Implementing Electronic Informed Consent in Rare Disease Genomics

Implementing Electronic Informed Consent in Rare Disease Genomics | 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 Implementing Electronic Informed Consent in Rare Disease Genomics Katja Ekholm, Annelie Augustinsson, Johan Sundström, Christian Johansen, and 14 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7906738/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 23 Dec, 2025 Read the published version in Scientific Reports → Version 1 posted 10 You are reading this latest preprint version Abstract Background In rare disease research, sharing of individual health data is essential for advancing diagnostics and therapies, requiring robust and ethically sound informed consent processes. Methods Within the Genomic Medicine Sweden Rare Diseases (GMS-RD) multicenter study, an electronic informed consent (eConsent) platform was developed to support data sharing, facilitate participation and enable research engagement. Tailored to the complex consent needs of rare disease contexts, the platform was piloted at three Genomic Medicine Centers in Sweden. Results A total of 2,244 individuals were invited in the clinical routine cohort, with an overall eConsent rate of 18.6%. Uptake was highest among adult singletons (27.8%) and lowest in trios (14.3%). In contrast, the Undiagnosed Diseases Network (UDN) Sweden cohort achieved a 94% consent rate, attributed to targeted communication and active patient organization involvement. Key challenges included technical accessibility limitations, digital literacy deficits, comprehension and language barriers, and the burden of multi-step processes, especially for families. Findings underscore the need to improve usability, strengthen communication, and implement flexible consent management over time. Conclusion eConsent can broaden participation in genomic research and promote responsible data sharing. However, in rare diseases contexts, it must be designed with inclusivity, clarity, and adaptability to meet the diverse participant needs. Biological sciences/Computational biology and bioinformatics Biological sciences/Genetics Health sciences/Health care Health sciences/Medical research electronic informed consent (eConsent) whole-genome sequencing rare diseases genomics Figures Figure 1 Figure 2 BACKGROUND Each rare disease affects fewer than one in 2,000 individuals, and approximately 72% are thought to have a genetic origin ( 1 , 2 ). The introduction of massive parallel sequencing has revolutionized rare disease diagnostics, enabling clinical exome and genome analysis with overall diagnostic yields ranging from 20% to 50%, depending on inclusion criteria (reviewed in ( 3 )). Despite these advances, many individuals continue to face prolonged diagnostic odysseys. Even with comprehensive approaches such as whole genome sequencing (WGS), more than 60% of cases remain undiagnosed ( 3 ). This diagnostic gap is due in part to incomplete phenotypic information, the challenge of interpreting variants of uncertain significance (VUS), and current technical, as well as knowledge-based, limitations in detecting the full spectrum of disease-causing variants. Given the small number of individuals affected by each specific condition, data sharing across centers and networks is crucial. By aggregating individual genomic and clinical data, researchers and clinicians can improve variant interpretation, uncover disease mechanisms, and accelerate progress toward precise diagnostics and personalized care and treatments. Importantly, there is an intimate relationship between clinical diagnostics and research in rare diseases, where new discoveries often emerge from studying individual cases. The active involvement of individuals living with rare diseases in research initiatives is essential, not only to improve diagnostic and therapeutic care at the individual level, but also to advance collective knowledge through responsible data sharing and collaboration ( 4 ). Informed consent is a fundamental principle in both research and medical practice, designed to safeguard participants' autonomy by ensuring that they voluntarily participate with a clear understanding of the associated risks, benefits, and procedures. The American Psychological Association (APA) defines informed consent as "the process by which researchers explain their study to human participants and obtain their approval based on their understanding of the research's methods and objectives" ( 5 ). The Declaration of Helsinki emphasizes that voluntary informed consent must be obtained before enrolling participants in research ( 6 ). Similarly, the Council for International Organizations of Medical Sciences (CIOMS) highlights the importance of respecting participants' autonomy and their right to withdraw at any