasound findings(cerebellar ipoplasia; Ventriculomegaly )
Reassessment of the NIPT data with
Amniocentesis
20^ week gestation
12^ weeks gestation
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del5p15.33p13.2
Chr. 5Chr. 5
PrenatalSafe® KaryoArray-CGH
cfDNAAmniotic Fluid
34 Mb
Detection of a deletion 5p confirmed by array-CGH
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32 y.o. patient
5
Multiple fetal abnormal ultrasound findings
Amniocentesis
13^ weeks gestation
Negative Result
21^ weeks gestation
Reassessment of the NIPT data with
Case Study 2
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Del18p11.32-p11.31
Chr. 18
PrenatalSafe® KaryoArray-CGH
3.8 Mb
Del18q21.32-q2321.3 Mb
Identification of 2 deletions (18p / 18q) confirmed by array-CGH
Chr. 18
cfDNAAmniotic Fluid
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32 y.o patientCarrier of a reciprocal translocation 46,XX,t(7;9)(p15;q22)
Abnormal Resultdetected fetal karyotype with an unbalanced translocation
Villocentesis
Chr. 7
Chr. 9
Results confirmed
Case Study 3
11^ weeks gestation
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PrenatalSafe® KaryoArray-CGHcfDNACVS
PrenatalSafe® KaryoArray-CGHCVS
Dup7p22.3p21.2 15 Mb Dup9p24.3-q31.1 107.5 Mb
cfDNA
Detected a fetal karyotype with an unbalanced translocation confirmed by array-CGH
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35 y.o patient
Amniocentesis(traditional karyotyping)
Negative Result(Fetale karyotype 46, XY)
(Suspected DiGeorge syndrome)
Identified deletion 22q11.2 (compatible with DiGeorge syndrome)
Amniocentesis
Case Study 4
13^ weeks gestation
20^ weeks gestation
Fetal abnormal ultrasound findings
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PrenatalSafe® KaryoArray-CGH
cfDNA
del22q11.21DiGeorge Syndrome
Plus
4 Mb
Chr.22
Amniotic Fluid
Identification of 22q11.2 deletionconfirmed by Array-CGH
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33 y.o. patient(She was not aware to be carrier of a chromosomal translocation)
Abnormal Resultdetected fetal karyotype with an unbalanced translocation
Paziente portatrice di traslocazione reciproca
46,XX,t(13;20)(q33;q13.3)
Chr. 13 Chr. 20
Case Study 5
12^ weeks gestation
Villocentesis
Results confirmed
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(cfDNA)
Del13q33.1q34 11.4 Mb Dup20q13.33 1.9 Mb
Array-CGH(CVS)
Chr. 13 Chr. 20
(cfDNA)Array-CGH
(CVS)PrenatalSafe® KaryoPrenatalSafe® Karyo
Detected a fetal karyotype with an unbalanced translocation confirmed by array-CGH
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40 y.o patient
Abnormal Resultdetected fetal karyotype with duplication 18p
Villocentesis
Results confirmed
Case Study 6
11^ weeks gestation
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Chr. 18
Detection of a duplication 18p confirmed by array-CGH
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38 y.o patient
Abnormal Resultdetected fetal karyotype with duplication 11p
Amniocentesis
Results confirmed
Case Study 7
10^ weeks gestation
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Detection of a duplication 11p confirmed by array-CGH
Chr. 11
PrenatalSafe® KaryoArray-CGH
cfDNAAmniotic
Fluid
Dup11p15.4p15.1
16 Mb
Dup11p15.4p15.1
16 Mb
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35 y.o patient
Abnormal Resultdetected fetal karyotype with deletion Xp
Amniocentesis
Results confirmed
Case Study 8
12^ weeks gestation
16^ weeks gestation
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PrenatalSafe® KaryoArray-CGH
cfDNAAmniotic Fluid
delXp22.33p11.1
58.5 Mb
delXp22.33p11.1
58.5 Mb
Detection of a deletion Xpconfirmed by array-CGH
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40 y.o. patient
NIPT(5 chromosomes screening)
Trisomy 21 not detectedMaternal CNV detected
causing the false positive result
Positive ResultHigh risk for Trisomy 21
Test performed by a different lab
Case Study 9
13^ weeks gestation
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Lower the risk of false positive results determined by maternal CNVs
PrenatalSafe® KaryocfDNA
Array-CGHMaternal blood
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Chudova et al., 2016 NEJM
Lower the risk of false positive results determined by maternal CNVs
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Strom et al., 2017 NEJM
Lower the risk of false positive results determined by maternal CNVs
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42 y.o patient
Abnormal Resultdetected fetal karyotype with Trisomy 9
Amniocentesis
Results confirmed
Case Study 10
14^ weeks gestation
16^ weeks gestation
Trisomy 9 mosaic (20%)
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Chr. 9
46,XX[80]/47,XX,+9[20]
Detection of Trisomy 9 mosaic confirmed by traditional karyotyping
PrenatalSafe® Karyo Traditional Karyotyping
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40 y.o patient
Abnormal Resultdetected fetal karyotype with Trisomy 22
Amniocentesis
Results confirmed
Case Study 11
10^ weeks gestation
16^ weeks gestation
Trisomy 22 mosaic (16%)
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Chr.22
46,XY[42]/47,XY,+22[8]
PrenatalSafe® Karyo Traditional Karyotyping
Detection of Trisomy 22 mosaic confirmed by traditional karyotyping
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31 y.o patient
Abnormal Resultdetected fetal karyotype with Trisomy 7
Amniocentesis
Results confirmed
Case Study 12
12^ weeks gestation
16^ weeks gestation
Trisomy 7 mosaic (4%)
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Chr. 7
46,XX[48]/47,XX,+7[2]
PrenatalSafe® Karyo Traditional Karyotyping
Detection of Trisomy 7 mosaic confirmed by traditional karyotyping
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Prospective study
Fiorentino et al., submitted
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Background Conventional cfDNA-based NIPT approaches focus on detection of common
trisomies and sex-chromosome aneuploidies.
