Preconception Expanded Carrier Screening Research Articles

Expanding families: a pilot study on preconception expanded carrier screening in Bahrain

BackgroundPreconception expanded carrier screening (ECS) is a genetic test that enables the identification of at-risk carriers of recessive disorders by screening for up to hundreds of genes. Next-generation sequencing (NGS) development has paved the way for its integration into ECS. This study aims to identify the carrier genetic status of couples experiencing or anticipating conception challenges through NGS-based ECS and to gain an overview of the rare genetic disorders in a population with increased consanguinity.MethodsThirty couples who presented to the Genetic Disease Clinic between 2015 and 2024 with failed reproductive outcomes or with a positive personal or family history of genetic disorders and underwent ECS were included and retrospectively analyzed.ResultsFifty-four individuals (90.00%) were found to carry at least one variant of 95 identified genes, totaling 174 variants. Six individuals (10.00%) tested negative for any variant. Seven individuals had one variant (11.67%), 13 had two variants (21.67%), and 34 had 3 or more variants (56.67%). The most common variants identified were of HBA, HBB, CYP21A2, and G6PD genes. Most of the detected variants were unknown or unexpected (n = 143, 82.18%). Eight couples carried two or more variants in common. Consanguinity was reported in 14 couples (46.67%).ConclusionsPreconception ECS is crucial for reproductive planning, permitting couples to evaluate their combined genetic risks and make informed decisions, reducing the chance of having children with genetic disorders.

P-508 Management of incidental findings after preconception expanded carrier screening: identifying genetic predispositions to cancer and metabolic conditions in 8010 screened ART patients

Abstract Study question How do individuals and fertility clinics navigate incidental findings from Expanded Carrier Screening (ECS) in reproductive decision-making? Summary answer Incidental ECS findings prompted varied responses from patients and gamete donors, influencing diverse reproductive choices and underscoring the pivotal role of pre-test genetic counseling. What is known already ECS aims to assess reproductive risk in the general population for specific autosomal recessive and X-linked conditions. These manifest in infancy or early childhood and impact life expectancy or the quality of life. ECS results may guide interventions to avoid affected pregnancies, such as the implementation of preimplantation genetic testing of embryos (PGT-M). Additionally, ECS has the potential to uncover incidental findings with significant health implications, such as an elevated cancer risk or diagnosis. However, the lack of comprehensive reporting guidelines necessitates meticulous analysis to ensure effective clinical guidance for these individual findings. Study design, size, duration This retrospective descriptive study assessed the results of ECS tests performed in 5475 patients and 2535 oocyte and semen donors from four different fertility clinics between July 2017 and December 2023. ECS reports with incidental findings in the ATM, FH or LDLR genes were identified and further examined. We calculated individual and reproductive risks for affected individuals and recorded the subsequent clinical management pertaining to each case. Participants/materials, setting, methods Pre-test counselling was offered to both patients and gamete donors before consenting to ECS. Testing was outsourced to an external genetics laboratory using a panel of 309 genes analyzed through next generation sequencing and complementary molecular techniques. The laboratory reported pathogenic and likely pathogenic variants that were subsequently manually reviewed by an internal genetics committee. Personal and reproductive risks were assessed for each case and genetic counseling was provided in a subsequent meeting. Main results and the role of chance Genetic variants in ATM, FH, or LDLR genes were reported in 134 out of 8010 individuals undergoing ECS (1.67%). Among these, 108 variants were identified in patients: 53.7% (n = 58) in ATM, 19.4% in FH (n = 21), and 26.8% (n = 29) in LDLR. Out of the variants identified as incidental findings, 20/108 were actionable and eligible for PGT-M: 19 were associated with an increased risk for breast cancer and 1 for renal cancer. After being informed of the findings and their implications, 7/20 couples opted to revoke treatment as, according to internal policies, PGT-M was mandatory in such cases; 6/20 couples chose to undergo double gamete donation; 6/20 couples opted for PGT-M. Patients with pathogenic variants in LDLR linked to autosomal dominant inheritance for familial hypercholesterolemia (20/108, 18.5%), received follow-up guidelines and family genetic counseling. Pathogenic variants in ATM, FH, and LDLR were also identified in 26 gamete donors (24 oocyte donors and 2 sperm donors). Following internal review, 14 of these variants were considered incidental findings with an increased risk for breast cancer (13/14) or familial hypercholesterolemia (1/14), leading to the exclusion of these potential donors from the donation program. Limitations, reasons for caution The reproductive handling of incidental findings in our population relies on subjective decisions by the internal genetics committee, which may evolve with scientific advancements and recommendations from professional societies. Follow-up data on long-term reproductive outcomes are lacking. Wider implications of the findings This study reveals the diverse reproductive decisions made in response to incidental findings, underscoring the importance of pre-test genetic counseling. Our findings also highlight the subsequent impact on fertility programs, which may lead to the exclusion of gamete donors or patients choosing to revoke treatment. Trial registration number Not Applicable

