Medical and ethical challenges in low penetrance copy number variants management: state-of-the-art in the Portuguese Clinical Genetics community

Medical and ethical challenges in low penetrance copy number variants management: state-of-the-art in the Portuguese Clinical Genetics community | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Medical and ethical challenges in low penetrance copy number variants management: state-of-the-art in the Portuguese Clinical Genetics community Ana Soares, Jorge Diogo Da Silva, Alberto Afonso, Ana Carvalho This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6857492/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Low-Penetrance Copy Number Variants (LP-CNVs) are well-known to contribute to neurodevelopmental disorders and are also found in healthy individuals, presenting significant challenges to genetic counselling. However, data on the clinical management of LP-CNVs in Portugal is lacking. To address this gap, an online questionnaire was administered to Clinical Geneticists in Portugal regarding their management of LP-CNV. The results showed a significant absence of agreement on LP-CNVs disclosure, particularly concerning whether decisions should be guided by expert panels or individualised for each case. Clinicians acknowledged the substantial challenges patients and families face in understanding genetic information, highlighting the need for a shared decision-making approach. Furthermore, there was considerable variability in ethical perspectives regarding prenatal diagnosis and preimplantation genetic testing for LP-CNVs, emphasising the need for clear guidelines. Our results strongly advocate for the development of national guidelines mirroring those established in other countries. This work underscores several complex ethical issues that require further exploration both in Portugal and internationally, including: equitable access to knowledge and economic fairness; balancing child/embryo welfare against parental autonomy and right to knowledge of parents/couples; the potential for genetic discrimination and stigma; the definitions of a "good"/"healthy" life and the authority to make such determination; and the imperative for enhanced training and education for Geneticists to facilitate effective communication and informed consent. Health sciences/Health care/Medical ethics Health sciences/Medical research/Genetics research Low-penetrance Copy Number Variants Genetic Counselling Reproductive Decision Making Ethics in Genomic Medicine Figures Figure 1 INTRODUCTION Copy Number Variants (hereafter CNVs) are well-known causes for several genetic syndromes and have been associated with multiple pathologies, from paediatric (such as congenital anomalies, global developmental delay (DD) and/or intellectual disorder (ID), autism spectrum disorder (ASD) and epilepsy) to adulthood (such as schizophrenia and psychiatric pathology), and from asymptomatic to very severe. ( 1 – 3 ) Due to the increasing availability of array techniques in the clinical setting, CNV detection is at an all-time high. Low-penetrance CNVs (LP-CNVs) are found in a small percentage of patients with clinical manifestations and a higher percentage of the healthy population.( 3 – 5 ) It is interesting to notice the wide variation in penetrance for different CNVs, with different clinical implications. Since then, these genetic alterations have been a subject of debate in the medical genetics community. While some groups classified these CNVs as pathogenic variants of low penetrance, others classified them as susceptibility loci for NDD, and others considered them variants of high penetrance with variable expressivity ( 6 – 9 ). More recently, some research groups concluded that "healthy" CNV carriers may have better performance than affected cases, but have lower education levels and less differentiated professions compared to non-carriers. Kendall et al also analysed a population carrying these CNVs described as "normal", and concluded that these individuals have subtle cognitive deficits, notably at the educational/school level and in their ability to earn a salary.( 10 ) These LP-CNVs are a frequent cause for referral patients to Clinical Genetics services: a report from Newcastle upon Tyne in 2019 revealed that, in 3 years, 163 cases were observed in the genetics clinic (including only the top 10 most common LP-CNVs), showing that a Clinical Geneticist observes at least 54 cases of LP-CNVs per year. ( 10 ) L. Govaerts et al found these alterations in 1–3% of pregnancies tested prenatally, depending on the cohort selection.( 7 ) Furthermore, LP-CNVs can be detected in different scenarios: i) as the genetic aetiology, both in pre or postnatal settings, where the CNV explains a phenotype; ii) as an incidental finding, both in pre or postnatal settings, when the detected CNV does not explain the phenotype; iii) in the study of familial CNV in so-called “normal and healthy” parents/family members. Interestingly, in the Newcastle upon Tyne study, CNVs were considered the cause for clinical manifestations in 78.5% of cases. In about 16.6% of cases, additional genetic testing was offered (and the CNV was considered a possible incidental finding).( 11 ) As such, LP-CNVs pose daily clinical and ethical challenges for Clinical Geneticists, mainly concerning which results should be reported to patients and their families and to whom genetic testing should be offered, or which reproductive options (mainly prenatal diagnosis (PND) and preimplantation genetic testing (PGT)) should be eligible. Accordingly, countries such as the United Kingdom and Belgium have established guidelines on which LP-CNVs should be reported, how they should be classified and addressed (depending on the clinical scenario), and what the repercussions of these kinds of results (i.e. whether to test parents or not, whether to offer PND/ PGT or not). As far as we know, there are no guidelines or consensus in most countries, including in Portugal. Ethical issues arising from the management of LP-CNV cases and the associated lack of consensus require proactive resolution to facilitate best clinical practice for patients and their families. Our work aims to understand the management practices of LP-CNVs among Portuguese Clinical Geneticists, alongside a critical analysis of the ethical dilemmas they present. Our ultimate goal is to utilise these findings to inform the establishment of best practice guidelines for the ethical care of LP-CNV patients, with implications beyond the Portuguese context. METHODOLOGY Study population, data collection and study type A survey regarding the personal experience of Clinical Geneticists in the diagnosis and management of LP-CNVs was conducted. This questionnaire was partially based on Shkedi-Rafid, S. questionnaire( 8 ) (translated to Portuguese), and it was composed of two sections: section one, related to demographic data; and section two, related to the state of LP-CNV management (S1 - Supplementary Questionnaire). Section two comprised 32 questions on a 5-point Likert scale (1 for “strongly disagree”, 2 for “disagree”, 3 for “neither agree nor disagree”, 4 for “agree” and 5 for “strongly agree”). The study population comprised all 43 Medical Genetics specialist physicians with active practice in the Portuguese National Health System by the end of 2022. All physicians were directly contacted via email with the survey in an attachment, and at least three contact attempts were made. The survey was electronically available in Google Forms (Google Forms (Google LLC, California, EUA), and responders could directly submit their answers through this platform. The first contact was performed on 26th November 2022, and the survey was open for response until 1st March 2023. The questionnaire was fully anonymised. The study was observational and cross-sectional, solely comprising descriptive and inferential analysis of data obtained from the survey responses. Statistical analysis Categorical variables were represented by their frequency and relative proportion; ordinal variables were represented by the median and interquartile range (IQR). In all statistical tests, the assumed confidence level was 95%. A Fisher’s exact test was performed to compare proportions between the two groups. Kendall’s tau correlation test was employed to assess for correlations between two ordinal variables. In order to compare medians between the two groups, a Kruskall-Wallis statistic was tested. Dimension-reduction analyses for the second section of the survey were not possible due to sample size limitations, and therefore, formal survey validation was not possible. Predictively, a sample size of about 10–15 times the number of measured variables would be suitable (in this case, about 320–480 participants); otherwise, a minimum number of 300 participants has also been reported as a sufficient sample size for a quality factor analysis.