time without negative consequences ( 7 ). In the context of genetic and genomic research, informed consent must address specific considerations such as the inability to make data anonymous, possibility of incidental findings, implications for biological relatives, long-term data storage, and future secondary use of genomic data. Participants should also be informed about the potential benefits, such as receiving a diagnosis or contributing to the development of targeted therapies. Given the sensitive and enduring nature of genomic information, clear communication about data privacy and sharing is essential ( 8 ). Informed consent has traditionally relied on paper-based processes, but electronic consent (eConsent) platforms are creating new opportunities for participant engagement. eConsent offers a flexible, participant-centered approach that uses interactive and digital tools to enhance understanding ( 9 , 10 ). This innovation is particularly relevant in an era of growing demands for transparency, faster research cycles, and remote or decentralized study designs ( 11 ). Participant comprehension is a known challenge in consent procedures, and integrating clear communication strategies and interactive elements into eConsent platforms may help address this issue ( 12 , 13 ). Furthermore, dynamic consents, a more flexible, patient-centered model, can foster long-term engagement and accommodate evolving preferences and study needs ( 14 ). However, it is important to acknowledge that some individuals may face difficulties navigating electronic systems ( 15 ) or may lack access to digital tools, emphasizing the need for accessible and inclusive design in eConsent implementation. Genetic data is particularly sensitive due to its uniquely identifiable nature, its potential to reveal disease predispositions, and its implications not only for the individual but also for their biological relatives. As the reuse of genetic data becomes more common in research, concerns about privacy and autonomy have grown, highlighting the importance of broad consent frameworks and established ethical guidelines in safeguarding participants. Such frameworks are essential not only to protect participants but also to ensure the continued trust of patients, demonstrating our commitment to safeguarding their data and privacy as we share and utilize genetic information ( 16 , 17 ). Nevertheless, people living with rare diseases have generally shown a high willingness to share their genetic data ( 4 ). Genomic Medicine Sweden (GMS), initiated in 2017, aims to integrate genomics-based diagnostics in routine healthcare and build a sustainable national infrastructure for precision medicine ( 18 , 19 ). As of 2025,WGS is offered as a clinical diagnostic test at four of Sweden’s seven university hospital laboratories, with more than 30,000 individuals tested within the Swedish healthcare system ( 20 ). In this article, we describe our experiences with informing and consenting individuals with rare diseases, who face diverse medical, cognitive, or practical challenges, using an electronic consent process. We focus on the benefits and challenges encountered during implementation and highlight the importance of flexible systems that support participant understanding, trust, and informed decision-making regardless of individual abilities, circumstances, or mode of consent. METHODS GMS-RD Project and Ethical Approval The national multicenter project “GMS-RD: Identification of Novel Causes of Rare Genetic Diseases” was registered and approved by the Swedish Ethical Review Authority in December 2019 (Ref no 2019–04746). In brief, the study allows for clinical, functional and psychosocial studies of patients as well as sharing of genomic data with national and international research initiatives such as the “Beyond 1 Million Genomes” initiative ( 21 ) and the European Health Data Space ( 22 ). The study is the foundation of national data sharing within GMS-RD where data will be stored in the National Genomics Platform (NGP), a high compute cluster that enables both storage and computation ( 18 ). Swedish healthcare has historically relied on paper-based informed consents, but an eConsent system was introduced to facilitate data sharing and research participation in the era of genomic medicine. The eConsent platform, minforskning.se, was further developed and tailored to the specific needs of the GMS-RD project through a collaboration between GMS and Uppsala University. The platform implementation commenced with the first participant enrollment on September 27, 2023. Inclusion sites and clinical cohorts The eConsent platform was piloted in a clinical routine setting at three Genomic Medicine Centers (GMC) in Sweden located at Sahlgrenska University Hospital (GMC West, Gothenburg), Karolinska University Hospital (GMC-K, Stockholm) and Skåne University Hospital (GMC South, Lund). All sites offer WGS as part of their clinical genetic diagnostics programs and analyses are performed as both trios and singletons and both with panel and whole-genome interpretation. eConsent evaluation included trio consent cohorts (affected child with both parents having also analyzed samples) and singleton consent cases (affected child or adult). eConsent was also separately evaluated for the nationwide Undiagnosed Diseases Network Sweden (UDN Sweden) initiative, which includes trio sample investigations of individuals with intellectual disability (ID) or ID syndromes who remain undiagnosed after short-read WGS. Technical solution for an electronic consent database and data collection We used the solution minforskning.se, originally developed as part of a research study at Uppsala University, but later commercialized in the company MinForskning AB (Uppsala, Sweden) ( 23 – 25 ). The system has been used in seven additional studies, including studies with and without the co-signature of a physician, studies where participants are recruited via social media without the need for a co-signature, clinical drug trials requiring a physician's co-signature and, one study where the legal guardians provide consent on behalf of their minor children. Minforskning.se provides public access to relevant study information, participant consent forms, and contact details via BankID, the largest Swedish electronic identification system that has a usage rate of 94% among smartphone users in Sweden ( 26 ) and is an accepted identification solution by national authorities. BankID is administered by Finansiell ID-Teknik BID AB, which is owned by several Swedish and Scandinavian banks. In minforskning.se, personal information is accessible only after logging in with BankID. Participants can view and download signed eConsents and access withdrawal instructions. Anyone can create a profile to receive study offers and studies can send secure, individualized messages through the platform. Participants can independently consent to studies, or, for studies requiring a physician’s co-signature, the system ensures that signatures occur in the correct sequence in the same session. Through real-time checks with the Swedish Population Register, the system allows legal guardians to consent for minors, and mandates all (one or two) guardians to consent before an eConsent is considered valid. The system tracks eConsent status in real-time, and manual paper consents can be recorded to obtain a complete eConsent database for a study. In addition, an Application Programming Interface (API) solution makes it possible to ask questions about valid eConsents from other authorized systems, such as genomic databases. The platform complies with key international standards for clinical research and electronic data management. These include the Good Automated Manufacturing Practice 5 (GAMP 5) ( 27 ), the International Council for Harmonisation Guideline for Good Clinical Practice E6 (ICH E6), the international Good Clinical Practice (GCP) guideline for clinical trials involving human participants ( 28 ), the U.S. Food and Drug Administration Code of Federal Regulations (FDA CRF) 21 Part 11, which defines the use of electronic records and electronic signatures in FDA-regulated environments ( 29 ), and EudraLex Annex 11, outlining the European Union’s requirements for computerized systems in pharmaceutical manufacturing and clinical trials ( 30 ). All personal data is securely stored in Sweden in compliance with the General Data Protection Regulation (GDPR), with MinForskning AB acting as the designated data processor. Registered patient consents and other study-specific data is owned by the respective research institutions, while MinForskning AB holds intellectual property rights for the technical platform. General eConsent process Individuals were invited to participate in the GMS-RD study through a letter in Swedish containing brief information about the study, the eConsent platform, and practical steps for consenting (examples of letter templates used translated to English are available as Supplementary materials (Additional file 1: Document S1)). In brief, for a singleton adult case, the process includes creation of a profile, choosing a study site, reading the informed consent and then signing with an electronic ID (BankID) (Fig. 1 ). For a singleton pediatric case, legal guardians (one or two) need to sign for the child. For a pediatric trio case, a complete trio consent is needed, where both biological parents need to sign for the child and also can choose to separately sign for themselves since their samples also has been collected. Experiences and questions Data were derived from participant inquiries and researcher notes, focusing