Accepting or declining preconception expanded carrier screening: An exploratory study with 407 couples.

Rapidly evolving genomic technologies have made genetic expanded carrier screening (ECS) possible for couples considering a pregnancy. The aim of ECS is to identify couples at risk of having a child affected with a severe disorder and to facilitate their reproductive decision-making process. The ECS test we offer at our center, called BeGECS (Belgian Genetic ECS), consists of 1268 autosomal recessive (AR) and X-linked pathogenic genes, including severe childhood-onset disorders. However, thus far data are scarce regarding the actual uptake of preconception ECS in a clinical setting. Therefore, our aim was to describe the characteristics of 407 couples to whom ECS was offered at the Center for Medical Genetics of the University Hospital Ghent (CMGG). In addition, we aimed to identify their reasons for accepting or declining BeGECS. Between October 2019 and January 2023, 407 preconception couples were offered BeGECS and were asked to fill in a questionnaire after their decision. Of the 407 couples participating in the survey, 270 (66%) decided to take the test and 137 (34%) declined. We observed that age, highest education level as well as indication for consultation were statistically different between the group that accepted to take the test and the group that declined (p = 0.037). In particular, age and education level were substantially higher in the group that accepted the test. Major reasons for taking BeGECS include prevention, wishing to obtain all information possible, helping preparing their future reproductive decision and increasing their sense of control by being informed. However, couples that do not chose to take BeGECS stated that too much information would make them anxious, that the result would not change their decision to have children, that they do not want to spend money on something that will not happen and that they do not worry about their family history. These findings show that the majority of preconception couples that were offered ECS, accepted the test.

Clinical application value of pre-pregnancy carrier screening in Chinese Han childbearing population.

To explore the clinical application value of pre-conception expanded carrier screening (PECS) in the Chinese Han ethnicity population of childbearing age. The results of genetic testing of infertile parents who underwent PECS in the Reproductive Medicine Center of the Second Affiliated Hospital of Zhengzhou University, China, from September 2019 to December 2021, were retrospectively analyzed. The carrier rate of single gene disease, the detection rate of high-risk parents, and the clinical outcome of high-risk parents were statistically analyzed. A total of 1372 Chinese Han ethnicity patients underwent PECS, among which 458 patients underwent the extended 108-gene test, their overall carrier rate was 31.7%, and the detection rate of high-risk parents was 0.3%. The highest carrier rates were SLC22A (2.4%), ATP7B (2.4%), MMACHC (2.2%), PAH (1.8%), GALC (1.8%), MLC1 (1.3%), UNC13D (1.1%), CAPN3 (1.1%), and PKHD1 (1.1%). There were 488 women with fragile X syndrome-FMR1 gene detection, and 6 patients (1.2%) had FMR1 gene mutation. A total of 426 patients were screened for spinal muscular atrophy-SMN1, and the carrier rate was 3.5%, and the detection rate of parents' co-carrier was 0.5%. Monogenic recessive hereditary diseases had a high carrier rate in the population. Pre-pregnancy screening could provide good prenatal and postnatal care guidance for patients and preimplantation genetic testing for monogenic/single gene disorders (PGT-M) and prenatal diagnosis could provide more precise reproductive choices for high-risk parents.