( 12 ) In our case, the complete population comprises 43 subjects, and it would therefore be impossible to meet the sample size requirements. Selecting a maximum of 4–5 variables for assessment would also be insufficient to generate factor data. Finally, the correlation matrix of our variables is not positive definite. Therefore, the Kaiser-Meyer-Olkin statistic cannot be computed, which also indicates the lack of suitability of our sample size. For these reasons, we opted to perform direct correlation analyses only as a measure of survey validation. All tests were performed using SPSS® version 26.0 or GraphPad Prism® version 9.3.0. Ethical statement Before the survey, respondents had to provide informed consent for this study, with all relevant information displayed in the first section of the form. The study was approved by the centre’s Ethics Committee (Protocol TA-DT, Ref. 2022-146(118-DEFI/120-CE)). Results Demographic characterisation of the sample By December 2022, a total of 43 Clinical Geneticists worked on national healthcare services, either full or part-time (17 in the north, 10 in the centre, and 16 in the south – according to the Nomenclature of Territorial Units for Statistics (NUTS)). Of 43 individuals, 24 (56%) responded to the anonymised online questionnaire, which we considered sufficiently representative to give us an overview of the Portuguese reality regarding LP-CNVs management. Supplementary Table 2 (S2) shows relevant demographic data, as well as which genetic tests are prescribed by the medical doctor and to where (private or public laboratory). Some demographic data (such as sex or working hospital) was not collected in order to mitigate the risk of re-identification. Overall responses to the survey Figure 1 presents the results of the survey (median and interquartile range of response scores) per individual question. Regarding answer distribution, we have already observed widespread responses in several questions by visual inspection. Comparison of LP-CNV reporting practices in the prenatal versus postnatal settings We started by assessing which variant types, per the ACMG classification criteria, are reported as LP-CNVs, either in the prenatal or postnatal setting (Table 1). It is interesting to highlight that different Portuguese laboratories report LP-CNVs as all possible classification subtypes ((likely) benign, VUS and (likely) pathogenic), showing a high rate of ambiguity and lack of consensus on this matter. The choice of classification did not differ when comparing LP-CNVs in the prenatal and postnatal settings. Type of Variant Prenatal, N (%) Postnatal, N (%) χ 2 Sig. Pathogenic/likely pathogenic 22 (92%) 23 (96%) 0.356 0.999 Variant of unknown significance 6 (25%) 9 (38%) 0.873 0.534 Variant of uncertain significance 8 (33%) 11 (46%) 0.784 0.556 Variant of uncertain or unknown significance (not discriminated) 11 (46%) 13 (54%) 0.333 0.773 Variant of susceptibility 3 (13%) 5 (21%) 0.600 0.701 Benign/likely benign 12 (50%) 15 (63%) 0.762 0.561 Table 1 – Types of variant classification reported for low-penetrance CNVs in the prenatal and postnatal settings. N (%), frequency (proportion). This situation poses several clinical and ethical issues, mainly due to the outcome of these results, which we propose to analyse through different scenarios: - In the first scenario, the lab reports the CNV as (likely) pathogenic and genetic counselling is performed as such, with reproductive options being offered to the couple and follow-up oriented accordingly. - In the second scenario, the lab reports the CNV as benign, a situation that can be criticised, as according to ACMG guidelines, benign variants must not be reported in any clinical situation. - In the third scenario of reporting CNV as a VUS (or even susceptibility locus), issues such as what to do with the result, what to tell patients or parents, and which reproductive options should be offered can be posed. Validation of survey responses The correlation matrix between the scores of each survey question is presented in Supplementary Table 3 (S3). First, a strong correlation between Q23 and Q30 (τ = - 0.575, p = 0.001), Q15 and Q31 (τ = - 0.642, p < 0.001), Q15 and Q27 (τ = 0.663, p < 0.001), Q12 and Q29 (τ = 0.643, p < 0.001) and Q3 and Q19 (τ = 0.637, p = 0.002), as well as a moderate correlation between Q27 and Q31 (τ = - 0.469, p = 0.008), allowed us to validate our results. Each pair of stated correlations were used to assess the same outcome but were formulated slightly differently or in reverse (regarding negative correlations). These correlations show that Clinical Geneticists were consistent in their responses to the same topic throughout the survey. Though the limited sample prevented other more appropriate statistical tests, it was possible to conclude these correlations as approximate reliability metrics for the questionnaire. Although dimension-reducing tests were not employed, and therefore we were not able to extract specific factors, we were able to group specific questions in general topics regarding LP-CNV management (Table 2): i) To disclose or not LP-CNVs; ii) Clinician Perception of LP-CNV impact on patients; iii) LP-CNVs and equitiy in information disclosure. In the table 2, each question of the survey was categorised into one of the specific themes adapted from the 4W's tool (the four basic questions: Who? What? Where? Why?) to gain a clearer picture of disclosing LP-CNVs by Clinical Geneticist in Portugal: i) Who decides to disclose; ii) When to disclose; iii) How disclosure impacts patients/families; iv; How disclosure impacts foetus/embryos. To disclose or not to disclose LP-CNVs The strong correlation between Q18 and Q25 (τ = - 0.603, p = 0.001) shows that those who think that decisions on reporting should be discussed in a panel of experts do not agree that each case should be thought of individually, but rather through guideline recommendations. The moderate correlations between Q4 and Q25 (τ = - 0.383, p = 0.039), Q2 and Q25 (τ = 0.485, p = 0.006) and between Q9 and Q25 (τ = - 0.456, p = 0.010) also show that the responders consider that the lab should report all results only in postnatal setting, and do not consider that parents should determine, or have a role deciding on, which LP-CNVs should be reported. On the other hand, the moderate correlations between Q2 and Q18 (τ = - 0.353, p = 0.047), Q6 and Q18 (τ = - 0.393, p = 0.038) and Q9 and Q18 (τ = 0.353, p = 0.047) revealed that those responders who think that the decisions should be personalised, do not agree that labs should report all findings only in postnatal, and think that parents should determine which variants should be reported, and not the clinicians. These results of LP-CNV disclosure reveal a significant ethical tension between standardised reporting practices, driven by expert panels and guidelines, and the imperative for individualised patient care. The observed discrepancies in clinician perspectives, particularly regarding parental involvement and the context-dependent reporting of results, underscore a critical lack of consensus. These findings represent a breach of the principle of justice, both in terms of equal access to knowledge and economic fairness, as highlighted in the seminal work of Buchanan et al.(13) All patients should receive the same standard of care and access to information, regardless of the specific genetic service they attend. The lack of standardised protocols can result in a "postcode lottery" scenario, where the quality of care and access to genetic services depend on the geographical location and resources of the healthcare provider. This inequity not only affects individual patients but also perpetuates systemic disparities in healthcare delivery. Clinician Perceptions of LP-CNV Impact on Patients The strong correlation between Q3 and Q6 (τ = - 0.559, p = 0.005) and Q3 and Q7 (τ = - 0.552, p = 0.004) shows that responders believe that the more patients struggle to understand results, the more anxiety they feel, and physicians should not choose the results to be reported according to “what patients want to know”. Moreover, after observing a strong correlation between Q8 and Q19 (τ = 0.575, p = 0.005), we understand that the responders who think the reported variants should be provided by national guidelines also believe that parents may struggle to understand genetic data. Furthermore, the significant correlation observed between Q8 and Q19 (τ = 0.575, p = 0.005) suggests that respondents who favour national guidelines for variant reporting also acknowledge the potential for parental difficulty in comprehending genetic information. The strong correlation between Q6 and Q19 (τ = - 0.573, p = 0.001) suggests that patients who struggle more to understand genetic information experience less anxiety about incidental findings. The widespread health illiteracy and reliance and trust on medical professionals for healthcare guidance may explain this. Also, the strong correlation between Q20 and Q21 (τ = - 0.522, p = 0.006) and the moderate correlations between Q19 and Q21 (τ = - 0,392 p = 0.041), and Q14 and Q21 (τ = -0.429, p = 0.020), reveal that those responders who believe that LP-CNVs should be reported, work in a department where LP-CNVs are reported, and believe that patients may have difficulty understanding the information, think that should not be the clinician who receives the report to decide which information should be reported to patients. Our results highlight ethical concerns about the potential compromise of decision-making capacity when individuals are presented with highly complex information in a vulnerable situation, and the subsequent implications for the adequacy of informed consent. Upholding the principles of beneficence and non-maleficence, to act in the best interest of the patients and avoid harm, alongside autonomy and the protection of vulnerable persons/families to ensure their