on the practical and logistical challenges encountered during the consent process. RESULTS Cohorts evaluated for eConsent For the clinical cohort in total, 709 adult singletons, 448 pediatric singletons, and 1087 individuals belonging to trios (369 affected affected individuals and 718 healthy relatives, most often parents) were invited by letter to participate by registering eConsent in the GMS-RD study. Consents were obtained for 197 adult singletons, 65 pediatric singletons, and 61 trios (155 individuals), respectively. In average, this represented a consent rate of 18,6%, albeit with large differences between subgroups. For the UDN cohort the corresponding consent rate was 94%. (Table 1 ). Table 1 Consent evaluation clinical cohorts and acceptance rates Cohort Cohort Type* Site Approached individuals eConsented individuals eConsent rate (%) Clinical cohorts Trio GMC South 420 72 17.1% Trio GMC Karolinska 120 3 2.5% Trio GMC West 547 80 14.6% Singleton pediatric GMC South 248 38 15.3% Singleton pediatric GMC West 200 27 13,5% Singleton adult GMC South 226 62 27.4% Singleton adult GMC Karolinska 340 105 30.9% Singleton adult GMC West 143 30 21,0% UDN Trio UDN Sweden 303 285 94% * For trios, consent was obtained from the child as well as from each parent, resulting in three individual consents in most families. Experiences from the national UDN Sweden study The 101 children with undiagnosed rare ID and ID syndromes that met the inclusion criteria for the national UDN Sweden project had already spent years in the diagnostic odyssey. They were recruited mainly through patient organizations for undiagnosed individuals with rare diseases (Wilhelm Foundation and Anonymous) which spread information about the study as well as about the eConsent platform. Several information sessions were held where families also had the possibility to ask questions. In the end, digital consents were obtained from 94% trios (95/101 trios). Registration of paper consents in the eConsent database In addition to primary electronic consents, a total of 2,178 paper consents (2,100 from Lund, 76 from Stockholm, 2 from Gothenburg) were registered retrospectively by study personnel in the eConsent database. These registrations are excluded from the above reported dataset. Participant experiences In the different groups, data from participant inquiries and researcher notes, focusing on the practical and logistical challenges encountered during the consent process was compiled. Letters describing the GMS-RD study and the eConsent platform were sent to 40 pediatric trio families in the GMC Karolinska cohort. Four families responded electronically, but only one successfully completed the digital consent for all family members. The remaining families either provided consent for only one parent and the child, or, in one case, for the parents only. Parents reported that the trio process was time-consuming and burdensome, as each parent or legal guardian was required to create separate accounts for themselves and for each child. Based on this feedback, we adopted a different approach for subsequent outreach, which was not included in the overall statistics for the initial pilot. In this adapted approach, 210 additional families were contacted by phone and offered the option to provide paper-based consent in addition to using the eConsent platform. Of note, among the families contacted using this modified strategy, all who chose to participate provided consent on paper. Many families called back multiple times, as one parent often wished to discuss participation with the other before making a decision. In several cases, families requested a callback the following day after internal discussions. In total, 148 of the 250 families opted to participate (60%). The uptake of correct electronic consent in the GMC South pediatric (trio and singleton) cohort was considerably higher than for GMC Karolinska (17.1% and 15.3%, respectively). Almost all these families handled the registration without problem. One participant sent an email to ask if they had managed to register the consent for all three individuals in the trio, but in this case, everything was already in order. In addition, six emails and five phone calls were registered where the legal guardian had general questions about the project, but none of these questions were related specifically to the consenting process on the eConsent platform. The uptake in the GMC West cohorts was similar to GMC South for the singleton pediatric and trio cohort. All three sites had higher up-take for the adult cohorts (21,0%, 27,4% and 30,4% for GMC West, GMC South and GMC Karolinska respectively). The GMC West cohort consisted almost exclusively of participants with a negative genetic screening result and hence differed in composition compared to the other sites. The