Preconceptionele uitgebreide dragerschapsscreening: een genetische test voor koppels met een kinderwens

Preconception expanded carrier screening: a genetic test for couples planning to conceive Approximately 1% to 2% of all couples have a risk of conceiving a child with a severe recessive disorder. Genetic expanded carrier screening (ECS) can determine this risk and allows couples planning a pregnancy to make informed reproductive choices. The Belgian genetic centers developed the ‘Belgian Genetic Expanded Carrier Screening’ (BeGECS), an ECS for 1,248 genes. The center for medical genetics (CMGG) of the Ghent University Hospital already received samples from over 350 couples. This article discusses the results of the first 250 analyses. Of the 250 couples, 70% consulted in the context of a preimplantation genetic testing (PGT) trajectory. These couples had an already known carriership in 1 or both partners of an autosomal dominant, autosomal recessive and/or X-linked disorder. These risks are of course not included in the results of the BeGECS analyses. The BeGECS analyses showed that 15 couples (6%) were at risk of having a child with an autosomal recessive disorder and 5 (2%) of having a child with a severe phenotype. In 7 couples (2.8%), 1 of the partners was carrier of an X-linked disorder. In 26% of those screened, individual carriership was identified for 1 of the highly frequent autosomal recessive disorders. Couples who are aware of this risk, prior to pregnancy, can make autonomous informed reproductive choices. To allow every couple to choose for ECS, it is essential that offering the test becomes part of standard preconception care.

Implementing preconception expanded carrier screening in a universal health care system: A model-based cost-effectiveness analysis

PurposeThe limited evidence available on the cost-effectiveness (CE) of expanded carrier screening (ECS) prevents its widespread use in most countries, including Italy. Herein, we aimed to estimate the CE of 3 ECS panels (ie, American College of Medical Genetics and Genomics [ACMG] Tier 1 screening, “Focused Screening,” testing 15 severe, highly penetrant conditions, and ACMG Tier 3 screening) compared with no screening, the health care model currently adopted in Italy. MethodsThe reference population consisted of Italian couples seeking pregnancy with no increased personal/familial genetic risk. The CE model was developed from the perspective of the Italian universal health care system and was based on the following assumptions: 100% sensitivity of investigated screening strategies, 77% intervention rate of at-risk couples (ARCs), and no risk to conceive an affected child by risk-averse couples opting for medical interventions. ResultsThe incremental CE ratios generated by comparing each genetic screening panel with no screening were: −14,875 ± 1,208 €/life years gained (LYG) for ACMG1S, −106,863 ± 2,379 €/LYG for Focused Screening, and −47,277 ± 1,430 €/LYG for ACMG3S. ACMG1S and Focused Screening were dominated by ACMG3S. The parameter uncertainty did not significantly affect the outcome of the analyses. ConclusionFrom a universal health care system perspective, all the 3 ECS panels considered in the study would be more cost-effective than no screening.

Preconception Expanded Carrier Screening: A Discourse Analysis of Dutch Webpages.

Preconception expanded carrier screening (PECS) informs prospective parents about the risk of conceiving a child with a heritable genetic condition. PECS will also, for many, become an important screening test, and websites will likely play a vital role in providing information on this practice. The aim of this article is to examine rationalities in the information on PECS on Dutch websites. The method used is multimodal critical discourse analysis. This method allows an examination of norms and assumptions in the descriptions, as well as of the positions that are discursively made available. The data consist of publicly available material on websites from two genetics departments in the Netherlands. In the results, we present the three main discourses and subject positions that were identified: risk and the couple as possible mediators of severe conditions; the focus on scientific facts and rational conceivers; and severity of the conditions and the responsible couple. In this study, we highlight the importance of acknowledging the interrelation between epistemology and ethics in the discourse on PECS. Finally, it is claimed that the focus on scientific facts in information on PECS risks making existential and ethical dilemmas and choices invisible.

Assessing clinical utility of preconception expanded carrier screening regarding residual risk for neurodevelopmental disorders

The magnitude of clinical utility of preconception expanded carrier screening (ECS) concerning its potential to reduce the risk of affected offspring is unknown. Since neurodevelopmental disorders (NDDs) in their offspring is a major concern of parents-to-be, we addressed the question of residual risk by assessing the risk-reduction potential for NDDs in a retrospective study investigating ECS with different criteria for gene selection and definition of pathogenicity. We used exome sequencing data from 700 parents of children with NDDs and blindly screened for carrier-alleles in up to 3046 recessive/X-linked genes. Depending on variant pathogenicity thresholds and gene content, NDD-risk-reduction potential was up to 43.5% in consanguineous, and 5.1% in nonconsanguineous couples. The risk-reduction-potential was compromised by underestimation of pathogenicity of missense variants (false-negative-rate 4.6%), inherited copy-number variants and compound heterozygosity of one inherited and one de novo variant (0.9% each). Adherence to the ACMG recommendations of restricting ECS to high-frequency genes in nonconsanguineous couples would more than halve the detectable inherited NDD-risk. Thus, for optimized clinical utility of ECS, screening in recessive/X-linked genes regardless of their frequency (ACMG Tier-4) and sensible pathogenicity thresholds should be considered for all couples seeking ECS.

