27 years of prenatal diagnosis for Huntington disease in the United Kingdom.

PURPOSE: There is little long-term, population-based data on uptake of prenatal diagnosis for Huntington disease (HD), a late-onset autosomal dominant neurodegenerative disorder, and the effect of the availability of preimplantation genetic diagnosis (PGD) on families' decisions about conventional prenatal diagnosis is not known. We report trends in prenatal diagnosis and preimplantation diagnosis for HD in the United Kingdom since services commenced. METHODS: Long-term UK-wide prospective case record-based service evaluation in 23 UK Regional Genetic Centres 1988-2015, and four UK PGD centers 2002-2015. RESULTS: From 1988 to 2015, 479 prenatal diagnoses were performed in the UK for HD. An exclusion approach was used in 150 (31%). The annual rate of HD prenatal diagnosis has remained around 18 (3.5/million) over 27 years, despite a steady increase in the use of PGD for HD since 2002. CONCLUSION: Although increasing number of couples are choosing either direct or exclusion PGD to prevent HD in their offspring, both direct and exclusion prenatal diagnosis remain important options in a health system where both PGD and prenatal diagnosis are state funded. At-risk couples should be informed of all options available to them, preferably prepregnancy.

Preimplantation genetic diagnosis: understanding what parents plan to tell their children about their conception.

Over 10,000 babies have been born by PGD and PGS worldwide (Simpson, Prenatal Diagnosis 30(7): 682-695 2010). The experience of parents who have undergone this procedure and their children's well-being are documented, but no research to date has explored whether parents intend to tell their children how they were conceived and whether this raises special issues for them. PGD practitioners recommend research in this area as parents of children born by PGD increasingly ask questions pertaining to disclosure. We conducted 30 in-depth interviews with couples who have had a baby conceived by PGD. We explored what couples plan to tell their children about how they were conceived, when they plan to do this, and issues they anticipate may arise. The couples had a family history of a monogenic disorder or chromosome rearrangement. Six themes emerged which highlight key issues: (1) To tell or not to tell? (2) Primary reason for undergoing PGD, (3) The ideal time to tell, (4) Situations which may warrant earlier disclosure, (5) Words which parents might choose, and (6) Issues which parents anticipate may arise. We conclude that parents are likely to inform their children about PGD because there is an affected sibling or relative about whom they ask questions, and/or their children are carriers of a condition their parents feel obliged to tell them about. Parents felt they would benefit from access to a genetic counsellor at the time of disclosure and are optimistic about the future of reproductive technology for their children.

Preimplantation genetic haplotyping: 127 diagnostic cycles demonstrating a robust, efficient alternative to direct mutation testing on single cells.

Preimplantation genetic diagnosis using whole genome amplification and a haplotyping approach (PGH) was first described in 2006 and suggested as an efficient alternative to single-cell PCR for monogenic disorders. DNA from single cells was amplified using multiple displacement amplification; the resulting products were then tested using disease-specific PCR multiplexes applied under standard laboratory conditions to determine the haplotypes in the embryo. This study reports on a total of 127 completed biopsy cycles for 101 couples at risk of: autosomal recessive disease (71 cycles, 53 couples including one germ-line mosaic carrier), autosomal dominant disease (31 cycles, 26 couples including one germ-line mosaic carrier), X-linked recessive disease (18 cycles, 16 couples including one germ-line mosaic carrier), X-linked dominant disease (six cycles, five couples) and a double inheritance of both autosomal and X-linked recessive diseases (one cycle, one couple). Of these, 107 cycles reached embryo transfer. Overall success rates were: fetal heart beat-positive pregnancies (FHB+)/biopsy cycle=28%; FHB+/embryo transfer=34%; FHB+/couple=36%; 26 babies born, 13 ongoing pregnancies. These data demonstrate that PGH provides a robust, efficient and successful alternative to single-cell PCR for monogenic diseases.

An approach to using care pathway records for research.

Previously, we have examined the use of integrated care pathways, a fine-grained form of medical guideline including the explicit recording of any deviation, or 'variance', for research purposes. Feeding the results of the analysis of variance into the development of a pathway could be an effective way of capturing evidence from practice. Building on this concept, in our principal case study we propose a system for extracting data from integrated care pathways (ICPs) using ontologies and a method for inferring ICPs from other patient records, combining these with data collected for retrospective and prospective studies in preimplantation genetic diagnosis (PGD) for assisted reproduction.

Preimplantation genetic diagnosis to prevent disorders in children.

Preimplantation genetic diagnosis (PGD) is an alternative reproductive option for couples at risk of having a child affected with a genetic disorder. Although prenatal diagnosis (PND) has been available for many years, it is not acceptable to many owing to issues relating to termination of pregnancy. PGD involves assisted-reproductive technology, even though most couples undertaking it are fertile. However, if the treatment is successful, the couple will not have to consider PND. PGD is only available at a small number of centres and for a limited number of genetic conditions. It is a complex and time-consuming procedure. The success rate is around 20%, consequently, there is a relatively low chance of success and this requires careful consideration by couples who generally can become spontaneously pregnant. However, PGD is now more widely understood and available to all at the point of referral. This article sets out to explain the PGD procedure, its implications, limitations, and regulation in the UK and to discuss associated dilemmas.