most frequent reason of correspondence and questions raised at this site (19 contacts) was about the offer of study inclusion in it-self (9 contacts) rather than problems with the eConsent platform (4 contacts). Phone calls, e-mails and experiences In all clinical cohorts, incoming questions from potential research participants were monitored following the distribution of invitation letters. In the GMC South singleton adult cohort (226 individuals approached), one email and five phone calls were received. In the GMC Karolinska adult cohort (340 individuals approached), 25 phone calls were received, and in the Sahlgrenska cohort (890 individuals approached), 19 emails were received. Most inquiries related to difficulties navigating the eConsent platform or clarifying the reason for inclusion. In one case, a letter had been sent to a deceased individual, underscoring the importance of cross-referencing participant lists with national registries to prevent distress to families. The following challenges were reported: Login difficulties Eighteen individuals had difficulties logging into the platform. Of note, in total nine elderly participants struggled with the eConsent platform and frequently required additional guidance. Two individuals from Stockholm and two from Lund lacked a digital identity verification system such as Bank-ID and could therefore not login to the system. Information Gaps Other questions showed confusion about the purpose of the project (n = 15), the need for additional sample collection (n = 3) as well as concerns regarding the duration of consent validity but also positive feedback about the possibility to contribute to research and requests for inclusion. Miscommunication led some participants to incorrectly believe they needed to provide new samples. We received feedback on information clarity and suggestions of allowing preferences for manual (paper-based) or oral consent (i.e., giving consent verbally rather than in writing). A specific challenge is the inclusion of patient with a considerable time span between the performed analysis and the study inclusion, especially with negative results. They might not remember the performed analysis and hence question the offer to be included. DISCUSSION This study outlines the experiences of GMS-RD in optimizing participant inclusion in a national multicenter rare disease project through the implementation of an electronic informed consent solution (eConsent) in addition to traditional paper-based consent (Fig. 2 ). Our findings indicate that the eConsent platform was more effective and practical for adult singleton cases than for pediatric scenarios (both singletons and trios), where additional logistical and communication challenges were encountered. In rare disease research, data sharing is essential for fostering collaboration and accelerating discovery. Because rare diseases affect small and often dispersed populations, research findings are more valuable when shared across institutions and borders. Effective data sharing maximizes the utility of limited patient data, enabling researchers to identify patterns, refine diagnostic criteria, and advance treatment development, ultimately improving healthcare and quality of life for people living with rare diseases. Aggregating genetic and clinical data through shared resources also enables insights that would be difficult to achieve from smaller, isolated studies. However, the collection and sharing of sensitive health data raise important ethical and privacy concerns. It is essential that informed consent processes are robust and transparent, especially when data sharing is involved. Participants in rare disease studies must clearly understand how their data will be used, stored, and shared, with strong safeguards to protect their privacy. They should also be made aware of their right to withdraw from data-sharing initiatives at any time without negative consequences. Consent models that allow participants to manage and update their preferences over time, such as dynamic consent, offer a promising approach to addressing these concerns ( 31 ). In the clinical cohorts, 28% (197/709) of adult singletons provided eConsent, compared to 14% (220/1,535) of pediatric patients and parents (Table 1 ). Although uptake was highest among adult singletons and lowest among pediatric trios, specific barriers differed between groups. Among elderly singleton participants, the most common challenges were login difficulties and low digital literacy, whereas in the pediatric trio scenario, the most frequently raised concern was the requirement for multiple guardian signatures to authorize participation. We predict that, even with an improved system, both of these scenarios will likely continue to benefit from personal guidance and support from trained personnel. Importantly, both