Expanded Preimplantation Genetic Testing. Nathan R. Treff PhD, HCLD(ABB) Cofounder, Chief Science Officer, and Clinical Laboratory Director

Transcription

1 Expanded Preimplantation Genetic Testing Nathan R. Treff PhD, HCLD(ABB) Cofounder, Chief Science Officer, and Clinical Laboratory Director

2 Disclosures Cofounder, Shareholder and CSO, Genomic Prediction Inc Director, Genomic Prediction Clinical Laboratory Inc Stephen Hsu SNP array (18) qpcr (22) NGS (19) Laurent Tellier

3 Monogenic Polygenic e.g. Type 1 e.g. Cystic 1% Fibrosis 15-25% Diabetes

4 monogenic polygenic

5 Power of Population Level Genetics Principle Component Analysis

6 UK BioBank (500K Genome-wide Data)

7 Million Veterans Program

8

9 Polygenic Risk Score Publications

10 Modern Polygenic Risk Score Algorithms Clinical Predictors (i.e. fracture risk assessment) GWAS one at a time Combined Testing? Polygenic Risk Scores machine learning Clinical Risk Out of Sample Validation Osteoporosis Variance Explained

11 Combined Risk

12 Family History

13 Actual Height (cm) Male Female Predicted Height (cm) Common and Reliable Phenotype (applies to idiopathic short stature) Methodology validation

14 Replication

15 Disease Examples Atrial Fibrillation Type 2 Diabetes We propose that it is time to contemplate the inclusion of polygenic risk prediction in clinical care, and discuss relevant issues. Inflammatory Bowel Disease Breast Cancer

16 Expanded Preimplantation Genomic Testing (epgt) Methodology (>900K SNPs) DNA amplification 1 Accurate Genome-wide Genotypes (PGT-M, PGT-P) Automated lysis and library template prep DNA amplification 2 Accurate copy number (PGT-A, PGT-SR)

17 Expanded Preimplantation Genomic Testing (epgt) Methodology (>900K SNPs) DNA amplification 3 96 samples per run Accurate Genome-wide Genotypes (PGT-M, PGT-P) Automated lysis and library template prep Accurate copy number (PGT-A, PGT-SR)

18 epgt Control Samples Copy number Aneuploidy (PGT-A): 6-7 cells from samples with prior karyotyping (whole chromosome aneuploid and euploid) Structural (PGT-SR): 6-7 cells from samples with segmental aneuploidy Genotyping Monogenic (PGT-M): 6-7 cells from samples with known CFTR delta F508 status Polygenic (PGT-P): cell free DNA from individuals with hypothyroidism (TSH)

19 Copy Number Accuracy PGT-A and PGT-S

20 PGT-A Examples (5-8 cells)

21 PGT-A Examples (Circos Plots)

22 PGT-A Performance (>99% Accuracy) 32% prevalence

23 average copy number PGT-SR Preliminary Results (>99% Accuracy) n=42 >900K SNPs = High Density size (Mbp)

24 Translocation Carrier Status

25 Genotyping Accuracy PGT-M and PGT-P

26 Concordance Genotyping Accuracy on Limited Quantities 100% 99% 98% 97% 96% 95% Large qty Small qty

27 Copy number + genotyping for PGT-A AA AAA AAB Monosomy ABB BB BBB AA AB Trisomy Disomy BB False Positives True Positives

28 Mendelian Rules

29 PGT-M: Typical Number of Markers (~60)

30 PGT-M: CFTR delta F508 (>99.9% Accuracy) 47% prevalence

31 PGT-P Results: Hypothyroidism Risk (4945 SNPs) emerge-gwas Set n=219,000 n=2,019

32 PGT-P Results: Hypothyroidism Risk (4945 SNPs) n=219,000 n=36

33 PGT-P: Hypothyroidism Risk (83% Accuracy) Note: Heritability studies suggest that up to 67% of hypothyroidism is genetically determined.

34 epgt Initial Polygenic Risk Targets Baade et al. BMJ Open 2015 CgvFactSheet. National Cancer Institute, Chen et al. BMC Medical Genetics American Speech-Language-Hearing Association Lee et al. Nature Genetics Lello et al. Genetics Lloyd-Jones et al. Circulation, August 31, Loukine et al. Population Health Metrics Patja et al. Journal of Intellectual Disability Research 2000 Sanchis-Gomar et al. Annals of Translational Medicine WebMD Wit et al. Growth Hormone & IGF Research 2008.

35 Utilization IVF population Higher risk of polygenic disorders (e.g. cancer risk in azoospermic males) Fewer embryos for selection General Population Family History Greater number of embryos for selection Genetic Counseling

36 Aneuploidy and Polygenic Risk Aneuploidy Risk Coronary Artery Disease Risk 4% 19% 45% 71%

37 Aneuploidy and Polygenic Risk Aneuploidy Risk Type 1 Diabetes Risk Intervention during honeymoon phase? 4% 74% 45% 71%

38 epgt Conclusions and Implications Novel use of machine learning algorithms and molecular genetic methods to expand testing for common heritable disease risk First method for simultaneous and accurate PGT of: Aneuploidy Monogenic Disease Risk Polygenic Disease Risk Structural Rearrangements (translocations) Polygenic risk scores may provide an additional embryo selection tool, increase utilization of IVF, and reduce the incidence of common genetic disease in humans

39 ASRM 2018 Ethically justified when the condition is serious and no safe, effective interventions are available. Reproductive liberty arguments ethically allow for PGT-M for adult-onset conditions of lesser severity or penetrance. Strongly recommend that an experienced genetic counselor with knowledge about PGT-M play a major role in counseling patients considering such procedures. As of this time, testing is not available for multifactorial diseases

40 Bob Edwards 1996 CRISPR

41 National Surveys 74% of Americans support use of PGT for serious conditions 1 72% of Americans 2 and 66% of British 3 were willing to gene edit their future children to reduce risk of serious disease 1. Awareness and Knowledge about Reproductive Genetic Technology Genetics and Public Policy Center, Johns Hopkins University, The Public and Gene Editing, Testing, and Therapy Harvard TH Chan School of Public Health, STAT, Industry News: UK Public Cautiously Optimistic About Genetic Technologies SelectScience, 2018

42 Future Directions

43 Acknowledgements