PGS & PGD. Preimplantation Genetic Screening Preimplantation Genetic Diagnosis

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1 1 PGS & PGD Preimplantation Genetic Screening Preimplantation Genetic Diagnosis

OUR MISSION OUR MISSION CooperGenomics unites pioneering leaders in reproductive genetics, Reprogenetics, Recombine, and Genesis Genetics, as part of the CooperSurgical family.

2 OUR MISSION OUR MISSION CooperGenomics unites pioneering leaders in reproductive genetics, Reprogenetics, Recombine, and Genesis Genetics, as part of the CooperSurgical family. Through expanded carrier screening, PGS, PGD, NIPS, and beyond, our team is committed to advancing the field of reproductive genetics, improving outcomes, and empowering families worldwide. >30 YEARS COMBINED EXPERIENCE PERSONAL GENETIC COUNSELING FOR ALL >700 SCIENTIFIC ABSTRACTS AND PUBLICATIONS UNMATCHED EXPERIENCE CooperGenomics brings together the historic expertise of PGD pioneer Dr. Mark Hughes and PGS pioneer Dr. Santiago Munne. Together our teams have: PERFORMED >100,000 PGS PROCEDURES PERFORMED >8,000 PGD PROCEDURES WORKED WITH >300 IVF CENTERS

3 PGS & PGD Preimplantation genetic testing involves biopsy of a developing embryo and genetic testing of the biopsied cell(s). Preimplantation genetic testing can be categorized as either preimplantation genetic screening (PGS) or preimplantation genetic diagnosis (PGD). PGS Preimplantation Genetic Screening PGD Preimplantation Genetic Diagnosis PATIENT POPULATION All IVF patients Patients at high-risk of having a child with a specific genetic disease GOAL Improve IVF success rates Reduce risk of passing on an inherited condition GENETIC TEST TYPE Screens for chromosome abnormalities Screens for a specific single gene disorder or inherited chromosome rearrangement REQUIRES PERSONALIZED TEST PREPARATION No Single gene disorders: Yes Chromosome rearrangements: Typically no ALSO KNOWN AS PGT-A: Preimplantation Genetic Testing for Aneuploidies CCS: Comprehensive Chromosome Screening PGT-M: Preimplantation Genetic Testing for Monogenic/Single Gene Defects PGT-SR: Preimplantation Genetic Testing for Chromosomal Structural Rearrangements 3

4 PGS CONFIDENT EMBRYO TRANSFER PGS provides information about the chromosome content of IVF embryos to help you and your team select the embryo most likely to lead to a successful pregnancy. Euploid embryos have the correct number of chromosomes and are more likely to lead to a successful IVF outcome than aneuploid embryos, which contain extra or missing chromosomes or parts of chromosomes. PGS is typically performed on a small sample of approximately 5-10 cells biopsied from the trophectoderm of a blastocyst stage (day 5) embryo. POSSIBLE PGS RESULTS Euploid Mosaic Aneuploid NUMBER OF CHROMOSOMES PER CELL Normal Mixed (some normal & some abnormal) Abnormal LIKELIHOOD OF PRODUCING A SUCCESSFUL PREGNANCY High Low, but possible Very unlikely TRANSFER PRIORITY High Intermediate; may be considered if no euploid embryos are available Low 4

5 PGS ANEUPLOIDY & AGE All patients are at risk of producing chromosomally abnormal embryos. As a woman ages, the risk of producing aneuploid embryos significantly increases. PGS RESULTS DISTRIBUTION 80% 70% 60% 50% 40% 30% 20% 10% % Euploid Mosaic Aneuploid 14.1% 31.7% 50.0% 13.9% 36.1% 42.8% 12.1% 45.1% Egg Donors < >42 (N=7304) (N=17329) (N=11541) (N=11328) (N=5325) (N=2653) 31.1% 9.9% MATERNAL AGE 59.0% 19.7% 7.5% 72.8% 14.5% 5.5% 79.9% Internal CooperGenomics data of blastocyst biopsies tested via Next Generation Sequencing ( ) Unlike aneuploidy, mosaicism is thought to be independent of maternal age. However, the number of embryos clinically classified as mosaic decreases slightly with age, as shown here. This is due to the increased liklihood that an embryo with a mosaic abnormality will also have a meiotic aneuploidy, which would result in that embryo being classified as aneuploid rather than mosaic. 5