This leaves a gap of approximately 17% of clinically relevant chromosomal/subchromosomal abnormalities that would go undetected.
Previous studies have shown the potential of extending conventional NIPT to detect fetal microdeletion syndromes from maternal plasma (Peters et al., 2011; Srinivasan et al., 2013).
Other studies showed how genome-wide cfDNA testing can contribute in lowering the incidence of false positive results generated by maternal copy number variants (Snyder et al., 2015; Chudova et al., 2016).
At present, there are limited data available on the potential of genome-wide screening to detect rare autosomal trisomies and structural chromosome anomalies in a general population of pregnant women.
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Aim of the study
From December 2015 through May 2016, genome-wide cell-free fetal DNA(cfDNA) testing was offered to pregnant women undergoing conventionalcfDNA-based non-invasive prenatal testing (NIPT) for common fetalaneuploidy.
We aimed to compare the performance of the two test in a general obstetricalpopulation.
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Demographic and pregnancy characteristics
Characteristics n
No. of eligible patients 12.114
Maternal age-yr- Mean ±SD 35.3±4.1
- Min-max 20-58
Gestational age at sample collection -wk- Mean ±SD 12.3±2.1
- Min-max 10-29
Indications for NIPT
- Parental Anxiety 3804 (31.4%)- Advanced maternal agea 4446 (36.7%)- Positive prenatal screen 1199 (9.9%)- Fetal ultrasound abnormality 472 (3.9%)- Prior pregnancy with fetal aneuploidy 157 (1.3%)- More than one indication 2035 (16.8%)
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Results of samples tested
Total
No. of patients analyzed 12.114
Samples with a call - no. (%) 12.078 (99.7)
Total cancellations - no. (%) 182 (1.5)
- Samples with low FF - no. (%) 145 (1.2)
- Samples with assay failure - no. (%) 36 (0.3)
Samples with a conclusive result - no. (%) 11.932 (98.5)
Chromosomally abnormal results
- Genome-wide cfDNA screening - no. (%) 196 (1.6)
- Conventional cfDNA screening - no. (%) 166 (1.4)
Pregnancies confirmed as chromosomally abnormal - no. (%)
- Genome-wide cfDNA screening - no. (%) 169 (1.4)
- Conventional cfDNA screening - no. (%) 151 (1.3)
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Clinically relevant chromosomal abnormalities classes detected by genome-wide cfDNA analysis
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Types of chromosome anomalies detected by conventional and genome-wide cfDNA testing
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^ Clinically relevant chromosomal abnormalities, not detected by conventional cfDNA screening, potentially resulting in the birth of babies with chromosomal anomalies, have been considered as false negative.
§ A P-value of less than 0.05 was considered to indicate statistical significance (**).
Performance of conventional cfDNA screening vs. genome-wide analysis
Conventional cfDNA
screening
Genome-wide cfDNAscreening
P-value§
No. of pregnancies assessed 11.932 11.932Clinical relevant chromosomal abnormalities detected - no. (%)
166 196
Pregnancies confirmed as chromosomally abnormal - no. (%)
151 169
False Positive 15 27
False Negative 12* 0
True Positive 151 169
True Negative 11.754 11.736
Sensitivity 92.64% 100.00% <0.001
Specificity 99.87% 99.77% 0.064
Positive Predictive Value (PPV) 90.96% 86.22% 0.161
Negative Predictive Value (NPV) 99.90% 100.00% <0.001
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Performance of the Genome-wide cfDNA screening
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Conclusion
The clinical utility of expanding NIPT to cover the entire genome iscontroversial, especially in low-risk pregnancies. In fact, it pertains a risk ofoverdiagnosis with a higher number of false positives because ofchromosomal rearrangements which are confined to the placenta, potentiallyleading to an increase in unnecessary invasive testing.
The results of this study demonstrate that a high specificity may bemaintained while extending the screen to all chromosomal abnormalities.
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Thank you for your attention
http://www.laboratoriogenoma.eu/
Rome Milan