Evaluating the model of offering expanded genetic carrier screening to high school students within the Sydney Jewish community

Programs offering reproductive genetic carrier screening (RGCS) to high school students within the Ashkenazi Jewish community in several countries including Canada and Australia have demonstrated high uptake and retention of educational messages over time. This study was undertaken to evaluate whether testing for an expanded number of conditions in a high school setting would impact the effectiveness of education. In this questionnaire-based study, genetic carrier testing for nine conditions was offered to 322 year 11 students from five high schools, with students attending a compulsory 1-h education session prior to voluntary testing. Comparison of pre- and post-education measures demonstrated a significant increase in knowledge, positive attitudes, and reduced concern immediately after the education session. Retention of knowledge, measures of positive attitude, and low concern over a 12-month period were significantly higher than baseline, although there was some reduction over time. In total, 77% of students exhibited informed choice regarding their intention to test. A significant increase in baseline knowledge scores and positive attitude was also demonstrated between our original 1995 evaluation (with testing for only one condition) and 2014 (testing for nine conditions) suggesting community awareness and attitudes to RGCS have increased. These findings validate the implementation of effective education programs as a key component of RGCS and are relevant as gene panels expand with the introduction of genomic technologies.

Ethical considerations in gene selection for reproductive carrier screening

Genetic carrier screening for reproductive purposes has existed for half a century. It was originally offered to particular ethnic groups with a higher prevalence of certain severe recessive or X-linked genetic conditions, or (as carrier testing) to those with a family history of a particular genetic condition. Commercial providers are increasingly offering carrier screening on a user-pays basis. Some countries are also trialing or offering public reproductive genetic carrier screening with whole populations, rather than only to those known to have a higher chance of having a child with an inherited genetic condition. Such programs broaden the ethical and practical challenges that arise in clinical carrier testing. In this paper we consider three aspects of selecting genes for population reproductive genetic carrier screening panels that give rise to important ethical considerations: severity, variable penetrance and expressivity, and scalability; we also draw on three exemplar genes to illustrate the ethical issues raised: CFTR, GALT and SERPINA1. We argue that such issues are important to attend to at the point of gene selection for RGCS. These factors warrant a cautious approach to screening panel design, one that takes into account the likely value of the information generated by screening and the feasibility of implementation in large and diverse populations. Given the highly complex and uncertain nature of some genetic variants, careful consideration needs to be given to the balance between delivering potentially burdensome or harmful information, and providing valuable information to inform reproductive decisions.

The Core Outcome DEvelopment for Carrier Screening (CODECS) study: protocol for development of a core outcome set

Background Reproductive genetic carrier screening is a type of genetic testing available to those planning a pregnancy, or during their first trimester, to understand their risk of having a child with a severe genetic condition. There is a lack of consensus for ‘what to measure’ in studies on this intervention, leading to heterogeneity in choice of outcomes and methods of measurement. Such outcome heterogeneity has implications for the quality and comparability of these studies and has led to a lack of robust research evidence in the literature to inform policy and decision-making around the offer of this screening. As reproductive genetic carrier screening becomes increasingly accessible within the general population, it is timely to investigate the outcomes of this intervention. Objectives The development of a core outcome set is an established methodology to address issues with outcome heterogeneity in research. We aim to develop a core outcome set for reproductive genetic carrier screening to clarify and standardise outcomes for research and practice. Methods In accordance with guidance from the COMET (Core Outcome Measures in Effectiveness Trials) Initiative, this study will consist of five steps: (i) a systematic review of quantitative studies, using narrative synthesis to identify previously reported outcomes, their definitions, and methods of measurement; (ii) a systematic review of qualitative studies using content analysis to identify excerpts related to patient experience and perspectives that can be interpreted as outcomes; (iii) semi-structured focus groups and interviews with patients who have undertaken reproductive genetic carrier screening to identify outcomes of importance to them; (iv) Delphi survey of key stakeholders, including patients, clinicians, and researchers, to refine and prioritise the list of outcomes generated from the previous steps; and (v) a virtual consensus meeting with a purposive sample of key stakeholders to finalise the core outcome set for reporting. Discussion This protocol outlines the core outcome set development process and its novel application in the setting of genetic testing. This core outcome set will support the standardisation of outcome reporting in reproductive carrier screening research and contribute to an evolving literature on outcomes to evaluate genetic testing and genetic counselling as health interventions. COMET core outcome set registration http://www.comet-initiative.org/Studies/Details/1381.