decision-making capacity in complex scenarios, presents significant ethical dilemmas in reproductive decision-making. The findings also underscore the imperative of a shared decision-making approach, which, despite the tendency in genetics to favour "nondirectiveness" in genetic counselling, is supported by current research and guidelines and emphasises the use of patient decision aids and collaborative communication models to ensure patients are active participants in their healthcare decisions. In the same line, the correlations between Q20, Q21, Q19, Q21, and Q14, Q21 reveal a tendency among clinicians to favour clinician-directed information disclosure, based on the perceived difficulty patients have in understanding the information. The significant correlation between Q8 and Q19 underscores the general trend of the results, pointing to the need for a shared decision-making approach, where the clinicians and the patients make the decisions together. This approach, however, necessitates that healthcare professionals receive adequate training and education to ensure effective communication and informed consent. The potential psychological impact of receiving and interpreting genetic information about LP-CNVs should not be underestimated. Access to appropriate counselling and support services is crucial to address the emotional and psychological needs of individuals and families facing these complex issues. Interestingly, the strong correlation between Q23 and Q32 (τ = 0.767, p < 0.001) confirms that clinicians working in departments where the study of a previously identified CNV is offered to parents, but not to other family members, endorse this procedure. However, the complexities of genetic information extend beyond the individual patient, often impacting family dynamics, communication, and relationships. Genetic counselling services must be equipped to address these intricate familial issues, offering support and guidance to individuals and families as they navigate the challenges of genetic testing and its potential consequences. The "spillover effect" of genetic testing results within families, where a single genetic variant can have different implications and interpretations for different family members, can lead to conflicts and tensions. This raises ethical issues about equitable access to genetic information. Therefore, considering the broader familial context, a holistic approach to genetic counselling is essential to ensure ethical and responsible genetic information and resources management. However, from a public good perspective, and considering the resource-intensive nature of comprehensive familial genetic testing, the principle of justice, specifically the fair allocation of resources to all, must also be carefully weighed in these complex clinical scenarios. The equitable allocation of resources must always be carefully considered, encompassing both the individual level (testing of family members) and the societal level (rationing of scarce resources). LP-CNVs and equity in information disclosure Another important finding was a moderate correlation between Q2 and Q28 (τ = - 0.495, p = 0.005), confirming that those who think all results should be reported only in postnatal diagnosis also think that not all the findings should be reported in the prenatal setting. This illustrates that the sensitivity of prenatal situations, which bring more anxiety and may have more dramatic outcomes, differs from the sensitivity in postnatal situations, where any result can be a clue for the answer to the diagnosis of a child with a neurodevelopmental disorder. The idea that the lab should report only variants that explain a fetal phenotype is supported by those responders who work in a department where only these variants are reported in the prenatal setting, as well as those who think that paretns should not choose what to disclose (but rather after guidelines). This is suggested by the moderate correlations Q7 and Q16 (τ = - 0.351, p = 0.043), Q8 and Q16 (τ = 0.429, p = 0.018), Q9 and Q16 (τ = - 0.381, p = 0.031), and Q13 and Q16 (τ = 0.356, p = 0.041). However, the strong correlation between Q16 and Q28 (τ = - 0.524, p = 0.003) shows that those who think the lab should report disclose only variants that provide a clinical explanation for the found fetal anomaly, do not agree that lab should disclose all findings, regardless of their clinical significance, even in prenatal cases. These results may suggest a tendency for clinicians to prioritise reporting variants that "explain the fetal phenotype", effectively limiting information based on perceived clinical relevance, potentially undermining parental autonomy. Ethically, this also raises questions about the transparency of information disclosure and the potential for clinicians to impose their values on reproductive decisions. On the other hand, the strong correlation between Q7 and Q15 (τ = - 0.573, p < 0.001) and Q7 and Q27 (τ = - 0.512, p = 0.003), as well as the moderate correlation Q7 and Q24 (τ = - 0.489, p = 0.005) revealed that the more responders think that the physician should choose which LP-CNVs should be reported or not, the less they think PND/PGT should be offered. This suggests that, if physicians determine which LP-CNVs to report, based primarily on clinical presentation (i.e., those that explain the phenotype), they would limit reporting to variants deemed actionable, such as those eligible for PND/PGT. These results indicate that clinicians who favour controlled variant reporting are less likely to support offering PND/PGT. This suggests a potential bias, where clinicians may limit access to reproductive options based on their interpretations of LP-CNV significance. Thus, ethical concerns regarding reproductive autonomy and the potential for discrimination based on genetic information are raised. The moderate correlation between Q15 and Q24 (τ = 0.388, p = 0.030) indicates that respondents who support offering PND for LP-CNVs also work in departments providing PGT. While this aligns with reproductive options, further in-depth ethical analysis of these practices is warranted. Another important and ethically questionable result is the strong correlation between Q2 and Q27 (τ = 0.561, p = 0.002), which reveals that those responders in favour of PND are also in favour of embryos with an LP-CNV being “excluded” from potential pregnancy. Also, the strong correlation between Q22 and Q31 (τ = - 0.510, p = 0.005) confirms consistency, as responders who think that embryos carrying an LP-CNV should be excluded also believe that PGT should be offered for this reason. These correlations reveal a link between supporting PND and advocating for the "exclusion" of embryos with LP-CNVs. This raises ethical questions about the definition of "severe" disease and the potential for eugenic practices. As Lombardo (2003) highlights, the historical misuse of genetic information, particularly in the context of eugenics, underscores the importance of carefully considering the potential consequences of reproductive genetic technologies.(14) Our results also highlight the need for careful consideration of the potential for stigmatisation and discrimination against individuals with LP-CNVs. Furthermore, the potential for genetic discrimination and stigma associated with LP-CNVs cannot be ignored, adding another layer of ethical complexity to consider. The decision to terminate a pregnancy or select against embryos with LP-CNVs raises profound moral and societal questions about what constitutes a "good" or "healthy" life and who has the right to make such decisions. Discussion Our findings confirm daily challenges faced by Clinical Genetics in Portugal, particularly concerning the ethical complexities surrounding LP-CNVs. Although this study addresses a previously identified issue, it was important to confirm and streamline the situation and the real problems in a country with growing genetic care expertise, allowing for the reinforcement of the ethical dilemmas that can and should be raised and considered by the lack of standardised national guidelines that leads to inconsistent practices, violating the principle of justice and creating a "postcode lottery" for patients. This absence of consensus also impacts reproductive decision-making, raising ethical dilemmas concerning beneficence, non-maleficence, and autonomy, particularly regarding prenatal diagnosis and preimplantation genetic testing, and the potential for genetic discrimination. Effective communication, informed consent, and shared decision-making are crucial, requiring better training for healthcare professionals and access to robust counselling services to address the psychological and familial impact of LP-CNV information. Ultimately, the findings underscore the urgent need for a concerted, multidisciplinary effort to establish a robust ethical framework that elucidates the uncertainties surrounding LP-CNVs, upholds patient autonomy, guarantees equitable access, and protects against potential genetic discrimination. This framework must emphasise the development of comprehensive, standardised guidelines, cultivate a culture of shared decision-making, and invest in the education and training of healthcare professionals. Ultimately, by adopting a holistic approach that acknowledges the intricate interplay of individual, familial, and societal factors, we can navigate the evolving landscape of clinical genetics with wisdom, compassion, and unwavering ethical integrity, ensuring that the potential of genetic knowledge empowers rather than marginalises the individuals and families it aims to assist. Declarations DATA AVAILABILITY STATEMENT All collected and generated data from this study is available in the manuscript and respective supplementary information. Acknowledgements: not applicable Authors' contributions: - Soares, Afonso and Carvalho prepared the questionnaire. - Soares contacted clinicians and retrieved information from questionnaires. - Da Silva worked on statistical data, figures and tables. - Soares and Carvalho wrote the main manuscript text. - All authors reviewed the manuscript. Funding: No funding for this project Ethical Approval This project was approved by the hospital Ethics Committee - Comissão de Ética do Centro Hospitalar Universitário de Santo António, EPE. All the participants who responded to the questionnaire gave their informed consent to participate and for publication. If they did not agree to proceed with the study, they did not fill out the questionnaire and dropped out. Competing interests: no competing interests References Morris E, O’Donovan M, Virani A, Austin J. An ethical analysis of divergent clinical approaches to the application of genetic testing for autism and schizophrenia. Hum Genet]. 