the letters and the approved informed consent form were available only in Swedish, which limited inclusion of individuals with other language backgrounds. The consent rate for trios was considerably higher in the GMC South (17.1%) and GMC West (14.6) cohorts than in the GMC Karolinska cohort (2.5%), despite similar procedures for contacting the families, and the reason for this may be a subject for future studies. It should also be noted that the rate of acceptance in the national UDN study was much higher than for any of the other subgroups (95/101, 94%), probably due to the fact that the families in the UDN Sweden are highly motivated and typically have been actively searching for a diagnosis for years, often involving numerous contacts and discussions with healthcare providers, and also that patient associations were involved in the recruitment of these families and could provide support. Improved communication may also enhance participation, especially in complex cases like pediatric studies. Clear and accessible materials that explain the study’s purpose, procedures, and benefits in simple terms help both participants and guardians better understand their role. In rare disease research, where medical concepts can be challenging, tailoring language and format to the audience is crucial. Future development of the eConsent platform should therefore focus not only on technical usability but also on improving information clarity. Furthermore, for an adult population the eConsent platform provides an unprecedented possibility to join advanced rare disease research, where this study indicates that acceptance rates of about 30% may be expected after sending an invitation letter, minimizing the burden on the healthcare system. Additionally, the eConsent enables broad recruitment without geographic and disease group bias. The possibility to manually add paper-based informed consents to the secure eConsent database is an important functionality, since consent queries over API will then be able to cover all participants in a study, regardless of the mode of consent registration. Recommendations for Improvement To optimize eConsent processes in rare disease research, several strategies should be considered : Enhancing Usability: The complexity of digital consent systems can be a barrier for some participants, especially elderly and others with limited digital literacy and lack of access to digital solutions. Developing step-by-step guides with visuals and simplifying the login process can make the system more user-friendly, ensuring that participants can easily navigate through consent procedures without feeling overwhelmed. Improving Communication: Tailoring study materials to ensure clarity about the purpose, procedures, risks, and benefits of the research is crucial. For rare disease studies, simplifying complex medical language and using clear, concise messaging can help participants better understand their role in the research and how it might benefit both them and others with the same condition. Strengthening Data Accuracy: Ensuring that participant data is accurate is critical for both research integrity and ethical compliance. Implementing automatic checks for duplicate registrations and deceased participants can reduce errors and ensure that consent remains valid and up to date. Facilitating Long-term Data Sharing: The rare disease community relies on long-term data sharing to accelerate research. eConsent systems should enable participants to manage their consent preferences over time, allowing them to update or withdraw consent if their views or circumstances change. CONCLUSION In conclusion, electronic consent systems hold significant promise for improving the informed consent process, particularly in rare disease research. By making the process more accessible, transparent, and user-friendly, eConsent platforms can enhance participant understanding, encourage data sharing, and streamline administrative tasks. The recommendations discussed, i.e. enhancing usability, improving communication, and strengthening data accuracy, are essential steps in ensuring that the consent process is ethical, robust and effective. This study offers valuable insights for optimizing eConsent processes, with implications not only for genomic research in rare diseases but also for broader adoption in clinical and epidemiological studies. Abbreviations APA; American Psychological Association API; Application Programming Interface BankID; Swedish electronic identification system CIOMS; Council for International Organizations of Medical Sciences eConsent; Electronic informed consent ERN; European Reference Network ERN-ITHACA; European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability FDA CRF 21 Part 11; U.S. Food and Drug Administration Code of Federal Regulations