Reproductive carrier screening: responding to the eugenics critique

Reproductive genetic carrier screening (RCS), when offered to anyone regardless of their family history or ancestry, has been subject to the critique that it is a form of eugenics. Eugenics describes a range of practices that seek to use the science of heredity to improve the genetic composition of a population group. The term is associated with a range of unethical programmes that were taken up in various countries during the 20th century. Contemporary practice in medical genetics has, understandably, distanced itself from such programmes. However, as RCS becomes more widespread, gains public funding and uses expanded gene panels, there are concerns that such programmes could be perceived as eugenic either in intent or outcome. The typical response to the eugenics critique of RCS is to emphasise the voluntary nature of both participating in screening and making subsequent reproductive choices. While safeguarding individuals’ freedom to choose in relation to screening is essential, we consider this response inadequate. By examining the specific ethical wrongs committed by eugenics in the past, we argue that to avoid the perception of RCS being a form of eugenics it is essential to attend to the broader normative context in which reproductive decisions occur. Furthermore, ethical RCS programmes must recognise and respond to their potential to shift societal norms that shape individual reproductive choices.

P–573 PGT-M for two or more disease carrier patients diagnosed after whole exome sequencing

Study question Can whole exome sequencing (WES) before PGT-M identify previously unknown mutations for consanguineous couples having an increased risk of carrying more than one genetic disease? Summary answer WES has been successfully applied in combination with PGT-M by identifying new pathogenic mutations in addition to known gene mutations, extending the scope of PGT-M. What is known already Most couples ignore their risk of being a carrier of an inherited genetic disease until they have an affected child. Rare, atypical, and undiagnosed autosomal-recessive disorders frequently occur in the offspring of consanguineous couples. Routine single gene diagnostic tests fail to detect any possible gene defects other than the clinically apparent one. Prospective WES or genetic carrier screening testing of consanguineous couples could identify couples who both are carriers of autosomal recessive diseases and thus encourage them to make informed reproductive decisions. Screening tests using NGS technology simultaneously sequence exons and exon-intron boundaries to determine disease carrier status. Study design, size, duration Between January 2017 and October 2020, a total of 206 PGT-M couples applied to Istanbul Memorial Hospital ART Center. Of these couples, multigene PGT-M workups were carried for twelve couples who were carriers of more than one inherited disease. Eight couples were found to be carriers for two different diseases and four couples were carrying three diseases. All biopsies were performed at the blastocyst stage. Participants/materials, setting, methods For the 12 couples with multigene PGT-M workups the average female age was 31.0 ± 6.2. Nine of them initiated an ART cycle and the mean number of cumulus-oocyte complexes, metaphaseII oocytes, biopsied blastocysts and transferrable PGT-M embryos were 15 ± 6.9, 13.3 ± 6.3, 5.9 ± 2.0 and 2.9 ± 1.9, respectively. PGT-A was routinely performed for all couples with transferrable PGT-M tested embryos except one couple who refused PGT-A. Main results and the role of chance A total of 28 different gene workups were completed for 26 genes. The inheritance mode of the 26 conditions was as follows: 20 autosomal recessive, four autosomal dominant and two X-linked recessive. Out of 12 couples, 9 of them initiated an ART cycle and transferrable embryos were found after PGT-M followed by PGT-A. Eight women had frozen embryo transfers resulting in five healthy babies (3 singletons and 1 twin), two pregnancies still ongoing and one biochemical miscarriage at the time of data collection. The couple who declined PGT-A testing prior to their frozen embryo transfer had anegative bhCG test. Three couples completed their workups but postponed their ART and PGT-M cycle due to Covid–19 pandemic. Limitations, reasons for caution The probability of finding at least one transferrable embryo after PGT-M is influenced by the inheritance mode of the disease. Late-onset diseases presumed to be caused by variants of unknown significance and polygenic diseases that are possibly influenced by environmental factors were not included in this study. Wider implications of the findings: With decreasing costs and improved availability of WES and genetic carrier screening panels, couples, especially consanguineous couples, who were previously shown to have one inherited disease may be offered to be screened for additional undiagnosed inherited diseases that may pose a threat for their offspring. Trial registration number Not applicable