6 PGS BENEFITS OF PGS PGS has been shown to increase implantation rates, reduce miscarriage rates, and increase live birth rates. PGS also enables more confident single embryo transfer, reducing the possibility of complications associated with twin or triplet multiples pregnancies. MISCARRIAGE RATE PGS REDUCES MISCARRIAGE RATES 60% 50% 40% 30% 20% 10% % 11.2% 16.8% 13.0% 25.0% 13.6% 37.9% 16.3% 58.8% 17.2% < >42 MATERNAL AGE LIVE BIRTH RATE PGS INCREASES LIVE BIRTH RATES 60% 50% 40% 30% 20% 10% % 56.6% 39.2% 54.2% 27.6% 52.2% 15.3% 46.7% 5.0% 42.4% < >42 MATERNAL AGE IVF without PGS IVF with PGS SAMPLE SIZE (NUMBER OF TRANSFERS) < >42 IVF WITHOUT PGS 29,989 13,144 10,497 4,678 3,009 IVF WITH PGS 5,326 3,366 2, SART.org data (2015) 6

7 PGS THE PGS PROCESS PGS can be seamlessly added to IVF to help increase the chances of cycle success. PGS typically requires that embryos are frozen prior to transfer. Genetic counselors are available to inform, support, and guide families throughout the process. IVF In vitro fertilization is performed and the resulting embryos are incubated. EMBRYO BIOPSY An embryologist carefully removes a small cell sample from each embryo. EMBRYO TRANSFER A chromosomally normal embryo is selected for transfer. Additional euploid embryos can remain frozen for future use. PGS Samples are sent to the PGS laboratory, testing is performed, and results are released to the IVF center. 7

8 PGS SUPERIOR TECHNOLOGY At CooperGenomics, we are committed to offering the most advanced PGS technology to enable the most informed embryo selection. Our high-resolution PGS (hr-pgs) is performed via Next Generation Sequencing (NGS) technology and investigates over half a million data points throughout the genome to provide unparalleled detection of: Aneuploidy Partial (segmental) aneuploidy Unbalanced translocations Some polyploidies Mosaicism Preimplantation Genetic Testing Results Patient Name: Jane Smith Patient ID: DOB: (44 y.o.) Sex: Female Donor Gamete: No Test Information Test: Preimplantation Genetic Screening (PGS) Testing Location: Livingston, NJ Methodology: NGS IVF Center Information Center Name: Miller MD Center Code: 675 Ordering Physician: Dr. Frank Miller Report Date: PROCEDURE ID: 001 SUMMARY OF RESULTS: 2 EUPLOID SAMPLES IDENTIFIED Biopsy Date: Biopsy Performed by: Miller MD & Associates Sample Type: Trophectoderm Sample(s) Received: Barcode: Sample Condition: All samples arrived in good condition. Sample ID Result Sex Chromosomes Impacted Interpretation 1 EUPLOID XY NORMAL 2 Aneuploid XX +21 Abnormal 3 Mosaic XY +9[mos] Low Level Mosaic 4 Mosaic XX -3[mos] High Level Mosaic 5 EUPLOID XX NORMAL 6 Aneuploid XX Complex Abnormal The interpretation provided in this report is intended as a guide; the selection of embryos for transfer is at the discretion of the physician. 1. Internal CooperGenomics data, N>10,000 (2015). 2. Munne & Wells. Detection of mosaicism at blastocyst stage with the use of high-resolution next-generation sequencing. Fertil Steril (2017). 3. Quality dependent. Results read/interpreted by: Bob Jones Results read/reviewed by: Susan Sands Report approved by: John Collins, PhD, HCLD 2017 CooperSurgical, Inc. All Rights Reserved. Reprogenetics CLIA ID: NYDOH #: Regent St, #301 Livingston, NJ Jane Smith s (DOB: ) PGS Report 1/3 8