Title 21 Part 11 GAMP 5; Good Automated Manufacturing Practice version 5 GMC; Genomic Medicine Center GMS; Genomic Medicine Sweden GMS-RD; Genomic Medicine Sweden – Rare Diseases ICH E6; International Council for Harmonisation Guideline for Good Clinical Practice E6 ID; Intellectual Disability NGP; National Genomic data Platform UDN Sweden; Undiagnosed Diseases Network Sweden VUS; Variant of Uncertain Significance WGS; Whole Genome Sequencing Declarations Acknowledgments This study was conducted within the Genomic Medicine Sweden Rare Disease Working Group and supported by Genomic Medicine Sweden. We gratefully acknowledge the contributions of all participants. Several authors are members of the European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability (ERN-ITHACA) [EU Framework Partnership Agreement ID: 3HP-HP-FPA ERN-01-2016/739516]. Funding The eConsent project was supported by Vinnova (2021-04229). AL and AN were supported by grants from the Swedish Research Council and the Swedish Brain Foundation. Availability of data All data is available in the article files. Author´s contributions AL, HE, MJS, SJ, AN, CIM and MF conceptualized the study. HE, JS, MS and CJ designed the electronic consent platform. KE, AA, LL, EE, FT and ME collected data and performed formal analysis. AL, MJS, CIM, AN, LLo and HE drafted the GMS ethical application. KE, AA, HE, AL, and AN wrote the first draft. FT made the figures. All authors read, edited and approved the final manuscript. Ethics approval and consent to participate Not applicable Consent for publication Not applicable Conflicts of Interest JS, MS and CJ are direct or indirect shareholders of MinForskning AB, the legal entity supplying the eConsent system discussed in this article. JS also reports direct or indirect shareholdership in companies Anagram kommunikation AB, Sence Research AB, and Symptoms Europe AB, providing services to companies and authorities in the health sector including Amgen, AstraZeneca, Bayer, Boehringer, Eli Lilly, Gilead, GSK, Göteborg University, Itrim, Ipsen, Janssen, Karolinska Institutet, LIF, Linköping University, Novo Nordisk, Parexel, Pfizer, Region Stockholm, Region Uppsala, Sanofi, STRAMA, Takeda, TLV, Uppsala University, Vifor Pharma, WeMind. The other authors declare no conflicts of interest. Supporting information Additional File 1: Document S1. Examples of letter templates sent to patients/families References Ferreira, C. R. The burden of rare diseases. Am. J. Med. 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Available from: https://www.epidemiologi.nu/wp-content/uploads/2021/12/Svepet-4-2021.pdf Sundstrom, J. et al. A registry-based randomised trial comparing an SGLT2 inhibitor and metformin as standard treatment of early stage type 2 diabetes (SMARTEST): Rationale, design and protocol. J. Diabetes Complications . 35 (10), 107996 (2021). Finansiell & ID–Teknik BID AB.. Statistik – BankID [Available from: https://www.bankid.com/en/om-oss/statistik International Society of Pharmaceutical Engineers. ISPE GAMP® 5: A Risk-Based Approach to Compliant GxP Computerized Systems (ISPE, 2022). TECHNICAL ICFHO, (ICH) RFPFHU. ICH Harmonised Guideline: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice E6(R2). 2016 11 July 2025. US Food and Drug Administration. Code of Federal Regulations Title 21, Part 11 (Electronic Records; Electronic Signatures, 1997). Commission E. EudraLex - Volume 4 - Good Manufacturing Practice (GMP) Guidelines: Annex 11 Computerised Systems. (2011). Mascalzoni, D. et al. Ten years of dynamic consent in the CHRIS study: informed consent as a dynamic process. Eur. J. Hum. Genet. 30 (12), 1391–1397 (2022). Additional Declarations Competing interest reported. JS, MS and CJ are direct or indirect shareholders of MinForskning AB, the legal entity supplying the eConsent system discussed in this article. JS also reports direct or indirect shareholdership in companies Anagram kommunikation AB, Sence Research AB, and Symptoms Europe AB, providing services to companies and authorities in the health sector including Amgen, AstraZeneca, Bayer, Boehringer, Eli Lilly, Gilead, GSK, Göteborg University, Itrim, Ipsen, Janssen, Karolinska Institutet, LIF, Linköping University, Novo Nordisk, Parexel, Pfizer, Region Stockholm, Region Uppsala, Sanofi, STRAMA, Takeda, TLV, Uppsala University, Vifor Pharma, WeMind. The other authors declare no conflicts of interest. Supplementary Files eConsentGenomeMedicineDocumentS1.docx Cite Share Download PDF Status: Published Journal Publication published 23 Dec, 2025 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 17 Nov, 2025 Reviews received at journal 15 Nov, 2025 Reviewers agreed at journal 15 Nov, 2025 Reviews received at journal 14 Nov, 2025 Reviewers agreed at journal 27 Oct, 2025 Reviewers invited by journal 24 Oct, 2025 Editor assigned by journal 24 Oct, 2025 Editor invited by journal 24 Oct, 2025 Submission checks completed at journal 22 Oct, 2025 First submitted to journal 22 Oct, 2025 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. 