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Choosing children Practical and Moral Choices in the Practice of Preimplantation Genetic Testing Mr Tarek El-Toukhy Department of Women’s Health Guy’s, King’s and St Thomas’ School of Medicine, King’s College London Centre for Preimplantation Genetic Diagnosis Preimplantation Genetic Testing Detection of genetic information in an embryo made by examining a representative sample taken at a preimplantation stage of development Centre for Preimplantation Genetic Diagnosis Centre for Preimplantation Genetic Diagnosis PGD principle Biopsy affected affected Test transfer only unaffected embryos back to the patient Fertilisation in vitro (IVF or ICSI) Appropriate Genetic Counselling Accurate genetic diagnosis Embryo biopsy Diagnosis by FISH PCR DENATURING Transfer 2 unaffected embryos Steps to PGD ANNEALING TAQ PRIMER TAQ EXTENSION Prenatal diagnosis and termination of pregnancy Chorion Villus Sampling Types of genetic disorders Single Gene disorders (PCR) Chromosome • Spinal Muscular Atrophy rearrangements (FISH) • • • • Cystic Fibrosis Huntingdon’s Disease Sickle cell disease EB 64 Reciprocal translocations 14 Robertsonian 6 Inversions Sex Linked disorders (FISH) e.g. OTC, Hunter’s, ALD etc Centre for Preimplantation Genetic Diagnosis Types and Use of Preimplantation Genetic Testing Preimplantation genetic diagnosis (PGD) Reducing recurrent genetic risk Preimplantation genetic screening (PGS) Reducing sporadic genetic risk to improve IVF outcome Preimplantation HLA testing (with PGD) Reducing genetic risk and helping sibling Preimplantation HLA testing (without PGD) IVF Biopsy & HLA test to provide tissue matched sibling Centre for Preimplantation Genetic Diagnosis PGD at GSTT ESHRE Reports 1-7 Report 8 GSTT 1997- October 2008 Cycles started Not reported Not reported 695 Cycles to OR 5107 1128 606 Cycles to ET 3719 (73%) 816 (72%) 470 (68%) CPR per OR 18% 17% 28% CPR per ET 25% 24% 35% Genuinely difficult practical issues to confront • Rights and duties of a doctor • Rights wishes and expectations of parent – For themselves – For their as yet unborn (potential) offspring • Rights of, and effects upon child once born All influenced by society mores, and sanctity and beginning of life arguments Different values for sanctity of life and start of personhood Moral Status of the Embryo Moral Status of the Embryo Inconsistency of Protective Legislation Embryos in vivo receive less respect than those in vitro Ethical concerns regarding PGD • Different views of moral status of the embryo at preimplantation stages • Fear and concern about manipulating humans genetically – choosing our offspring • Use of the embryo (or the person) as a commodity • Worry where it will all lead; getting out of control (slippery slope) Where will it all end? Genuinely difficult practical issues to confront • Rights and duties of a doctor • Rights wishes and expectations of parent – For themselves – For their as yet unborn (potential) offspring • Rights of, and effects upon child once born All influenced by society mores, and sanctity and beginning of life arguments Rights and duties of a doctor • Welfare of the Child: Limiting a child’s right to an open future • Long term safety of embryo biopsy • Lack of, or disputed efficacy of PGD or PGS • Restricted access to (expensive) technology What might parents want? • Child survival and health in the face of a lethal dominant or recessive disorder • Prevention of transmission of late onset disease • Reducing risk of pregnancy loss • Avoiding termination of pregnancy Parent choices that might conflict • • • • • • Reducing risk of disease - better health Eliminating disease from blood line Being of a preferred sex Attaining a physical or mental advantage Attaining health for a sibling Just being more like them – even selecting for disease trait Transfer of carrier embryos (Alport’s disease: Sex selection against males) Transfer of carrier embryos (recessive disorder: CF) Normal Phenotype Impact of affected child on parental choice • Carrier of X linked muscular dystrophy • Boys will die in late teens early 20s • Miscarriage after PND • Want to “complete” family • Requests sexing for females Impact of affected child on parental choice • Carrier of X-linked haemophiiia • George has haemophilia and loves football which he will be stopped playing at age 10 • Wants sexing for female so as not to compete with George • Refused use of test which would identify normal males Non-medical Sex Selection • Either sex as an alternative to previous child - ‘family balancing’ • Preference for a particular sex when male child has genetic disease • Sex is revealed as part of process for something else being tested • Males as cultural preferred gender Late onset disease (example: HD autosomal dominant) ? ? HD family dynamics She at risk of HD gene, but no symptoms yet Progressive degenerative disorder Will develop symptoms age 35-45 years old Her mother dying of the disorder Brother is normal and has family Wants a family but the child could inherit the disease What should she do? Difficulties of late onset disease Example: Huntington’s disease • Many years of disease free life • Knowledge of genetic status changes personal and reproductive prospects • Desire not to know HD status has implications for testing and children born • Termination not undertaken after PND changes child’s freedom not to know status Current options for patients with HD risk • • • • • • Reproduce at 50% risk Prenatal diagnosis & TOP Remain childless Gamete donation Adoption (unlikely) PGD To know, or not to know, HD status Decision to reproduce but Against Termination of Pregnancy Know - affected Don’t wish to know On knowing that one has the HD gene When we had the result that I had the gene it was still a shock. We had feelings which were similar to a bereavement: firstly we knew I would get HD, and secondly the loss of not having a child….. We both felt