9 PGS DETECTING MOSAICISM Our current data suggest that 10-20% of PGS samples are clinically classified as mosaic. 1 While mosaic embryos typically have a reduced implantation potential and higher likelihood of miscarrying, they can sometimes lead to live birth. 2 EUPLOID CELL ANEUPLOID CELL MOSAIC REPORTING hr-pgs via NGS is the only methodology validated for the reliable detection of mosaicism, and CooperGenomics is proud to be one of the first laboratories reporting mosaic results. 2, 3 In accordance with society guidelines and current research, we report mosaicism based on the percent aneuploidy and the number of chromosomes impacted. LOW-LEVEL MOSAICS (20-40% abnormal cells) have been shown to frequently have euploid ICMs and result in a 50% ongoing pregnancy rate (n=102). 4,5 Samples with low-level mosaicism involving a single chromosome may be prioritized when no euploid embryos are available. HIGH-LEVEL MOSAICS (>40-80% abnormal cells) have been shown to result in a 30% ongoing pregnancy rate (n=44). 4,5 Samples with high-level mosaicism, as well as samples with low-level mosaicism involving two chromosomes, may be given lower priority. COMPLEX MOSAICS 6 (Mosaicism in 3 chromosomes) have been shown to result in a 6% ongoing pregnancy rate (n=32). 4,5 Complex mosaics may be given lowest priority. Appropriate counseling by a physician and/or genetic counselor is recommended for all PGS cases. Prenatal diagnosis by amniocentesis should be offered for all pregnancies resulting from mosaic embryo transfer. 1. Internal CooperGenomics data, N>10,000 (2015) 2. Munne & Wells. Detection of mosaicism at blastocyst stage with the use of high-resolution next-generation sequencing. Fertil Steril (2017). 3. Quality dependent 4. Munne et al. Detailed investigation into the cytogenetic constitution and pregnancy outcome of replacing mosaic blastocysts detected with the use of high-resolution next-generation 5. CooperGenomics & Genoma internal data ( ) 6. Complex mosaics are reported as Complex Abnormal on CooperGenomics PGS reports. 9

10 PGD PGD FOR SINGLE GENE DISORDERS 1/ 28 1 in 28 couples are at increased risk of having a child affected with a single gene disorder 1 > 95 % PGD mutation detection rate 2 PGD, or preimplantation genetic diagnosis, is a genetic test performed before pregnancy to significantly reduce the risk of having a child with a specific genetic disease. PGD involves screening embryos created through in vitro fertilization (IVF) for a particular condition and then transferring only unaffected embryos. Candidates for PGD may have learned of their risk status through an affected family member, child, or pregnancy, or as a result of carrier screening, like CooperGenomics CarrierMap SM. PGD can be performed for almost any single gene disorder with an identified mutation and availability of appropriate family members. Our detailed case review process plus individualized test design enables us to select the technology most appropriate for each family. The latest PGD technique, Karyomapping, investigates >300,000 data points across the genome to increase the accuracy of embryo diagnosis. Karyomapping enables: > 70 % Implantation rate of healthy embryos as identified through PGD+PGS 3 Faster test preparation in ~4 weeks Testing of multiple conditions at once Addition of PGS without the need for an additional sample HLA matching PGD CAN BE PERFORMED FOR >6,000 SINGLE GENE DISORDERS, INCLUDING: BRCA1&2 Cystic Fibrosis Fragile X Syndrome Spinal Muscular Atrophy Huntington s Disease Sickle-Cell Disease Internal CooperGenomics CarrierMap data inclusive of autosomal recessive and X-linked disease 2. Internal CooperGenomics data 3. Jaroudi et al 2016 ASRM. PGD via Karyomapping, PGS via hr-ngs.

11 KARYOMAPPING TECHNOLOGY PGD UNAFFECTED EXAMPLE: PGD BY KARYOMAPPING FOR AN AUTOSOMAL RECESSIVE CONDITION CARRIER CARRIER FATHER CARRIER MOTHER AFFECTED Chromosome region analyzed by PGD { EMBRYO 1 UNAFFECTED EMBRYO 2 CARRIER EMBRYO 3 CARRIER EMBRYO 4 AFFECTED PGD uses linkage analysis to diagnose embryos. When PGD is performed for an autosomal recessive condition as shown above, unaffected and carrier embryos may be available for transfer (embryos 1-3). 11

12 PGD PGD FOR CHROMOSOME REARRANGEMENTS in 200 individuals is a carrier of a balanced chromosome rearrangement. 1 PGD is also available for carriers of balanced reciprocal translocations, Robertsonian translocations, inversions, and other complex chromosome rearrangements. Though carriers of balanced chromosome rearrangements are typically healthy, they are at increased risk for producing embryos with the incorrect amount of chromosomal material, resulting in reduced viability or potential for children with physicial or intellectual disability. PGD can help identify embryos with the correct amount of chromosomal material that are most likely to lead to a successful pregnancy and healthy live birth. 80 % If one parent is a carrier of a reciprocal translocation, approximately 80% of resulting embryos will be unavailable for transfer. 2 The most appropriate technology is selected for each case. The majority of cases are performed via NGS and: Require no familial testing Are automatically paired with PGS at no additional charge Harper, Peter S. Practical Genetic Counseling. London: Butterworth-Heinemann, Print. 2. Internal CooperGenomics data 3. Exclusions apply