P-733 Implementing preconception expanded carrier screening in a universal healthcare system: insights from a cost-effectiveness analysis

Abstract Study question Would reimbursement of expanded carrier screening (ECS) panels of different gene content be cost-effective in a universal healthcare system? Summary answer Both tested ECS panels would be cost-effective if reimbursed by the Italian national healthcare system for a population without personal/familiar or racial/ethnic preconception genetic risks. What is known already Collectively, Mendelian diseases are a significant cause of infant mortality and hospitalization. Current preconception screening strategies test a limited number of individuals based on self-reported personal/familiar or racial/ethnic background. Consequently, the majority of at risk couples (ARCs) remain hidden in the general population. If adopted at a population level, multiplex platforms can thus improve screening effectiveness by allowing rapid ECS for a large number of conditions. Available economic evaluations assume the perspective of private/commercial payers. However, the decision to reimburse ECS in a tax-based national healthcare system would benefit from a cost-effectiveness analysis from the perspective of the public payer. Study design, size, duration This cost-effectiveness decision model compared lifetime costs and effects of two preconception ECS panels (i.e., “Strategy A1” (testing Cystic Fibrosis, Spinal-Muscular-Atrophy, Beta Thalassemia, Phenylketonuria and Fragile-X-Syndrome) and “Strategy A2” (testing “Strategy A1” + 16 common severe highly-penetrant childhood conditions in the Mediterranean population)) with no screening (“Strategy B”). We embraced the perspective of the Italian National Healthcare System. The time horizon for each condition equals an affected child’s life expectancy. Participants/materials, setting, methods We included couples seeking pregnancy without personal/familiar or racial/ethnic genetic risk. The cost-effectiveness analysis was based on a decision tree model where: i) the ECS panels sensitivity was 100%; ii) the probability for at risk couples (ARCs) to be risk-adverse was 77% based on data available from the literature; iii) all the forms of intervention that risk-adverse couples opted for lowered to zero the risk to conceive an affected child for the considered conditions. Main results and the role of chance Unitary cost of €240 for Strategy A1 and of €270 for Strategy A2 for each couple were estimated through a market analysis simulating a public ECS provision. For risk-adverse couples, the cost of intervention was estimated as equal to €8,376. This resulted from the weighted mean of the cost of the different options available (i.e., in vitro fertilization (IVF) with preimplantation testing for monogenic disorders (PGT-M) or, in case of natural conception, prenatal diagnosis and, eventually, termination of pregnancy). Strategy A1 was dominant versus no screening: Strategy A1 entailed savings equal to €1,395 and an incremental benefit of 0.0154 life years gained. Strategy A2 was dominant versus no screening: Strategy A2 entailed savings of €2,273 and an incremental benefit of 0.0238 life years gained. Strategy A2, when compared with Strategy A1, entailed an incremental cost of €649 and higher health benefits (0.7688 life years gained) (incremental cost-effectiveness ratio (ICER): €844). Limitations, reasons for caution This decision analytic model relies on input parameters on costs and life expectancy associated to each Mendelian disease derived from the literature. However, the feasibility to generate experimental evidence to inform this type of studies is very limited. The cost-effectiveness profiles established are valid under the assumptions listed. Wider implications of the findings Cost-effectiveness analyses like the one performed are useful policy tools to inform decisions regarding preconception screening programs for detectable severe recessive highly penetrant early-onset genetic conditions. Trial registration number not applicable

Patterns in Preconception Expanded Carrier Screening: Race, Wealth, and Marriage [A142

Patterns in Preconception Expanded Carrier Screening: Race, Wealth, and Marriage [A142

Qualitative study of GPs’ views and experiences of population-based preconception expanded carrier screening in the Netherlands: bioethical perspectives

ObjectiveBetween 2016 and 2017, a population-based preconception expanded carrier screening (PECS) test was developed in the Netherlands during a pilot study. It was subsequently made possible in mid-2018 for couples...

