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Non-invasive Prenatal Trisomy test

Non-invasive Prenatal Trisomy test. A safe prenatal testing for fetal chromosomal aneuploidy . Leon Liang BGI Health Europe. Common fetal aneuploidy. Others: Turner syndrome (XO), Klinefelter syndrome (XXY), triple X syndrome (XXX), etc. Current screening & diagnostic tests.

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Non-invasive Prenatal Trisomy test

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  1. Non-invasive Prenatal Trisomy test A safe prenatal testing for fetal chromosomal aneuploidy Leon Liang BGI Health Europe

  2. Common fetal aneuploidy Others: Turner syndrome (XO), Klinefelter syndrome (XXY), triple X syndrome (XXX), etc.

  3. Current screening & diagnostic tests * Data present in 5% false positive rate Fergal D, Jacob A, et al. The New England Journal of Medicine, 2005

  4. NIFTY Screening tests Diagnostic tests • Serum biochemical test; ultrasound scan • Non-invasive • Cheap • Less accurate • Low detection rate • High false positive rate • Karyotyping (G-banding or FISH) • Invasive • Expensive • Highly accurate • High detection rate • Low false positive rate

  5. What’s NIFTY test? • Non-Invasive Fetal TrisomY • A superior screening test • High detection rate and low false positive rate • Non-invasive method based on NGS and bioinformatics • Analysis of fetal cell free DNA in maternal plasma • Evaluate the likelihood of fetal trisomy 21, 18, and 13

  6. Features of NIFTY New detection technology based on NGS; Sensitivity and specificity > 99% No risks of intrauterine infection and miscarriage NIFTY Fetal trisomy risk can be evaluated as early as 12 gestational week Reduce clinical pressure of unnecessary invasive tests Only 5ml of peripheral blood is needed; easy to handle in clinical practice

  7. Scientific discovery • Fundamental Features of Cell-Free Fetal DNA • Short fragments of 145-200bp, derived from placental trophocytes • 970 times greater than fetal cells DNA in maternal blood. • Detectable in maternal plasma from the 5th week of gestation. • Concentration increase as the gestation age grows • Disappears soon after childbirth.

  8. Sequencing revolution NGS Sanger

  9. Principle of NIFTY Normal T-21 Plasma DNA Total cfDNA sequencing Chr6 Chr18 ChrX Chr21 Chr7 Chr13 Chr11 ChrY Reads alignment ….. Reads count Bioinformatics analysis

  10. Clinical validation in 3464 samples • Study design and aim: • Validation of the NIFTY in predicting the fetal risk of trisomy 21, 18, and 13 in high risk population by a double blind test • Evaluation of sensitivity and specificity of the NIFTY by comparing to karyotyping result (clinical gold standard) • provide supports for large-scale test in real clinical setting

  11. NIFTY results in 3464 samples *caused by insufficient sequencing depth

  12. Large scale clinical test (2009-2011) Qualified maternal blood samples (n=11184) • Gestational week from 9 – 28 weeks, averagely 20 weeks • Maternal age from 18 – 45 years, averagely 31 years • 4522 screening test high risk pregnancies • 2426 screening test low risk pregnancies • 2720 other high risk factors (AMA, abnormal NT, previous abnormal pregnancy, etc.) • 1387 screening not done 0.7% of all samples Unable to produce results (n=79; failed DNA extraction, library construction, or sequencing) 99.3% of all samples Pregnant women with NIFTY results (n=11105) Positive (n=190) Negative (n=10915) Shan Dan, et al., Prenatal Diagnosis, 2012: p. 1-8.

  13. NIFTY results in 11105 samples Shan Dan, et al., Prenatal Diagnosis, 2012: p. 1-8.

  14. Other rare aneuploidies A T21 case was missed by biochemical screening Sample ID: PDP10003761 Age: 31 Screening test: 1/510（Low risk） NIFTY: T21 Karyotyping: 47, XX, +21

  15. T9 Sample ID: PDB11AJ00026 Age: 41 NIFTY: T9 Karyotyping: T9

  16. T16 Sample ID: PDB11AJ00783 Age: 30 NIFTY: T16 FISH: T16

  17. Mosaic T21 Sample ID: PDB12AO00267 Age: 38 NIFTY: T21 Karyotyping: 47, XX, +21 (88%)

  18. T21-T7-XXY complex placental mosaic Sample ID: PDB12AL00732 Age: 37 NIFTY: T21-T7-XXY/XY Karyotyping: CVS T21-T7-XXY/XY; AF euploid

  19. NIFTY clinical pipeline AMA, Previous affected fetus, Recurrent miscarriage, Aneuploidy background

  20. Test workflow Hospital • Post-test counseling BGI Clinical Laboratories: 10 days

  21. Sample Management System • Unique Identification • Sample Location • Storage Capability Laboratory System Effective lab space separation Progressively decreased pressure Restricted traffic flow

  22. NIFTY is not suitable for Detection of balanced rearrangements and low level of mosaicism The pregnant woman is a chromosomal aneuploidy carrier If either of the parent has chromosomal structural abnormalities e.g. duplication, deletion, translocation, etc. If the pregnant woman receives allogenic DNA importation prior to NIFTY e.g. blood transfusion, transplantation, stem cell therapy, etc.

  23. Report Genetic testing report Low risk: the fetus is unlikely to be T21, T18, or T13. No special medical procedure is recommended. Routine prenatal checks is suggested. High risk: the fetus is likely to be T21, or T18, or T13. diagnostic procedure such as amniocentesis or cordocentesis is recommended. More than 98% of cases

  24. Delay notification QC: Caused by either the experiment or blood sample quality; need to repeat the experiment Data fluctuation: Caused by high data deviation; need to repeat the experiment cfDNA concentration low: Need to repeat the experiment If repeating experiment still cannot solve the problem, blood re-sampling is required.

  25. Re-sampling notification QC: Caused by poor blood sample quality cfDNA concentration low Previous NIFTY failed to produce informative result, and gestational age is more than 22 weeks

  26. Sample requirement

  27. BGI papers

  28. More Choice

  29. NIFTY express Validated on 1647 samples Performed on Ion Proton platform, extremely fast Performed in Czech Republic BGI-GENNET co-lab. EU based service. Similar price

  30. NIFTY plus Detection of Microdeletion syndromes Non-invasive Monogenic disease detection Results of other prenatal tests such as biochemical and ultrasound tests should be considered. Diagnostic procedure such as amniocentesis/cordocentesis is suggested.

  31. Summary

  32. About BGI • Largest genomics research center in the world • 137 Hiseq2000, 27 AB Solid, 1 Roche 454, 1 Ion Torrent, 30 AB 3730 • Strong leader board and qualified employees • More than 4000 employees including 1500 bioinformaticians • Extraordinary super computer and cutting-edge cloud computing technique • 102T flops/ 10PB storage/ 20TB memory • Numerous high-quality publications on top academic Journals • Nature/ Science/ …

  33. Selected Top Publications of BGI

  34. Milestones of BGI BGI-Beijing, 1999 BGI-Americas, 2010 BGI-WH, 2010 BGI-HZ, 2001 BGI-SZ, 2007 BGI-Europe, 2010 BGI-HK, 2009

  35. Platforms of BGI • Sequencing platform • Computing and bioinformatics platform • Proteomics platform • Agricultural genomics platform • Microbiology platform • Cloning platform • Healthcare platform

  36. Research collaborators worldwide

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