Basic Genetics Ion Pgd Centre Thornhill

Organisation of a PGD centre Basic genetics for ART practitioners March 23, 2007 Alan R. Thornhill Ph.D. Scientific Director, The London Bridge Fertility, Gynaecology and Genetics Centre Assistant Director, Bridge genoma

Organisation of a PGD centre • • • • •

What makes an excellent PGD centre? Building the PGD puzzle Patient vs centre experience of PGD Satellite/transport PGD - Pros and Cons More to come from PGD?

What makes an excellent PGD centre? • Excellent Genetic Evaluation and Counselling • Excellent IVF Platform • Excellent Diagnostics Laboratory • Excellent Patient experience • Integration of Services • Rigorous Quality Control/Quality Assurance • Commitment to Follow-up/Comprehensive Ethical Review

Building the PGD puzzle • Ensure appropriate testing (counselling/testing) • In Vitro Fertilization • Embryo biopsy • Diagnostic test on biopsied blastomere • Reporting and explaining results • Transfer of selected embryos to the uterus • Follow-up of pregnancy and resulting child

Diagnostics Genetics Embryology Fertility

Genetics • • • • • • • •

Family and medical history Assess severity of condition Estimate genetic risk Provide realistic expectations Explain process, disorder and tests Ensure appropriate tests offered Discuss options (risk/benefit) Obtain consent

Options for potential ‘PGD’ patients • • • • • •

Contraception Childlessness Prenatal testing (± pregnancy termination) Donation (egg, sperm, embryo) Adoption Reproductive roulette (emotional, physicial & financial cost of affected child?)

Genetics

Ensure appropriate testing Ensure PGD valid option Provide realistic expectations

Fertility • • • • • • •

Reproductive and medical history Provide realistic expectations Explain IVF process and tests Discuss options (risk/benefit) Obtain consent Prescribe IVF medication Perform IVF procedures (EC and ET)

Obtain appropriate consents Set realistic expectations Facilitate high quality eggs

Fertility

Ensure appropriate stimulation

Embryology • • • • • •

Prepare and introduce gametes in vitro Culture embryos Biopsy embryos Prepare diagnostic sample (single cells) Culture biopsied embryos Select embryo(s) for transfer (based on genetic result and morphology)

Embryo Biopsy Polar Body

Day 1

Cleavage stage

Day 3

Blastocyst

Day 5/6

Fluorescent In Situ Hybridization (FISH)

Biopsied blastomere

Polymerase Chain reaction (PCR)

A 38 year old woman… 1

2

3

Monosomy 21 Monosomy 22

5

6



Trisomy 22 and 16

9 Monosomy 16

4



Trisomy 21

7

8 Chaotic



10 Chaotic

Select the best two embryos for transfer

Provide accurate & comprehensive documentation Meet diagnostic centre’s acceptance criteria Prepare high quality samples Obtain high quality embryos

Embryology Obtain high quality embryos

Diagnostics • • • • •

Develop and validate single cell test Receive and accession sample Run test Report results Provide interpretation

Diagnostics Provide appropriate test Provide high quality test Meet rapid turn-around time

Provide user- friendly report

Centre’s Patient experience experienceofofPGD PGD • Confusing • Complex • Control (lack of) • Communication (absolutely necessary)

PGD clock - consultation to baby (noon til midnight)

fertility consultation genetic consultation test development fertility testing menstrual period begins down regulation begins ovarian stimulation begins hCG injection Egg collection/insemination Embryo culture Embryo biopsy Blastomere testing Results and embryo transfer Pregnancy test Pregnancy scan Prenatal diagnosis Birth

Satellite/transport PGD - Pros and Cons • Pros – – – –

Improved patient access and convenience Lower costs Experienced reference diagnostics lab Centres of excellence model

• Cons – – – –

Quality of sample preparation Transportation risks and timings Inadequate counselling/pre-cycle screening Negligible follow-up /responsibilities

More to come from PGD? • • • • • • •

More quality control/quality assurance More tests (whole genome amplification) More screening (aneuploidy, gene expression, protein) More funding for PGD More satellite and transport PGD More access for patients More efficient but more complex

Relevant bibliography • Kuliev A, Verlinsky, Y. (2004) Thirteen years' experience of preimplantation diagnosis: report of the Fifth International Symposium on Preimplantation Genetics. Reprod Biomed Online. 8(2):229-35. • Robertson JA. (2003) Extending preimplantation genetic diagnosis: the ethical debate Ethical issues in new uses of preimplantation genetic diagnosis. Hum Reprod. 18(3):465-71 • ESHRE PGD Consortium Steering Committee (2002) ESHRE Preimplantation Genetic Diagnosis Consortium: data collection III (May 2001). Hum Reprod. 17(1):233-46 • Geraedts et al. (2001) Preimplantation genetic diagnosis (PGD), a collaborative activity of clinical genetic departments and IVF centres. Prenat Diagn. 21(12):1086-92. • Soini et al. (2006) The interface between assisted reproductive technologies and genetics: technical, social, ethical and legal issues. Eur J Hum Genet. 14(5):588-645. • Thornhill et al (2005) ESHRE PGD Consortium 'Best practice guidelines for clinical preimplantation genetic diagnosis (PGD) and preimplantation genetic screening (PGS)'. Hum Reprod. 20(1):35-48.