CONGENITAL ADRENAL HYPERPLASIA DUE TO 21-OH DEFICIENCY CARRIER STATUS IS NOT ASSOCIATED WITH IMPAIRED OOCYTE OR EMBRYONIC QUALITY

Limited research has been published about infertility and patients who are heterozygous carriers for Congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21-OH CAH). Some studies have shown that 21-OH CAH carriers experience some degree of hormonal disturbances, especially in androgen biosynthesis [1,2]. Our study aims to evaluate whether 21-OH CAH carriers who undergo IVF are at a greater risk of having suboptimal ovarian stimulation and IVF outcomes as compared with the general infertile population. Patients at a single center who underwent their first IVF treatment from 2018 to 2021 were analyzed. PGT-A with NGS was performed for all cases. All couples underwent preconception expanded carrier screening. Patients were segregated into groups based on female CYP21A12 carrier status: heterozygote carriers for 21-OH CAH; and patients who were not found to carry any pathogenic variants in CYP21A2. Patients with biallelic CYP21A2 mutations were excluded. Baseline characteristics, ovarian stimulation parameters, oocyte quality, blastulation and embryo ploidy rates were compared. Comparative statistics and an adjusted regression analysis was performed. A sample size of 121 patients per cohort was calculated to ensure an 80% power to detect a difference of 15% on euploidy rates (α=0.05). 2,587 cycles were included. A 7.65% 21-OH CAH Carrier status prevalence was observed. 22 different pathogenic variants in CYP21A2 were identified being c.841G>T, p. V281L (60.6%) the most common. 198 carriers were compared with 2,389 non-carrier controls. No differences in age, BMI, AMH, AFC, FSH, DHEAS and testosterone levels were observed among cohorts. A significant difference was found in progesterone level at surge (A=1.01±0.6 vs B=1.1±0.5, p=0.01) and 17 OH progesterone levels (67.0±73.9 vs 226.5±322.1, p=<0.0001), but no differences were found in days of stimulation, gonadotropin dose and oocytes. Furthermore, maturity rates, fertilization, blastulation, and euploidy rates were comparable between the two groups. In a multivariate analysis adjusted for age, BMI, AMH, year of treatment and ethnicity, no association was found with between 21-OH CAH carrier status and lower oocyte maturity (OR 1.11 CI95% 0.5-2.3); lower fertilization (OR 1.63, 0.7-3.4); lower blastulation (OR 1.04, 0.4-2.2); or lower euploidy rates (OR 1.7, 0.8-3.8). Finally, the type of 21-OH CAH gene variant (classic vs non-classic) was not associated with lower oocyte maturity, fertilization, blastulation and euploidy rates. It has been suggested that 21-OH CAH carriers might experience some degree of disruption in 21-hydroxylase enzymatic activity, raising the question of potential impact on fertility treatment outcomes. Our study shows that 21-OHCAH carriers have similar ovarian stimulation outcomes as the general infertile population.

P–539 The use of expanded carrier screening of gamete donors

Abstract Study question What are the sperm and egg donor rejection rates after expanded carrier screening (ECS)? Summary answer Using an ECS panel looking at 46/47 genes, 17.6% of donors were rejected. What is known already The use of ECS is becoming commonplace in assisted reproductive technology, including testing of egg and sperm donors. Most national guidelines recommend rejection of donors if they are carriers of a genetic disease. If the use of ECS increases, there will be a decline in the number of donors available. Study design, size, duration A review of the current preconception ECS panels available to donors was carried out through an online search. The genetic testing results of donors from Cryos International were analysed to determine how many were rejected on the basis of the ECS. Participants/materials, setting, methods Data on gamete donors and their carrier status was provided by Cryos International, who screen donors using their own bespoke ECS panel. The ECS panels identified through the review were compared to the Cryos International panel and data. Main results and the role of chance A total of 16 companies and 42 associated ECS panels were reviewed. There were a total of 2673 unique disorders covered by the panels examined, with a mean of 329 disorders screened. None of these disorders were common to all panels. Cryos International screen 46 disorders in males and 47 in females. From 883 candidate donors, 17.6% (155/883) were rejected based on their ECS result. Carriers of alpha-thalassaemia represented the largest proportion of those rejected (19.4%, 30/155), then spinal muscular atrophy (15.5%, 24/155) and cystic fibrosis (14.8%, 23/155). Limitations, reasons for caution Panel information was found on company web sites and may not have been accurate. Wider implications of the findings: This study highlights the need for consistent EU regulations and guidelines which allow genetic matching of gamete donors to recipients, preventing the need to reject donors who are known carriers. A larger ECS panel would be most beneficial, however, this would not be viable without matching of donors and recipients. Trial registration number Not applicable