Benefits and drawbacks of preimplantation genetic diagnosis (PGD) for reciprocal translocations: lessons from a prospective cohort study.

Preimplantation genetic diagnosis (PGD) using fluorescence in situ hybridisation probes was carried out for 59 couples carrying reciprocal translocations. Before treatment, 85% of pregnancies had resulted in spontaneous miscarriage and five couples had achieved a healthy live-birth delivery. Following treatment, 33% of pregnancies failed and 21 of 59 couples had a healthy live-born child. The accuracy of diagnosis was 92% (8% false abnormal and 0% false normal results). The overall incidence of 2:2 alternate segregation products was 44%; however, products consistent with 2:2 adjacent segregation were ~twice as likely from male heterozygotes, and those with 3:1 disjunction were three times more likely from female heterozygotes. Our results indicate that up to three stimulation cycles per couple would give an ~50% chance of a successful live birth, with the risk of miscarriage reduced to the level found in the general population. In our study, 87% of all normal/balanced embryos available were identified as being suitable for transfer. We conclude that PGD provides benefit for couples with high-risk translocations by reducing the risk of miscarriage and avoiding a pregnancy with an unbalanced form of the translocation; however, for fertile carriers of translocations with a low risk of conceiving a chromosomally unbalanced offspring, natural conception may be a more viable option.

Preimplantation genetic diagnosis for the prevention of sickle cell disease: current trends and barriers to uptake in a London teaching hospital.

INTRODUCTION: Sickle cell disease (SCD) is a clinically significant hemoglobinopathy with increasing global incidence. We describe our experience of using pre-implantation genetic diagnosis (PGD) for the prevention of SCD at a tertiary referral centre in London. METHODS: Between January 2002 and December 2007, of 78 at-risk couples referred for PGD treatment, 12 couples (15%) underwent 16 PGD cycles for the prevention of SCD. RESULTS. The live birth rate was 13% per initiated cycle, 18% per embryo transfer and 17% per couple. CONCLUSIONS: Although PGD for prevention of the birth of a child affected by SCD is a viable treatment option for couples at risk of having an affected child, potential barriers to uptake of this service need to be fully addressed to ensure its availability to all couples seeking to avoid having a child affected with SCD.

The future of prenatal diagnosis: rapid testing or full karyotype? An audit of chromosome abnormalities and pregnancy outcomes for women referred for Down's Syndrome testing.

OBJECTIVE: To assess the implications of a change in prenatal diagnosis policy from full karyotype analysis to rapid trisomy testing for women referred primarily for increased risk of Down's Syndrome. DESIGN: Retrospective collection and review of data. SETTING: The four London Regional Genetics Centres. POPULATION: Pregnant women (32,674) in the London area having invasive prenatal diagnosis during a six-year three-month period. METHODS: Abnormal karyotypes and total number of samples referred for raised maternal age, raised risk of Down's Syndrome following serum screening or maternal anxiety were collected. Abnormal karyotypes detected by molecular trisomy detection were removed, leaving cases with residual abnormal karyotypes. These were assessed for their clinical significance. Pregnancy outcomes were ascertained by reviewing patient notes or by contacting obstetricians or general practioners. MAIN OUTCOME MEASURES: Proportion of prenatal samples with abnormal karyotypes that would not have been detected by rapid trisomy testing, and the outcome of those pregnancies with abnormal karyotypes. RESULTS: Results from 32,674 samples were identified, of which 24,891 (76.2%) were from women referred primarily for Down's Syndrome testing. There were 118/24,891 (0.47%) abnormal sex chromosome karyotypes. Of the samples with autosomal abnormalities that would not be detected by rapid trisomy testing, 153/24,891 (0.61%) were in pregnancies referred primarily for Down's Syndrome testing. Of these, 98 (0.39%) had a good prognosis (46/98 liveborn, 3/98 terminations, 1/98 intrauterine death, 1/98 miscarriage, 47/98 not ascertained); 37 (0.15%) had an uncertain prognosis (20/37 liveborn, 5/37 terminations; 12/37 not ascertained) and 18 (0.07%) had a poor prognosis (1/18 liveborn, 2/18 miscarriage, 11/18 terminations, 4/18 not ascertained). CONCLUSIONS: For pregnant women with a raised risk of Down's Syndrome, a change of policy from full karyotype analysis to rapid trisomy testing would result in the failure to detect chromosome abnormalities likely to have serious clinical significance in approximately 0.06% (1 in 1659) cases. However, it should be noted that this figure may be higher (up to 0.12%; 1 in 833) if there were fetal abnormalities in some of the pregnancies in the uncertain prognosis group for which outcome information was not available.