2021 Aug 28 [cited 2022 Apr 11]. Miller DT, Adam MP, Aradhya S, Biesecker LG, Brothman AR, Carter NP, et al. Consensus Statement: Chromosomal Microarray Is a First-Tier Clinical Diagnostic Test for Individuals with Developmental Disabilities or Congenital Anomalies. The American Journal of Human Genetics. 2010 May;86(5):749–64. 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Prenatal diagnosis of susceptibility loci for neurodevelopmental disorders – genetic counseling and pregnancy outcome in 57 cases: Prenatal diagnosis of susceptibility CNVs. Prenat Diagn. 2017 Jan;37(1):73–80. Shkedi-Rafid S, Fenwick A, Dheensa S, Wellesley D, Lucassen AM. What results to disclose, when, and who decides? Healthcare professionals’ views on prenatal chromosomal microarray analysis: Healthcare professionals’ views on prenatal CMA testing. Prenat Diagn. 2016 Mar;36(3):252–9. Kendall KM, Bracher-Smith M, Fitzpatrick H, Lynham A, Rees E, Escott-Price V, et al. Cognitive performance and functional outcomes of carriers of pathogenic copy number variants: analysis of the UK Biobank. Br J Psychiatry. 2019 May;214(5):297–304. Proceedings of the 23rd Annual Meeting of the Portuguese Society of Human Genetics. Medicine. 2020 Feb;99(9):e19291. Christiansen J, Dyck JD, Elyas BG, Lilley M, Bamforth JS, Hicks M, et al. Chromosome 1q21.1 Contiguous Gene Deletion Is Associated With Congenital Heart Disease. Circulation Research. 2004 Jun 11;94(11):1429–35. MacCallum RC, Widaman KF, Zhang S, Hong S. Sample size in factor analysis. Psychological Methods. 1999 Mar;4(1):84–99. Buchanan A, Brock DW, Daniels N, Wikler D. From Chance to Choice: Genetics and Justice. 1st ed. Cambridge University Press; 2000. Lombardo P. Taking Eugenics Seriously: Three Generations of ??? are Enough? Fla St U L Rev. 2003;30(2). Table 2 Table 2 is available in the Supplementary Files section. Additional Declarations There is no duality of interest Supplementary Files S1Supplementary1Questionnairetranslated.pdf Supplementary 1 S2SupplementaryTable2.docx Supplementary 2 S3SupplementaryTable3.xlsx Supplementary 3 Table2.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6857492","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":473112829,"identity":"27c3280a-a409-40df-b16a-84cfedfdb4d0","order_by":0,"name":"Ana Soares","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9klEQVRIiWNgGAWjYLCCBATTBogZGw8Q1oLQkwbS0kBYC5I1h8EkXi38s5uffXj4wy5avh3I+PDnvN3a9sNAW2psonFpkbhzzHhGQkJy7oYzx4xnzmy7nbztTCJQy7G03AZcem4kGAP9wpy7QSLBmJm34Xay2QGgFsaGwzi1yN9I/wzUUp87f0b6Z+Y/f84lm51/iF+LwY0ckC1ABUAGMwPbATuzGwRsMbyRU8yQkHYc6JczxYy9bckJZjeAtiTg8YvcjfTNjD9sqnPnt7dvZvjxx87e7Hz6wwcfamxwex8dJIJVJhCrHATsSVE8CkbBKBgFIwMAALAiaAqSkW51AAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0001-7817-9889","institution":"Centro Hospitalar Universitário de Santo António","correspondingAuthor":true,"prefix":"","firstName":"Ana","middleName":"","lastName":"Soares","suffix":""},{"id":473112830,"identity":"2b51ccd8-67f1-4205-8868-fa43c7a7b389","order_by":1,"name":"Jorge Diogo Da Silva","email":"","orcid":"https://orcid.org/0000-0001-7863-0406","institution":"Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal","correspondingAuthor":false,"prefix":"","firstName":"Jorge","middleName":"Diogo Da","lastName":"Silva","suffix":""},{"id":473112831,"identity":"41d5f2ce-f519-43f8-b7e8-79d880684edb","order_by":2,"name":"Alberto Afonso","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Alberto","middleName":"","lastName":"Afonso","suffix":""},{"id":473112832,"identity":"7b1e7bdf-2d0b-4ad4-a26c-1032e6aed3d5","order_by":3,"name":"Ana Carvalho","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Ana","middleName":"","lastName":"Carvalho","suffix":""}],"badges":[],"createdAt":"2025-06-09 21:40:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6857492/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6857492/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":85177192,"identity":"a07bed6a-c785-46f9-8bd4-25e29dfb0061","added_by":"auto","created_at":"2025-06-23 06:41:39","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":97009,"visible":true,"origin":"","legend":"\u003cp\u003eSummary of results of the survey\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-6857492/v1/031edd5f1f140dcd4e45ad09.png"},{"id":92623826,"identity":"100d5bb1-427f-4171-9181-7d496458eff6","added_by":"auto","created_at":"2025-10-01 21:08:52","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":633601,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6857492/v1/99263be9-99b6-4a47-b5d8-45cc9ad660ac.pdf"},{"id":85177194,"identity":"86816a1e-7726-4c9b-891a-f60ba3b578f2","added_by":"auto","created_at":"2025-06-23 06:41:39","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":32467,"visible":true,"origin":"","legend":"Supplementary 1","description":"","filename":"S1Supplementary1Questionnairetranslated.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6857492/v1/59ff754794668fe414178fa3.pdf"},{"id":85176036,"identity":"bb9391bd-0d97-4155-a239-42855592c30c","added_by":"auto","created_at":"2025-06-23 06:33:39","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":13564,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary 2\u003c/p\u003e","description":"","filename":"S2SupplementaryTable2.docx","url":"https://assets-eu.researchsquare.com/files/rs-6857492/v1/6da8d9574177182db8ce5138.docx"},{"id":85176041,"identity":"45d44c94-c1fa-4c31-bd8c-bee1a04293e7","added_by":"auto","created_at":"2025-06-23 06:33:40","extension":"xlsx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":29047,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary 3\u003c/p\u003e","description":"","filename":"S3SupplementaryTable3.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6857492/v1/aa30218c6f64059431b7c9f3.xlsx"},{"id":85175447,"identity":"713081d4-f52f-4e20-80b5-e465be266dd1","added_by":"auto","created_at":"2025-06-23 06:25:39","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":18565,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.docx","url":"https://assets-eu.researchsquare.com/files/rs-6857492/v1/c1a839f02b310e2fe4f4f623.docx"}],"financialInterests":"There is no duality of interest","formattedTitle":"Medical and ethical challenges in low penetrance copy number variants management: state-of-the-art in the Portuguese Clinical Genetics community","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eCopy Number Variants (hereafter CNVs) are well-known causes for several genetic syndromes and have been associated with multiple pathologies, from paediatric (such as congenital anomalies, global developmental delay (DD) and/or intellectual disorder (ID), autism spectrum disorder (ASD) and epilepsy) to adulthood (such as schizophrenia and psychiatric pathology), and from asymptomatic to very severe. (\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) Due to the increasing availability of array techniques in the clinical setting, CNV detection is at an all-time high.\u003c/p\u003e \u003cp\u003eLow-penetrance CNVs (LP-CNVs) are found in a small percentage of patients with clinical manifestations and a higher percentage of the healthy population.(\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) It is interesting to notice the wide variation in penetrance for different CNVs, with different clinical implications. Since then, these genetic alterations have been a subject of debate in the medical genetics community. While some groups classified these CNVs as pathogenic variants of low penetrance, others classified them as susceptibility loci for NDD, and others considered them variants of high penetrance with variable expressivity (\u003cspan additionalcitationids=\"CR7 CR8\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). More recently, some research groups concluded that \"healthy\" CNV carriers may have better performance than affected cases, but have lower education levels and less differentiated professions compared to non-carriers. Kendall et al also analysed a population carrying these CNVs described as \"normal\", and concluded that these individuals have subtle cognitive deficits, notably at the educational/school level and in their ability to earn a salary.