more at peace now we knew I had the gene. I’m sure fear can build up around something that might or might not happen and sometimes it is better to know. Sue Wright in “The Troubled Helix”; Marteau and Richards 1996 On not wanting to know “What’s the point of predictive testing if there’s no cure for the disease. No thanks, I’m just not brave enough. I have always been so active. I always want to be doing something. I can’t just sit around, and to end up in some wheelchair without a life is not very appealing. From the age of 19 or 20 I made a conscious decision not to have a life into which men, marriage and babies came; especially the last two.” Julia in “The Troubled Helix”; Marteau and Richards 1996 To know, or not to know, HD status & PGD Decision to reproduce but Against Termination of Pregnancy Know - affected Direct testing of embryos for HD expansion Don’t wish to know Direct testing of embryos for HD expansion BUT result NOT to be revealed Direct Testing for Huntington’s Disease (patient knows their HD status) H D Affected unaffected unaffected Affected Affected unaffected Affected Non-disclosure Direct Testing of Embryos for Huntington’s -1 (patient does NOT wish to know HD status) ? unaffected unaffected Affected Unknown Affected unaffected Affected Non-disclosure Direct Testing of Embryos for Huntington’s -2 (patient does NOT wish to know HD status but lab and ART centre know!) H D Affected unaffected unaffected Affected Affected unaffected Affected Non-disclosure Direct Testing of Embryos for Huntington’s -3 (patient does NOT wish to know HD status but lab and ART centre know!) H D Affected unaffected Affected Affected Affected Affected Affected Non-disclosure Direct Testing of Embryos for Huntington’s -4 (patient does NOT wish to know HD status but lab and ART centre know!) unaffected unaffected unaffected unaffected unaffected unaffected To know, or not to know, HD status & PGD Decision to reproduce but Against Termination of Pregnancy Know - affected Direct testing of embryos for HD expansion Don’t wish to know Direct testing of embryos for HD expansion BUT result NOT to be revealed Testing of embryos using linkage to grandparental alleles Exclusion of Huntington’s using Linkage testing of Embryos bb aa Affected Unaffected ? 50% risk Unaffected a 50% risk a 50% risk b unaffected b unaffected Other “late onset” disorders Suitable for PGD? • Muscular dystrophies • Spinal Muscular Atrophy type II or III • Familial cancer predisposition The Slippery Slope: Significant risk and seriousness Is there a limit as to what we should test for? And if so, who should decide? Significant Risk: Predisposition and penetrance Familial Adenomatous Polyposis Coli [100%] Retinoblastoma [90%] Li Fraumeni syndrome [90%] HNPCC [70-90%] Breast malignancy (BRCA1, BRCA2) [50-80%] Von Hippel Lindau disease [40%] Hypercholestrolaemia Short stature Is Seriousness important as an indicator for PGD? • Should criteria for PGD be aligned to criteria for PND? • Is seriousness an appropriate indicator which embryos should be discarded or not? • What does undertaking PGD say about the disabled? “Discrimination against disabled people is still socially acceptable and people think they mean well when they support genetic testing and the elimination of disease. As a disabled person, I find it threatening to have the quality of my life judged to be not worth living.” Public consultation Screening in vs screening out disorders? Dwarf Dwarf Aa Aa Normal Normal aa aa Curing Sibling Genetic Disease PGD and HLA typing • Fertile couple with serious genetic risk undergoes ICSI to produce embryos in vitro • Embryos are biopsied and screened for genetic defect as well as HLA match to affected sibling chance • Embryo (s) transferred to produce child who can be a bone marrow match for affected sibling 3:4 unaffected / carrier embryo 1:4 embryo HLA matches sibling = 3:16 chance of both matching Curing sibling non genetic disease - HLA typing embryos • Fertile couple without substantial genetic risk undergoes ICSI to produce embryos in vitro • Embryos are biopsied and screened for HLA match to affected sibling (1:4) chance • Embryo (s) transferred to produce child who can be a bone marrow or tissue match for affected sibling IVF undertaken and embryos created and good parent? biopsied to alleviate disease in a sibling uncle friend? or- aunt? Undertaking PGT where efficacy doubtful and safety unknown 1. Conception spontaneously may be equally efficacious or likely 2. In infertility where IVF is needed, and embryos are removed from the cohort, following preimplantation screening How effective is PGD for translocations? Guy’s SGD Guy’s Trans. ESHRE Recip ESHRE Rob Egg Collection Biopsy 135 148 592 347 125 125 555 329 ET 113 93 397 260 Clin Preg 38 30 73 66 (%/ET/biop/EC) (33 / 30 / 28) (32 / 26/ 18) (18 / 13/ 12) Livebirth 33 (%/ET/biop/EC) (29 / 26 / 24) (27 /20 /17) 25 (25/ 20/ 19) • 55 • 50 (13/ 10/ 9) (19/ 15/ 14) SGD = single gene defects; rearr.=reciprocal and Robertsonian translocations; • Assume 75% continue Spontaneous livebirth rate in women after previous miscarriage (Based on > 6000 patients from the St Mary’s Miscarriage Clinic) Courtesy of Prof Lesley Regan & Mr Raj Rai Imperial College London Outcome in recurrent miscarriers (>3) with translocations Rai, Backos, El-Gaddal, Regan SGI abstract 889 (2004) Outcome in next pregnancy in 52 couples (APC negative) Livebirth miscarriage LBR (%) Recip 12 11 52 Robert 2 2 50 Female 28/52 (54%) Male Recip 7 8 47 Robert 7 3 70 Background outcome APC negative with normal karyotype 65% (808/1253) Is PGD for translocations worth it? It all depends on why couples want to embark on PGD • Previous affected child with high liveborn risk • Infertility and translocation (e.g. Rob 13;14) • Feel unable to cope with further pregnancy loss A child has a right to an open future “Choosing between Possible Lives” Rosamund Scott Centre for Preimplantation Genetic Diagnosis