What women want: General population perspectives and access to preconception expanded carrier screening.

Expanded carrier screening (ECS) assesses the risk of individuals and couples of having a child affected with a set of genetic conditions. Carriers have options available to optimize pregnancy outcomes based on personal values and preferences. The greatest range of options is available prior to pregnancy, therefore professional societies recommend this screening be performed preconception. This study aimed to assess awareness of, and interest in, ECS in women preconception. Additionally, it aimed to evaluate preferences for timing and location of education and availability of ECS. A total of 260 nulliparous women from the general population were surveyed through Qualtrics, a national market research survey platform. Data were delineated using descriptive statistics. Of this cohort, 43.5% reported being aware of ECS prior to the survey and 77.8% indicated interest. Those previously aware were first informed by family, friends, or independent online research. Interest was primarily driven by a desire for reassurance and to make informed decisions about future pregnancies. Interested respondents indicated a willingness to request testing from providers. Participants showed a preference for education and access from a healthcare provider in person. These findings provide insight regarding when and where to best educate and reach women prior to pregnancy about ECS to maximize pregnancy outcomes.

Clinical validity and utility of preconception expanded carrier screening for the management of reproductive genetic risk in IVF and general population.

What is the clinical validity and utility of preconception Expanded Carrier Screening (ECS) application on the management of prospective parents? The high detection rate of at-risk couples (ARCs) and the high proportion opting for IVF/preimplantation genetic testing (PGT) treatment demonstrate the clinical utility of ECS in the preconception space in IVF and general population. About 2-4% of couples are at risk of conceiving a child with an autosomal recessive or X-linked genetic disorder. In recent years, the increasing cost-effectiveness of genetic diagnostic techniques has allowed the creation of ECS panels for the simultaneous detection of multiple recessive disorders. Comprehensive preconception genetic screening holds the potential to significantly improve couple's genetic risk assessment and reproductive planning to avoid detectable inheritable genetic offspring. A total of 3877 individuals without a family history of genetic conditions were analyzed between January 2017 and January 2020. Of the enrolled individuals, 1212 were gamete donors and 2665 were patients planning on conceiving from both the IVF and the natural conception group. From the non-donor cohort, 1133 were analyzed as individual patients, while the remaining ones were analyzed as couples, for a total of 766 couples. A focused ECS panel was developed following American College of Obstetrics and Gynecology ACOG-recommended criteria (prevalence, carrier rate, severity), including highly penetrant severe childhood conditions. Couples were defined at-risk when both partners carried an autosomal recessive pathogenic/likely pathogenic variant (PLP) on the same gene or when the woman was a carrier of an X-linked PLP variant. ARC detection rate defined the clinical validity of the ECS approach. Clinical utility was evaluated by monitoring ARCs reproductive decision making. A total of 402 individuals (10.4%) showed PLP for at least one of the genes tested. Among the 766 couples tested, 173 showed one carrier partner (22.6%), whereas 20 couples (2.6%) were found to be at increased risk. Interestingly, one ARC was identified as a result of cascade testing in the extended family of an individual carrying a pathogenic variant on the Survival Of Motor Neuron 1SMN1 gene. Of the identified ARCs, 5 (0.7%) were at risk for cystic fibrosis, 5 (0.7%) for fragile X syndrome, 4 (0.5%) for spinal muscular atrophy, 4 (0.5%) for Beta-Thalassemia/Sickle Cell Anemia, 1 (0.1%) for Smith-Lemli-Opitz Syndrome and 1 (0.1%) for Duchenne/Becker Dystrophy. Fifteen ARCs were successfully followed up from both the IVF and the natural conception groups. All of these (15/15) modified their reproductive planning by undergoing ART with Preimplantation Genetic Testing for Monogenic disease and Aneuploidies (PGT-M and PGT-A). To date, 6/15 (40%) couples completed their PGT cycle with euploid/unaffected embryos achieving a pregnancy after embryo transfer and three of them have already had an unaffected baby. The use of a limited panel of core gene-disease pairs represents a limitation on the research perspective as it can underestimate the rate of detectable carriers and ARCs in this cohort of prospective parents. Expanding the scope of ECS to a larger panel of conditions is becoming increasingly feasible, thanks to a persistent technological evolution and progressive cataloging of gene-disease associations. These results highlight the potential clinical validity and utility of ECS in reducing the risk of a pregnancy affected by a detectable inheritable genetic condition. The steady reduction in the costs of genetic analyses enables the expansion of monogenic testing/screening applications at the preimplantation stage, thus, providing valid decisional support and reproductive autonomy to patients, particularly in the context of IVF. No external funding was used for this study. A.C., M.F., S.C., M.P., L.G., and C.P. are employees of Igenomix Italy. C.S. is the head of the scientific board of Igenomix. N/A.