(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eThese LP-CNVs are a frequent cause for referral patients to Clinical Genetics services: a report from Newcastle upon Tyne in 2019 revealed that, in 3 years, 163 cases were observed in the genetics clinic (including only the top 10 most common LP-CNVs), showing that a Clinical Geneticist observes at least 54 cases of LP-CNVs per year. (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eL. Govaerts et al found these alterations in 1\u0026ndash;3% of pregnancies tested prenatally, depending on the cohort selection.(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eFurthermore, LP-CNVs can be detected in different scenarios: i) as the genetic aetiology, both in pre or postnatal settings, where the CNV explains a phenotype; ii) as an incidental finding, both in pre or postnatal settings, when the detected CNV does not explain the phenotype; iii) in the study of familial CNV in so-called \u0026ldquo;normal and healthy\u0026rdquo; parents/family members. Interestingly, in the Newcastle upon Tyne study, CNVs were considered the cause for clinical manifestations in 78.5% of cases. In about 16.6% of cases, additional genetic testing was offered (and the CNV was considered a possible incidental finding).(\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eAs such, LP-CNVs pose daily clinical and ethical challenges for Clinical Geneticists, mainly concerning which results should be reported to patients and their families and to whom genetic testing should be offered, or which reproductive options (mainly prenatal diagnosis (PND) and preimplantation genetic testing (PGT)) should be eligible.\u003c/p\u003e \u003cp\u003e Accordingly, countries such as the United Kingdom and Belgium have established guidelines on which LP-CNVs should be reported, how they should be classified and addressed (depending on the clinical scenario), and what the repercussions of these kinds of results (i.e. whether to test parents or not, whether to offer PND/ PGT or not). As far as we know, there are no guidelines or consensus in most countries, including in Portugal.\u003c/p\u003e \u003cp\u003eEthical issues arising from the management of LP-CNV cases and the associated lack of consensus require proactive resolution to facilitate best clinical practice for patients and their families.\u003c/p\u003e \u003cp\u003eOur work aims to understand the management practices of LP-CNVs among Portuguese Clinical Geneticists, alongside a critical analysis of the ethical dilemmas they present. Our ultimate goal is to utilise these findings to inform the establishment of best practice guidelines for the ethical care of LP-CNV patients, with implications beyond the Portuguese context.\u003c/p\u003e"},{"header":"METHODOLOGY","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy population, data collection and study type\u003c/h2\u003e \u003cp\u003eA survey regarding the personal experience of Clinical Geneticists in the diagnosis and management of LP-CNVs was conducted. This questionnaire was partially based on Shkedi-Rafid, S. questionnaire(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) (translated to Portuguese), and it was composed of two sections: section one, related to demographic data; and section two, related to the state of LP-CNV management (S1 - Supplementary Questionnaire). Section two comprised 32 questions on a 5-point Likert scale (1 for \u0026ldquo;strongly disagree\u0026rdquo;, 2 for \u0026ldquo;disagree\u0026rdquo;, 3 for \u0026ldquo;neither agree nor disagree\u0026rdquo;, 4 for \u0026ldquo;agree\u0026rdquo; and 5 for \u0026ldquo;strongly agree\u0026rdquo;).\u003c/p\u003e \u003cp\u003eThe study population comprised all 43 Medical Genetics specialist physicians with active practice in the Portuguese National Health System by the end of 2022. All physicians were directly contacted via email with the survey in an attachment, and at least three contact attempts were made. The survey was electronically available in Google Forms (Google Forms (Google LLC, California, EUA), and responders could directly submit their answers through this platform. The first contact was performed on 26th November 2022, and the survey was open for response until 1st March 2023. The questionnaire was fully anonymised.\u003c/p\u003e \u003cp\u003eThe study was observational and cross-sectional, solely comprising descriptive and inferential analysis of data obtained from the survey responses.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eCategorical variables were represented by their frequency and relative proportion; ordinal variables were represented by the median and interquartile range (IQR). In all statistical tests, the assumed confidence level was 95%. A Fisher\u0026rsquo;s exact test was performed to compare proportions between the two groups. Kendall\u0026rsquo;s tau correlation test was employed to assess for correlations between two ordinal variables. In order to compare medians between the two groups, a Kruskall-Wallis statistic was tested.\u003c/p\u003e \u003cp\u003eDimension-reduction analyses for the second section of the survey were not possible due to sample size limitations, and therefore, formal survey validation was not possible. Predictively, a sample size of about 10\u0026ndash;15 times the number of measured variables would be suitable (in this case, about 320\u0026ndash;480 participants); otherwise, a minimum number of 300 participants has also been reported as a sufficient sample size for a quality factor analysis.(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e) In our case, the complete population comprises 43 subjects, and it would therefore be impossible to meet the sample size requirements. Selecting a maximum of 4\u0026ndash;5 variables for assessment would also be insufficient to generate factor data. Finally, the correlation matrix of our variables is not positive definite. Therefore, the Kaiser-Meyer-Olkin statistic cannot be computed, which also indicates the lack of suitability of our sample size. For these reasons, we opted to perform direct correlation analyses only as a measure of survey validation. All tests were performed using SPSS\u0026reg; version 26.0 or GraphPad Prism\u0026reg; version 9.3.0.\u003c/p\u003e \u003c/div\u003e\u003cp\u003eEthical statement\u003c/p\u003e\n\u003cp\u003eBefore the survey, respondents had to provide informed consent for this study, with all relevant information displayed in the first section of the form. The study was approved by the centre\u0026rsquo;s Ethics Committee (Protocol TA-DT, Ref. 2022-146(118-DEFI/120-CE)).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eDemographic characterisation of the sample\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBy December 2022, a total of 43 Clinical Geneticists worked on national healthcare services, either full or part-time (17 in the north, 10 in the centre, and 16 in the south \u0026ndash; according to the Nomenclature of Territorial Units for Statistics (NUTS)). Of 43 individuals, 24 (56%) responded to the anonymised online questionnaire, which we considered sufficiently representative to give us an overview of the Portuguese reality regarding LP-CNVs management. Supplementary Table 2 (S2) shows relevant demographic data, as well as which genetic tests are prescribed by the medical doctor and to where (private or public laboratory). Some demographic data (such as sex or working hospital) was not collected in order to mitigate the risk of re-identification.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOverall responses to the survey\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFigure 1 presents the results of the survey (median and interquartile range of response scores) per individual question. Regarding answer distribution, we have already observed widespread responses in several questions by visual inspection. \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eComparison of LP-CNV reporting practices in the prenatal versus postnatal settings\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe started by assessing which variant types, per the ACMG classification criteria, are reported as LP-CNVs, either in the prenatal or postnatal setting (Table 1). It is interesting to highlight that different Portuguese laboratories report LP-CNVs as all possible classification subtypes ((likely) benign, VUS and (likely) pathogenic), showing a high rate of ambiguity and lack of consensus on this matter. The choice of classification did not differ when comparing LP-CNVs in the prenatal and postnatal settings.\u0026nbsp;\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"548\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 198px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eType of Variant\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePrenatal, N (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePostnatal, N (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026chi;\u003csup\u003e2\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSig.\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 198px;\"\u003e\n \u003cp\u003ePathogenic/likely pathogenic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e22 (92%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e23 (96%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.356\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e0.999\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 198px;\"\u003e\n \u003cp\u003eVariant of unknown significance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e6 (25%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e9 (38%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.873\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e0.534\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 198px;\"\u003e\n \u003cp\u003eVariant of uncertain significance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e8 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e11 (46%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.784\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e0.556\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 198px;\"\u003e\n \u003cp\u003eVariant of uncertain or unknown significance (not discriminated)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e11 (46%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e13 (54%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.333\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e0.773\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 198px;\"\u003e\n \u003cp\u003eVariant of susceptibility\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e3 (13%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e5 (21%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.600\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e0.701\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 198px;\"\u003e\n \u003cp\u003eBenign/likely benign\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e12 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 114px;\"\u003e\n \u003cp\u003e15 (63%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.762\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 66px;\"\u003e\n \u003cp\u003e0.561\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eTable 1 \u0026ndash; Types of variant classification reported for low-penetrance CNVs in the prenatal and postnatal settings. N (%), frequency (proportion).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;This situation poses several clinical and ethical issues, mainly due to the outcome of these results, which we propose to analyse through different scenarios:\u003c/p\u003e\n\u003cp\u003e- In the first scenario, the lab reports the CNV as (likely) pathogenic and genetic counselling is performed as such, with reproductive options being offered to the couple and follow-up oriented accordingly.\u003c/p\u003e\n\u003cp\u003e- In the second scenario, the lab reports the CNV as benign, a situation that can be criticised,\u0026nbsp;as according to ACMG guidelines, benign variants must not be reported\u0026nbsp;in\u0026nbsp;any clinical situation.\u003c/p\u003e\n\u003cp\u003e- In the third scenario of reporting CNV as a VUS (or even susceptibility locus), issues such as what to do with the result, what to tell patients or parents, and which reproductive options should be offered can be posed.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eValidation of survey responses\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe correlation matrix between the scores of each survey question is presented in Supplementary Table 3 (S3).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFirst, a strong correlation between Q23 and Q30 (\u0026tau; = - 0.575, p = 0.001), Q15 and Q31 (\u0026tau; = - 0.642, p \u0026lt; 0.001), Q15 and Q27 (\u0026tau; = 0.663, p \u0026lt; 0.001), Q12 and Q29 (\u0026tau; = 0.643, p \u0026lt; 0.001) and Q3 and Q19 (\u0026tau; = 0.637, p = 0.002), as well as a moderate correlation between Q27 and Q31 (\u0026tau; = - 0.469, p = 0.008), allowed us to validate our results. Each pair of stated correlations were used to assess the same outcome but were formulated slightly differently or in reverse (regarding negative correlations). These correlations show that Clinical Geneticists were consistent in their responses to the same topic throughout the survey. Though the limited sample prevented other more appropriate statistical tests, it was possible to conclude these correlations as approximate reliability metrics for the questionnaire. Although dimension-reducing tests were not employed, and therefore we were not able to extract specific factors, we were able to group specific questions in general topics regarding LP-CNV management (Table 2): i) To disclose or not LP-CNVs; ii) Clinician Perception of LP-CNV impact on patients; iii) LP-CNVs and equitiy in information disclosure. In the table 2, each question of the survey was categorised into one of the specific themes adapted from the 4W\u0026apos;s tool (the four basic questions: Who? What? Where? Why?) to gain a clearer picture of disclosing LP-CNVs by Clinical Geneticist in Portugal: i) Who decides to disclose; ii) When to disclose; iii) How disclosure impacts patients/families; iv; How disclosure impacts foetus/embryos.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eTo disclose or not to disclose LP-CNVs\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe strong correlation between Q18 and Q25 (\u0026tau; = - 0.603, p = 0.001) shows that those who think that decisions on reporting should be discussed in a panel of experts do not agree that each case should be thought of individually, but rather through guideline recommendations. The moderate correlations between Q4 and Q25 (\u0026tau; = - 0.383, p = 0.039), Q2 and Q25 (\u0026tau; = 0.485, p = 0.006) and between Q9 and Q25 (\u0026tau; = - 0.456, p = 0.010) also show that the responders consider that the lab should report all results only in postnatal setting, and do not consider that parents should determine, or have a role deciding on, which LP-CNVs should be reported.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOn the other hand, the moderate correlations between Q2 and Q18 (\u0026tau; = - 0.353, p = 0.047), Q6 and Q18 (\u0026tau; = - 0.393, p = 0.038) and Q9 and Q18 (\u0026tau; = 0.353, p = 0.047) revealed that those responders who think that the decisions should be personalised, do not agree that labs should report all findings only in postnatal, and think that parents should determine which variants should be reported, and not the clinicians.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThese results of LP-CNV disclosure reveal a significant ethical tension between standardised reporting practices, driven by expert panels and guidelines, and the imperative for individualised patient care. The observed discrepancies in clinician perspectives, particularly regarding parental involvement and the context-dependent reporting of results, underscore a critical lack of consensus. These findings represent a breach of the principle of justice, both in terms of equal access to knowledge and economic fairness, as highlighted in the seminal work of Buchanan et al.(13) All patients should receive the same standard of care and access to information, regardless of the specific genetic service they attend. The lack of standardised protocols can result in a \u0026quot;postcode lottery\u0026quot; scenario, where the quality of care and access to genetic services depend on the geographical location and resources of the healthcare provider. This inequity not only affects individual patients but also perpetuates systemic disparities in healthcare delivery. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinician Perceptions of LP-CNV Impact on Patients\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe strong correlation between Q3 and Q6 (\u0026tau; = - 0.559, p = 0.005) and Q3 and Q7 (\u0026tau; = - 0.552, p = 0.004) shows that responders believe that the more patients struggle to understand results, the more anxiety they feel, and physicians should not choose the results to be reported according to \u0026ldquo;what patients want to know\u0026rdquo;. Moreover, after observing a strong correlation between Q8 and Q19 (\u0026tau; = 0.575, p = 0.005), we understand that the responders who think the reported variants should be provided by national guidelines also believe that parents may struggle to understand genetic data. Furthermore, the significant correlation observed between Q8 and Q19 (\u0026tau; = 0.575, p = 0.005) suggests that respondents who favour national guidelines for variant reporting also acknowledge the potential for parental difficulty in comprehending genetic information.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe strong correlation between Q6 and Q19 (\u0026tau; = - 0.573, p = 0.001) suggests that patients who struggle more to understand genetic information experience less anxiety about incidental findings. The widespread health illiteracy and reliance and trust on medical professionals for healthcare guidance may explain this. Also, the strong correlation between Q20 and Q21 (\u0026tau; = - 0.522, p = 0.006) and the moderate correlations between Q19 and Q21 (\u0026tau; = - 0,392 p = 0.041), and Q14 and Q21 (\u0026tau; = -0.429, p = 0.020), reveal that those responders who believe that LP-CNVs should be reported, work in a department where LP-CNVs are reported, and believe that patients may have difficulty understanding the information, think that should not be the clinician who receives the report to decide which information should be reported to patients.