13 PGD THE PGD PROCESS CASE REVIEW Prospective parents speak with a genetic counselor and discuss if additional genetic testing of the couple or other family members is required. PGD TEST PREPARATION The PGD lab collects DNA samples from the couple and appropriate family members and designs a test unique to each family. EMBRYO BIOPSY An embryologist carefully removes a small cell sample from each embryo. Embryos are frozen while awaiting PGD results and transfer. IVF In vitro fertilization is performed and the resulting embryos are incubated. PGD Samples are sent to the PGD laboratory, testing is performed, and results are released to the IVF center. EMBRYO TRANSFER An unaffected embryo is transferred. Additional unaffected embryos can remain frozen for future use. 13

SEAMLESS SUPPORT CooperGenomics is dedicated to providing our clinical partners individualized customer service through thoughtful patient coordination, comprehensive genetic counseling, and

All PGS & PGD patients are paired with an experienced patient coordinator whose goal is to make the logistics of genetic testing as simple and seamless as possible, being sensitive to each family s

GENETIC COUNSELING At CooperGenomics, we are committed to offering personal, in-depth genetic counseling to responsibly guide patients through the preimplantation genetic testing process.

14 SEAMLESS SUPPORT CooperGenomics is dedicated to providing our clinical partners individualized customer service through thoughtful patient coordination, comprehensive genetic counseling, and simplified logistics. PATIENT COORDINATION Dealing with fertility struggles or genetic risks during the family planning process can be overwhelming. All PGS & PGD patients are paired with an experienced patient coordinator whose goal is to make the logistics of genetic testing as simple and seamless as possible, being sensitive to each family s unique circumstances. GENETIC COUNSELING At CooperGenomics, we are committed to offering personal, in-depth genetic counseling to responsibly guide patients through the preimplantation genetic testing process. Our team of board-certified, licensed genetic counselors are specially trained in PGS and PGD and are available to patients before, during, and after testing. LOGISTICS Requesting Kits CooperGenomics provides embryo biopsy kits for PGS & PGD sample collection. In addition, we supply shipping boxes, Styrofoam coolers, and if desired, ice packs for your return shipments. Please courier@coopergenomics.com to request kits (72 hour notice is requested). Sending Samples Sending PGS & PGD samples is easier than ever with CooperGenomics concierge courier services. Simply courier@coopergenomics.com prior to biopsy to request package pick-up, and our dedicated logistics team handles the rest.* We partner with private medical couriers and monitor package status to ensure safe, reliable, and expedient sending of patient samples. 14 *24 hour notice is requested for frozen transfers and 48 hour notice for fresh transfers.

15 THE CARRIERMAP ADVANTAGE CooperGenomics PGS >100,000 Cases Performed High Resolution PGS via NGS Methodology Only Methodology Validated for Mosaicism Detection Mosaicism Reporting Available Comprehensive Genetic Counseling Concierge Courier Services Provided CooperGenomics PGD >8,000 Cases Performed Single Gene Disorders and Chromosome Rearrangements Karyomapping and/or NGS Technology Option to Add hr-pgs to Any PGD Case Able to Test for Multiple Conditions with a Single Sample HLA Matching Available Comprehensive Genetic Counseling Concierge Courier Services Provided V1 15

16 CooperGenomics unites pioneering leaders in reproductive genetics, Reprogenetics, Recombine, and Genesis Genetics, as part of the CooperSurgical family. Through expanded carrier screening, PGS, PGD, NIPS, and beyond, our team is committed to advancing the field of reproductive genetics, improving outcomes, and empowering families worldwide. Testing is performed by Reprogenetics, Recombine, Genesis Genetics, or other clinical laboratories affiliated with CooperGenomics. All information correct at time of print CooperSurgical, Inc. All Rights Reserved.

Increase your chance of IVF Success. PGT-A Preimplantation Genetic Testing for Aneuploidy (PGS 2.0)

Increase your chance of IVF Success PGT-A Preimplantation Genetic Testing for Aneuploidy (PGS 2.0) What is PGT-A? PGT-A, or Preimplantation Genetic Testing for Aneuploidy (PGS 2.0), is a type of genomic