Preconception expanded carrier screening: a focus group study with relatives of mucopolysaccharidosis type III patients and the general population

Preconception expanded carrier screening (ECS) enables prospective parents to assess their risk of having a child with an autosomal recessive disorder. Knowledge on motivations, feelings, and considerations people have towards the offer and use of ECS is limited. To enrich the public and professional discussion on ECS implementation, this study explored the perspectives towards various aspects of ECS in seven focus groups compromising first- and second-degree relatives of MPS III patients (N=9, N=4, N=5, N=5) and members of the general Dutch population (N=6, N=7, N=5). The focus groups were audio recorded and the transcripts were qualitatively analyzed to identify themes. Both relatives of MPS III patients and participants from the general population supported offering ECS, in particular for severe, childhood-onset disorders. Important barriers identified for ECS were a lack of genetic knowledge and a perceived lack of personal relevance and awareness, as well as out-of-pocket costs of testing. The majority of participants would prefer full disclosure of individual test results instead of couple-based test results. Moreover, offering people a choice for the way of reporting was proposed. All participants agreed that more efforts, for example by governmental campaigns, should be made to increase awareness on the availability, potentials, and limitations of ECS. Educating prospective parents about ECS is essential for increasing awareness and informed decision making. This study provides valuable insights that can be used by governments and public health authorities when considering implementation of preconception ECS.

The ethics of preconception expanded carrier screening in patients seeking assisted reproduction.

ABSTRACTExpanded carrier screening (ECS) entails a screening offer for carrier status for multiple recessive disorders simultaneously and allows testing of couples or individuals regardless of ancestry or geographic origin. Although universal ECS—referring to a screening offer for the general population—has generated considerable ethical debate, little attention has been given to the ethics of preconception ECS for patients applying for assisted reproduction using their own gametes. There are several reasons why it is time for a systematic reflection on this practice. Firstly, various European fertility clinics already offer preconception ECS on a routine basis, and others are considering such a screening offer. Professionals involved in assisted reproduction have indicated a need for ethical guidance for ECS. Secondly, it is expected that patients seeking assisted reproduction will be particularly interested in preconception ECS, as they are already undertaking the physical, emotional and economic burdens of such reproduction. Thirdly, an offer of preconception ECS to patients seeking assisted reproduction raises particular ethical questions that do not arise in the context of universal ECS: the professional’s involvement in the conception implies that both parental and professional responsibilities should be taken into account. This paper reflects on and provides ethical guidance for a responsible implementation of preconception ECS to patients seeking assisted reproduction using their own gametes by assessing the proportionality of such a screening offer: do the possible benefits clearly outweigh the possible harms and disadvantages? If so, for what kinds of disorders and under what conditions?

Preconception expanded carrier screening: Impact of information presented by text or video on genetic knowledge and attitudes.