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOur results highlight ethical concerns about the potential compromise of decision-making capacity when individuals are presented with highly complex information in a vulnerable situation, and the subsequent implications for the adequacy of informed consent. Upholding the principles of beneficence and non-maleficence, to act in the best interest of the patients and avoid harm, alongside autonomy and the protection of vulnerable persons/families to ensure their decision-making capacity in complex scenarios, presents significant ethical dilemmas in reproductive decision-making. The findings also underscore the imperative of a shared decision-making approach, which, despite the tendency in genetics to favour \u0026quot;nondirectiveness\u0026quot; in genetic counselling, is supported by current research and guidelines and emphasises the use of patient decision aids and collaborative communication models to ensure patients are active participants in their healthcare decisions. In the same line, the correlations between Q20, Q21, Q19, Q21, and Q14, Q21 reveal a tendency among clinicians to favour clinician-directed information disclosure, based on the perceived difficulty patients have in understanding the information. The significant correlation between Q8 and Q19 underscores the general trend of the results, pointing to the need for a shared decision-making approach, where the clinicians and the patients make the decisions together. This approach, however, necessitates that healthcare professionals receive adequate training and education to ensure effective communication and informed consent. The potential psychological impact of receiving and interpreting genetic information about LP-CNVs should not be underestimated. Access to appropriate counselling and support services is crucial to address the emotional and psychological needs of individuals and families facing these complex issues. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eInterestingly, the strong correlation between Q23 and Q32 (\u0026tau; = 0.767, p \u0026lt; 0.001) confirms that clinicians working in departments where the study of a previously identified \u0026nbsp;CNV is offered to parents, but not to other family members, endorse this procedure. However, the complexities of genetic information extend beyond the individual patient, often impacting family dynamics, communication, and relationships. Genetic counselling services must be equipped to address these intricate familial issues, offering support and guidance to individuals and families as they navigate the challenges of genetic testing and its potential consequences. The \u0026quot;spillover effect\u0026quot; of genetic testing results within families, where a single genetic variant can have different implications and interpretations for different family members, can lead to conflicts and tensions. This raises ethical issues about equitable access to genetic information. Therefore, considering the broader familial context, a holistic approach to genetic counselling is essential to ensure ethical and responsible genetic information and resources management. However, from a public good perspective, and considering the resource-intensive nature of comprehensive familial genetic testing, the principle of justice, specifically the fair allocation of resources to all, must also be carefully weighed in these complex clinical scenarios. The equitable allocation of resources must always be carefully considered, encompassing both the individual level (testing of family members) and the societal level (rationing of scarce resources).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLP-CNVs and equity in information disclosure\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAnother important finding was a moderate correlation between Q2 and Q28 (\u0026tau; = - 0.495, p = 0.005), confirming that those who think all results should be reported only in postnatal diagnosis also think that\u0026nbsp;not all the\u0026nbsp;findings should be reported in the prenatal setting. This illustrates that the sensitivity of prenatal situations, which bring more anxiety and may have more dramatic outcomes, differs from the sensitivity in postnatal situations, where any result can be a clue for the answer to the diagnosis of a child with a neurodevelopmental disorder. The idea that the lab should report only variants that explain a fetal phenotype is supported by those responders who work in a department where only these variants are reported in the prenatal setting, as well as those who think that paretns should not choose what to disclose (but rather after guidelines). This is suggested by the moderate correlations Q7 and Q16 (\u0026tau; = - 0.351, p = 0.043), Q8 and Q16 (\u0026tau; = 0.429, p = 0.018), Q9 and Q16 (\u0026tau; = - 0.381, p = 0.031), and Q13 and Q16 (\u0026tau; = 0.356, p = 0.041).\u003c/p\u003e\n\u003cp\u003eHowever, the strong correlation between Q16 and Q28 (\u0026tau; = - 0.524, p = 0.003) shows that those who think the lab should report disclose only variants that provide a clinical explanation for the found fetal anomaly, do not agree that lab should disclose all findings, regardless of their clinical significance, even in prenatal cases. These results may suggest a tendency for clinicians to prioritise reporting variants that \u0026quot;explain the fetal phenotype\u0026quot;, effectively limiting information based on perceived clinical relevance, potentially undermining parental autonomy. Ethically, this also raises questions about the transparency of information disclosure and the potential for clinicians to impose their values on reproductive decisions.\u003c/p\u003e\n\u003cp\u003eOn the other hand, the strong correlation between Q7 and Q15 (\u0026tau; = - 0.573, p \u0026lt; 0.001) and Q7 and Q27 (\u0026tau; = - 0.512, p = 0.003), as well as the moderate correlation Q7 and Q24 (\u0026tau; = - 0.489, p = 0.005) revealed that the more responders think that the physician should choose which LP-CNVs should be reported or not, the less they think PND/PGT should be offered. This suggests that, if physicians determine which LP-CNVs to report, based primarily on clinical presentation (i.e., those that explain the phenotype), they would limit reporting to variants deemed actionable, such as those eligible for PND/PGT. These results indicate that clinicians who favour controlled variant reporting are less likely to support offering PND/PGT. This suggests a potential bias, where clinicians may limit access to reproductive options based on their interpretations of LP-CNV significance. Thus, ethical concerns regarding reproductive autonomy and the potential for discrimination based on genetic information are raised.\u003c/p\u003e\n\u003cp\u003eThe moderate correlation between Q15 and Q24 (\u0026tau; = 0.388, p = 0.030) indicates that respondents who support offering \u0026nbsp;PND for LP-CNVs also work in departments providing PGT. While this aligns with reproductive options, further in-depth ethical analysis of these practices is warranted.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAnother important and ethically questionable result is the strong correlation between Q2 and Q27 (\u0026tau; = 0.561, p = 0.002), which reveals that those responders in favour of PND are also in favour of embryos with an LP-CNV being \u0026ldquo;excluded\u0026rdquo; from potential pregnancy. Also, the strong correlation between Q22 and Q31 (\u0026tau; = - 0.510, p = 0.005) confirms consistency, as responders who think that embryos carrying an LP-CNV should be excluded also believe that PGT should be offered for this reason. These correlations reveal a link between supporting PND and advocating for the \u0026quot;exclusion\u0026quot; of embryos with LP-CNVs. This raises ethical questions about the definition of \u0026quot;severe\u0026quot; disease and the potential for eugenic practices. \u0026nbsp;As Lombardo (2003) highlights, the historical misuse of genetic information, particularly in the context of eugenics, underscores the importance of carefully considering the potential consequences of reproductive genetic technologies.(14)\u003c/p\u003e\n\u003cp\u003eOur results also highlight the need for careful consideration of the potential for stigmatisation and discrimination against individuals with LP-CNVs. Furthermore, the potential for genetic discrimination and stigma associated with LP-CNVs cannot be ignored, adding another layer of ethical complexity to consider. The decision to terminate a pregnancy or select against embryos with LP-CNVs raises profound moral and societal questions about what constitutes a \u0026quot;good\u0026quot; or \u0026quot;healthy\u0026quot; life and who has the right to make such decisions.