MALBAC Technology and Its Application in Non-invasive Chromosome Screening (NICS)

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1 MALBAC Technology and Its Application in Non-invasive Chromosome Screening (NICS)

2 The Power of One Adapted from Internet

3 Single Cell Genomic Studies Ultra Low Sample Input Advances and applications of single-cell sequencing technologies. Wang Y et al. Mol Cell. 2015

4 Single Cell Genomic Studies Downstream Analysis Single cell pg level DNA ng to µg level DNA MALBAC TM single cell whole genome amplification (WGA) technology (Multiple Annealing and Looping Based Amplification Cycles)

5 Coverage MALBAC TM Single Cell WGA Technology Genome-Wide Detection of Single Nucleotide and Copy Number Variations of a Single Human Cell, Science, 2012

6 MALBAC TM Single Cell WGA Technology - Sensitivity Single cell Single chromosome Limited amount of tissue samples Genomic DNA

7 Coverage MALBAC TM Single Cell WGA Technology - Genome Coverage MALBAC MDA Genome-Wide Detection of Single Nucleotide and Copy Number Variations of a Single Human Cell, Science, 2012

8 MALBAC Uniformity TM Single Cell WGA Technology - Uniformity Single-Cell Whole-Genome Amplification and Sequencing: Methodology and Applications, Annu. Rev. Genomics Hum. Genet. 2015

9 MALBAC TM Single Cell WGA Technology Allele Drop Rate (ADO) A True Genotype B ADO Single-Cell Whole-Genome Amplification and Sequencing: Methodology and Applications, Annu. Rev. Genomics Hum. Genet. 2015

10 Features of MALBAC TM Single Cell WGA Technology High Genome Coverage High Uniformity High Sensitivity Low Allele Drop Out Rate

11 MALBAC TM Single Cell WGA Technology Single cell pg level DNA MALBAC TM Amplification Next Generation Sequencing (NGS) Microarray qpcr Molecular Cloning.

The Application of MALBAC TM Technology 2012 2012 2013 2013 2014 2015 2015 2016 2016 Genome-Wide Detection of Single-Nucleotide and

Probing Meiotic Recombination and Aneuploidy of Single Sperm Cells by Whole-Genome Sequencing.

Cell, 2013, 155: 1492-1506 Reproducible Copy Number Variation Patterns Among Single Circulating Tumor Cells of Lung Cancer Patients.

aneuploidy screening of cleavage-stage embryos.

Rev. Genomics Hum. Genet., 2015, 16: 16.1-16.

12 The Application of MALBAC TM Technology Genome-Wide Detection of Single-Nucleotide and Copy-Number Variations of a Single Human Cell. Science, 2012, 338, Probing Meiotic Recombination and Aneuploidy of Single Sperm Cells by Whole-Genome Sequencing. Science, 2012, 338(6114, ) Genome Analyses of Single Human Oocytes. Cell, 2013, 155: Reproducible Copy Number Variation Patterns Among Single Circulating Tumor Cells of Lung Cancer Patients. PNAS, 2013, 110(52): Validation of multiple annealing and looping-based amplification cycle sequencing for 24-chromosome aneuploidy screening of cleavage-stage embryos. Fertility and Sterility, 2014, 102: Single-Cell Whole-Genome Amplification and Sequencing: Methodology and Applications. Annu. Rev. Genomics Hum. Genet., 2015, 16: Live Births after Simultaneous Avoidance of Monogenic Diseases and Chromosome Abnormality by Next-Generation Sequencing with Linkage Analyses. PNAS, 2015, 112(52): A New Next-generation Sequencing-based Assay for Concurrent Preimplantation Genetic Diagnosis of Charcot-Marie- Tooth Disease Type A1 and Aneuploidy Screening. JGG, 2016, Available online 21 January 2016 Validation of a next-generation sequencing-based protocol for 24-chromosome aneuploidy screening of blastocysts. Fertility and Sterility, 2016

13 Application of MALBAC TM Technology Single Cell Genomic Studies Lu S et al, 2012, Science, 338: Hou Y et a., Cell Dec 19;155(7):

14 Application of MALBAC TM Technology in Cancer Genomic Studies Profiling of CTCs Xi. Ni, et al., PNAS (52)

Fertil & steril, 2014; 102: 1685-1691 Huang

15 Application of MALBAC TM Technology in Reproductive Genetic Testing Huang J et al. Fertil & steril, 2014; 102: Huang J et a.l, Fertil Steril Jun;105(6):

16 Results of MALBAC TM -PGS (Preimplantation Genetic Screening) 47,XN,+4 Multiple Chromosomal Aneuploidy 46,XN 46,XN,+6q(q24.1 qter) 46,XN,-5 (mos*)

17 Conventional Preimplantation Genetic Screening Oocyte In Vitro Fertilization Embryo Culture Embryo Biopsy Sample Prep CGH Array Fish NGS Result Reporting

18 Non-invasive Chromosomal Screening (NICS) Technology Result Reporting Blastocyst

19 Features of NICS Non-invasive Embryos remain intact and only culture medium will be collected Convenience No need for embryo biopsy; Less strict requirements on equipment and techniques No sample loss Effectively address the sample loss issue during conventional PGS High sensitivity Can detect pg level genetic materials Flexible Compatible with both Illumina and Ion Torrent NGS platforms

20 Validation of NICS Culture Medium NICS Assay 42 Blastocyst Stage Embryos PGS Result Whole Embryo Conventional PGS Key Performance Parameters Specificity 84.0% Sensitivity 88.2% Positive predictive value (PPV) 78.9% Negative predictive value (NPV) 91.3% Xu J, et al. Noninvasive chromosome screening of human embryos by genome sequencing of embryo culture medium for in vitro fertilization. PNAS, 2016.

21 Validation of NICS

22 Clinical Application of NICS IVF Cycles Wife Husband 3 Premature ovarian failure No. of Blastocyst Embryos No. of Transferrable Embryos Clinical Outcome t(14;15)(q22;q24) 3 1 Healthy boy was born at wk

23 Clinical Application of NICS IVF Cycles Wife Husband 3 Premature ovarian failure No. of Blastocyst Embryos No. of Transferrable Embryos Clinical Outcome t(14;15)(q22;q24) 3 1 Healthy boy was born at wk Embryo 1 Medium 1 Embryo 2 Medium 2 Medium 3

24 Non-invasive Chromosomal Screening (NICS)

25 Future of MALBAC TM Technology Faster Simpler Compatible

26 Thank You!

SNP array-based analyses of unbalanced embryos as a reference to distinguish between balanced translocation carrier and normal blastocysts

J Assist Reprod Genet (2016) 33:1115 1119 DOI 10.1007/s10815-016-0734-0 TECHNOLOGICAL INNOVATIONS SNP array-based analyses of unbalanced embryos as a reference to distinguish between balanced translocation