Preconception expanded carrier screening (ECS) aims to identify couples with an increased risk of having a child with an autosomal recessive (AR) disorder before pregnancy, thereby enabling reproductive choices. Genetic knowledge and experiential knowledge both influence the uptake of ECS. As people in the general public often lack such knowledge, it is essential to provide appropriate and understandable information when offering ECS. This study investigated the effect of an educational video, compared to an educational text, on the knowledge and attitudes toward preconception ECS in the general population. Both the text and video consisted of a brief educational summary on AR inheritance and on the type of disorders included in ECS, with the progressive neurodegenerative condition mucopolysaccharidosis type III (MPS III) as an example. Participants in the reproductive age were invited in collaboration with a research agency. Respondents (N = 789) were offered an educational video prior to completing an online questionnaire that examined genetic knowledge, the perceived severity of MPS III, perceived risk, and attitudes toward ECS. Outcomes were compared to reference data collected previously in which respondents had been offered an educational text (N = 781). We first again studied the attitudes toward ECS in a smaller educational text group (N = 266) in order to assess whether attitudes had changed over time due to increased media coverage on ECS, which did not reveal any significant changes. Respondents who were offered the video had a better genetic knowledge, perceived MPS III as more severe, perceived their risks higher and were more likely to participate in ECS compared to those who were offered text. Online video may well be used as supportive tool to the genetic counseling process, creating more knowledge on ECS and severe genetic disorders included in preconception screening panels.

Attitudes of relatives of mucopolysaccharidosis type III patients toward preconception expanded carrier screening.

Preconception expanded carrier screening (ECS) aims to detect carrier couples of autosomal recessive (AR) disorders before pregnancy in order to increase reproductive autonomy of prospective parents. Genetic knowledge and knowledge gained from experience influence decision making on participation in genetic testing and understanding carrier test results. In this study we assessed whether parents and relatives of patients with the severe AR condition mucopolysaccharidosis type III (MPS III), who are expected to have genetic and experiential knowledge, have more positive attitudes toward ECS than the Dutch reference group. Parents of all MPS III patients known to the Dutch expert center were invited to participate and asked to invite first and second degree relatives. The online questionnaire started with an educational text, and assessed attitudes toward ECS, genetic knowledge and perceived MPS III severity. Results were compared with the Dutch population. Parents and relatives of MPS III patients (n = 159) scored higher on the genetic knowledge test and perceived MPS III as more severe compared with the general Dutch population (n = 781). Parents and relatives reported to be more likely to participate in ECS (84.3% and 62.5%, respectively) compared with the public (31%) (p < 0.001). Being a relative of a MPS III patient was the strongest variable in the regression analyses for intended ECS participation. Our results show that genetic knowledge influences ECS decision making. Therefore, appropriate information on ECS and genetic counseling is needed to enable prospective parents from the general population, including relatives of patients with severe hereditary disorders, to make informed decisions.

Autonomous decisions by couples in reproductive care

BackgroundPreconception Expanded Carrier Screening (ECS) is a genetic test offered to a general population or to couples who have no known risk of recessive and X-linked genetic diseases and are interested in becoming parents. A test may screen for carrier status of several autosomal recessive diseases at one go. Such a program has been piloted in the Netherlands and may become a reality in more European countries in the future. The ethical rationale for such tests is that they enhance reproductive autonomy. The dominant conception of autonomy is individual-based. However, at the clinic, people deciding on preconception ECS will be counselled together and are expected to make a joint decision, as a couple. The aim of the present study was to develop an understanding of autonomous decisions made by couples in the context of reproductive technologies in general and of preconception ECS in particular. Further, to shed light on what occurs in reproductive clinics and suggest concrete implications for healthcare professionals.Main textBased on the shift in emphasis from individual autonomy to relational autonomy, a notion of couple autonomy was suggested and some features of this concept were outlined. First, that both partners are individually autonomous and that the decision is reached through a communicative process. In this process each partner should feel free to express his or her concerns and preferences, so no one partner dominates the discussion. Further, there should be adequate time for the couple to negotiate possible differences and conclude that the decision is right for them. The final decision should be reached through consensus of both partners without coercion, manipulation or miscommunication. Through concrete examples, the suggested notion of couple autonomy was applied to diverse clinical situations.ConclusionsA notion of couple autonomy can be fruitful for healthcare professionals by structuring their attention to and support of a couple who is required to make an autonomous joint decision concerning preconception ECS. A normative implication for healthcare staff is to allow the necessary time for decision-making and to promote a dialogue that can increase the power of the weaker part in a relationship.