Expanded Preimplantation Genetic Testingcme-utilities.com/mailshotcme/Material for...
Transcript of Expanded Preimplantation Genetic Testingcme-utilities.com/mailshotcme/Material for...
Expanded Preimplantation Genetic Testing
Nathan R. Treff PhD, HCLD(ABB)
Cofounder, Chief Science Officer, and Clinical Laboratory Director
Disclosures
• Cofounder, Shareholder and CSO, Genomic Prediction Inc
• Director, Genomic Prediction Clinical Laboratory Inc
Stephen Hsu Laurent Tellier
SNP array (18)
qPCR (22) NGS
(19)
Monogenic Polygenic
e.g. Cystic Fibrosis e.g. Type 1 Diabetes 1% 15-25%
monogenic
polygenic
Power of Population Level Genetics
Principle Component Analysis
UK BioBank (500K Genome-wide Data)
Million Veterans Program
Polygenic Risk Score Publications
Modern Polygenic Risk Score Algorithms
Clinical Predictors (i.e. fracture risk assessment)
GWAS “one at a time”
Polygenic Risk Scores “machine learning”
Osteoporosis Variance Explained
Combined Testing?
Clinical Risk
Out of Sample Validation
Combined Risk
Family History
Common and Reliable Phenotype (applies to idiopathic short stature)
Methodology validation
Predicted Height (cm)
Act
ual
He
igh
t (c
m) Male
Female
Replication
Atrial Fibrillation
Inflammatory Bowel
Disease
Type 2 Diabetes
Breast Cancer
Disease Examples
“We propose that it is time to contemplate the inclusion of polygenic risk prediction in clinical care, and discuss relevant
issues.”
Accurate Genome-wide
Genotypes (PGT-M, PGT-P)
Accurate copy number
(PGT-A, PGT-SR)
Automated lysis and library
template prep DNA amplification 2
DNA amplification 1
Expanded Preimplantation Genomic Testing (ePGT) Methodology (>900K SNPs)
Accurate Genome-wide
Genotypes (PGT-M, PGT-P)
Accurate copy number
(PGT-A, PGT-SR)
Automated lysis and library
template prep
Expanded Preimplantation Genomic Testing (ePGT) Methodology (>900K SNPs)
96 samples per run
DNA amplification 3
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)
Copy Number Accuracy PGT-A and PGT-S
PGT-A Examples (5-8 cells)
PGT-A Examples (Circos Plots)
PGT-A Performance (>99% Accuracy)
32% prevalence
PGT-SR Preliminary Results (>99% Accuracy)
n=42
ave
rage
co
py
nu
mb
er
size (Mbp) >900K SNPs = High Density
Translocation Carrier Status
Genotyping Accuracy PGT-M and PGT-P
Genotyping Accuracy on Limited Quantities
Large qty Small qty
Co
nco
rdan
ce
100%
99%
98%
97%
96%
95%
Copy number + genotyping for PGT-A
False Positives True Positives
AAA
AAB ABB
BBB
AB
BB
AA
BB
AA
Trisomy Disomy Monosomy
Mendelian Rules
PGT-M: Typical Number of Markers (~60)
PGT-M: CFTR delta F508 (>99.9% Accuracy)
47% prevalence
PGT-P Results: Hypothyroidism Risk (4945 SNPs)
eMERGE-GWAS Set
n=219,000 n=2,019
PGT-P Results: Hypothyroidism Risk (4945 SNPs)
n=219,000 n=36
PGT-P: Hypothyroidism Risk (83% Accuracy)
Note: Heritability studies suggest that up to 67% of hypothyroidism is genetically determined.
ePGT Initial Polygenic Risk Targets
Baade et al. BMJ Open 2015 CgvFactSheet. National Cancer Institute, 2012. Chen et al. BMC Medical Genetics 2017. American Speech-Language-Hearing Association. 2018. Lee et al. Nature Genetics 2018. Lello et al. Genetics 2018 .
https://www.ahajournals.org 2018 Lloyd-Jones et al. Circulation, August 31, 2004. Loukine et al. Population Health Metrics 2012. Patja et al. Journal of Intellectual Disability Research 2000 Sanchis-Gomar et al. Annals of Translational Medicine 2016. WebMD. 2018. Wit et al. Growth Hormone & IGF Research 2008.
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
Aneuploidy and Polygenic Risk
45% 4% 19% 71%
Coronary Artery
Disease Risk
Aneuploidy Risk
Aneuploidy and Polygenic Risk
45% 4% 74% 71%
Type 1 Diabetes
Risk
Aneuploidy Risk
Intervention during honeymoon phase?
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
• 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
ASRM 2018
“CRISPR”
Bob Edwards 1996
National Surveys
• 74% of Americans support use of PGT for serious conditions1
• 72% of Americans2 and 66% of British3 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, 2002
2. “The Public and Gene Editing, Testing, and Therapy” Harvard TH Chan School of Public Health, STAT, 2018 3. “Industry News: UK Public Cautiously Optimistic About Genetic Technologies” SelectScience, 2018
Future Directions
Acknowledgements