\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur findings confirm daily challenges faced by Clinical Genetics in Portugal, particularly concerning the ethical complexities surrounding LP-CNVs. Although this study addresses a previously identified issue, it was important to confirm and streamline the situation and the real problems in a country with growing genetic care expertise, allowing for the reinforcement of the ethical dilemmas that can and should be raised and considered by the lack of standardised national guidelines that leads to inconsistent practices, violating the principle of justice and creating a \u0026quot;postcode lottery\u0026quot; for patients. This absence of consensus also impacts reproductive decision-making, raising ethical dilemmas concerning beneficence, non-maleficence, and autonomy, particularly regarding prenatal diagnosis and preimplantation genetic testing, and the potential for genetic discrimination. Effective communication, informed consent, and shared decision-making are crucial, requiring better training for healthcare professionals and access to robust counselling services to address the psychological and familial impact of LP-CNV information. Ultimately, the findings underscore the urgent need for a concerted, multidisciplinary effort to establish a robust ethical framework that elucidates the uncertainties surrounding LP-CNVs, upholds patient autonomy, guarantees equitable access, and protects against potential genetic discrimination.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis framework must emphasise the development of comprehensive, standardised guidelines, cultivate a culture of shared decision-making, and invest in the education and training of healthcare professionals. Ultimately, by adopting a holistic approach that acknowledges the intricate interplay of individual, familial, and societal factors, we can navigate the evolving landscape of clinical genetics with wisdom, compassion, and unwavering ethical integrity, ensuring that the potential of genetic knowledge empowers rather than marginalises the individuals and families it aims to assist.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eDATA AVAILABILITY STATEMENT\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll collected and generated data from this study is available in the manuscript and respective supplementary information.\u003c/p\u003e\u003cp\u003eAcknowledgements: not applicable\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Authors\u0026apos; contributions:\u003c/p\u003e\n\u003cp\u003e- Soares, Afonso and Carvalho prepared the questionnaire.\u003c/p\u003e\n\u003cp\u003e- Soares contacted clinicians and retrieved information from questionnaires.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e- Da Silva worked on statistical data, figures and tables.\u003c/p\u003e\n\u003cp\u003e- Soares and Carvalho wrote the main manuscript text.\u003c/p\u003e\n\u003cp\u003e- All authors reviewed the manuscript.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Funding: No funding for this project\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Ethical Approval\u003c/p\u003e\n\u003cp\u003eThis project was approved by\u0026nbsp;the hospital Ethics Committee - Comiss\u0026atilde;o de \u0026Eacute;tica do Centro Hospitalar Universit\u0026aacute;rio de Santo Ant\u0026oacute;nio, EPE.\u003c/p\u003e\n\u003cp\u003eAll the participants who responded to the questionnaire gave their informed consent to participate and for publication. If they did not agree to proceed with the study, they did not fill out the questionnaire and dropped out.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Competing interests: no competing interests\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMorris E, O\u0026rsquo;Donovan M, Virani A, Austin J. An ethical analysis of divergent clinical approaches to the application of genetic testing for autism and schizophrenia. Hum Genet]. 2021 Aug 28 [cited 2022 Apr 11].\u003c/li\u003e\n\u003cli\u003eMiller DT, Adam MP, Aradhya S, Biesecker LG, Brothman AR, Carter NP, et al. Consensus Statement: Chromosomal Microarray Is a First-Tier Clinical Diagnostic Test for Individuals with Developmental Disabilities or Congenital Anomalies. The American Journal of Human Genetics. 2010 May;86(5):749\u0026ndash;64. \u003c/li\u003e\n\u003cli\u003eRosenfeld JA, Coe BP, Eichler EE, Cuckle H, Shaffer LG. Estimates of penetrance for recurrent pathogenic copy-number variations. Genetics in Medicine. 2013 Jun;15(6):478\u0026ndash;81. \u003c/li\u003e\n\u003cli\u003eCooper GM, Coe BP, Girirajan S, Rosenfeld JA, Vu TH, Baker C, et al. A copy number variation morbidity map of developmental delay. Nat Genet. 2011 Sep;43(9):838\u0026ndash;46. \u003c/li\u003e\n\u003cli\u003eGoh S, Thiyagarajan L, Dudding-Byth T, Pinese M, Kirk EP. A systematic review and pooled analysis of penetrance estimates of copy-number variants associated with neurodevelopment. Genetics in Medicine. 2025 Jan;27(1):101227. \u003c/li\u003e\n\u003cli\u003eMuys J, Blaumeiser B, Janssens K, Loobuyck P, Jacquemyn Y. Chromosomal microarray analysis in prenatal diagnosis: ethical considerations of the Belgian approach. J Med Ethics. 2020 Feb;46(2):104\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003eGovaerts L, Srebniak M, Diderich K, Joosten M, Riedijk S, Knapen M, et al. Prenatal diagnosis of susceptibility loci for neurodevelopmental disorders \u0026ndash; genetic counseling and pregnancy outcome in 57 cases: Prenatal diagnosis of susceptibility CNVs. Prenat Diagn. 2017 Jan;37(1):73\u0026ndash;80. \u003c/li\u003e\n\u003cli\u003eShkedi-Rafid S, Fenwick A, Dheensa S, Wellesley D, Lucassen AM. What results to disclose, when, and who decides? Healthcare professionals\u0026rsquo; views on prenatal chromosomal microarray analysis: Healthcare professionals\u0026rsquo; views on prenatal CMA testing. Prenat Diagn. 2016 Mar;36(3):252\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003eKendall KM, Bracher-Smith M, Fitzpatrick H, Lynham A, Rees E, Escott-Price V, et al. Cognitive performance and functional outcomes of carriers of pathogenic copy number variants: analysis of the UK Biobank. Br J Psychiatry. 2019 May;214(5):297\u0026ndash;304. \u003c/li\u003e\n\u003cli\u003eProceedings of the 23rd Annual Meeting of the Portuguese Society of Human Genetics. Medicine. 2020 Feb;99(9):e19291. \u003c/li\u003e\n\u003cli\u003eChristiansen J, Dyck JD, Elyas BG, Lilley M, Bamforth JS, Hicks M, et al. Chromosome 1q21.1 Contiguous Gene Deletion Is Associated With Congenital Heart Disease. Circulation Research. 2004 Jun 11;94(11):1429\u0026ndash;35. \u003c/li\u003e\n\u003cli\u003eMacCallum RC, Widaman KF, Zhang S, Hong S. Sample size in factor analysis. Psychological Methods. 1999 Mar;4(1):84\u0026ndash;99. \u003c/li\u003e\n\u003cli\u003eBuchanan A, Brock DW, Daniels N, Wikler D. From Chance to Choice: Genetics and Justice. 1st ed. Cambridge University Press; 2000. \u003c/li\u003e\n\u003cli\u003eLombardo P. Taking Eugenics Seriously: Three Generations of ??? are Enough? Fla St U L Rev. 2003;30(2).\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table 2","content":"\u003cp\u003eTable 2 is available in the Supplementary Files section.\u003c/p\u003e\n"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Low-penetrance Copy Number Variants, Genetic Counselling, Reproductive Decision Making, Ethics in Genomic Medicine","lastPublishedDoi":"10.21203/rs.3.rs-6857492/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6857492/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eLow-Penetrance Copy Number Variants (LP-CNVs) are well-known to contribute to neurodevelopmental disorders and are also found in healthy individuals, presenting significant challenges to genetic counselling. However, data on the clinical management of LP-CNVs in Portugal is lacking.\u003c/p\u003e \u003cp\u003eTo address this gap, an online questionnaire was administered to Clinical Geneticists in Portugal regarding their management of LP-CNV. The results showed a significant absence of agreement on LP-CNVs disclosure, particularly concerning whether decisions should be guided by expert panels or individualised for each case. Clinicians acknowledged the substantial challenges patients and families face in understanding genetic information, highlighting the need for a shared decision-making approach. Furthermore, there was considerable variability in ethical perspectives regarding prenatal diagnosis and preimplantation genetic testing for LP-CNVs, emphasising the need for clear guidelines. Our results strongly advocate for the development of national guidelines mirroring those established in other countries.\u003c/p\u003e \u003cp\u003e This work underscores several complex ethical issues that require further exploration both in Portugal and internationally, including: equitable access to knowledge and economic fairness; balancing child/embryo welfare against parental autonomy and right to knowledge of parents/couples; the potential for genetic discrimination and stigma; the definitions of a \"good\"/\"healthy\" life and the authority to make such determination; and the imperative for enhanced training and education for Geneticists to facilitate effective communication and informed consent.\u003c/p\u003e","manuscriptTitle":"Medical and ethical challenges in low penetrance copy number variants management: state-of-the-art in the Portuguese Clinical Genetics community","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-23 06:25:34","doi":"10.21203/rs.3.rs-6857492/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d16d7c50-89be-4813-8e4e-7ddb265385ff","owner":[],"postedDate":"June 23rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":50244467,"name":"Health sciences/Health care/Medical ethics"},{"id":50244468,"name":"Health sciences/Medical research/Genetics research"}],"tags":[],"updatedAt":"2025-10-01T21:00:45+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-23 06:25:34","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6857492","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6857492","identity":"rs-6857492","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}