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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-7906738","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":539995299,"identity":"e8a3a20d-385a-4c11-8d1f-db15694ccc46","order_by":0,"name":"Katja Ekholm","email":"","orcid":"","institution":"Karolinska University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Katja","middleName":"","lastName":"Ekholm","suffix":""},{"id":539995300,"identity":"2de2e284-5080-4c56-8d99-35c153dd6c25","order_by":1,"name":"Annelie Augustinsson","email":"","orcid":"","institution":"Lund 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04:17:24","extension":"html","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":91361,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7906738/v1/94daba5c8810a73f8f8fd924.html"},{"id":95260346,"identity":"24c7188d-242d-448d-895a-9a17f7047c99","added_by":"auto","created_at":"2025-11-06 04:17:24","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":439101,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eeConsent platform and consent process\u003c/strong\u003e. Each Genomic Medicine Center (GMC) functions as a study site with its own portal entry. During the pilot phase, only GMC South (red arrow), GMC West (pink arrow), and GMC Karolinska (green arrow) were active. Invited potential participants received a letter with instructions for logging in using a digital ID, reviewing the Participant Information Sheet, and providing consent to participate. The signed consents were stored in a database accessible to both the GMCs and the National Genomic Data Platform (NGP). Created with BioRender.com.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7906738/v1/5c948487a08ad58aa8e0da35.jpeg"},{"id":95260349,"identity":"d6278f4a-81d5-4d64-b0ee-25157d6938aa","added_by":"auto","created_at":"2025-11-06 04:17:24","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":263095,"visible":true,"origin":"","legend":"\u003cp\u003eThe GMS-RD eConsent\u003cstrong\u003e \u003c/strong\u003eexperience.\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7906738/v1/929ff6ccf655cfb42a4093b8.jpeg"},{"id":99172409,"identity":"82ce187f-a639-4126-ba24-7fd79dc20fe4","added_by":"auto","created_at":"2025-12-29 16:09:01","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1581765,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7906738/v1/876cba9c-43b1-4c23-8924-6afc8571a05b.pdf"},{"id":95313362,"identity":"b3c13335-ccc4-4a0f-b5d1-d08681bc1738","added_by":"auto","created_at":"2025-11-06 15:51:18","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":18840,"visible":true,"origin":"","legend":"","description":"","filename":"eConsentGenomeMedicineDocumentS1.docx","url":"https://assets-eu.researchsquare.com/files/rs-7906738/v1/bc81f40d86a92b867e9ce4da.docx"}],"financialInterests":"Competing interest reported. JS, MS and CJ are direct or indirect shareholders of MinForskning AB, the legal entity supplying the eConsent system discussed in this article.\nJS also reports direct or indirect shareholdership in companies Anagram kommunikation AB, Sence Research AB, and Symptoms Europe AB, providing services to companies and authorities in the health sector including Amgen, AstraZeneca, Bayer, Boehringer, Eli Lilly, Gilead, GSK, Göteborg University, Itrim, Ipsen, Janssen, Karolinska Institutet, LIF, Linköping University, Novo Nordisk, Parexel, Pfizer, Region Stockholm, Region Uppsala, Sanofi, STRAMA, Takeda, TLV, Uppsala University, Vifor Pharma, WeMind.\nThe other authors declare no conflicts of interest.","formattedTitle":"Implementing Electronic Informed Consent in Rare Disease Genomics","fulltext":[{"header":"BACKGROUND","content":"\u003cp\u003eEach rare disease affects fewer than one in 2,000 individuals, and approximately 72% are thought to have a genetic origin (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). The introduction of massive parallel sequencing has revolutionized rare disease diagnostics, enabling clinical exome and genome analysis with overall diagnostic yields ranging from 20% to 50%, depending on inclusion criteria (reviewed in (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)). Despite these advances, many individuals continue to face prolonged diagnostic odysseys. Even with comprehensive approaches such as whole genome sequencing (WGS), more than 60% of cases remain undiagnosed (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). This diagnostic gap is due in part to incomplete phenotypic information, the challenge of interpreting variants of uncertain significance (VUS), and current technical, as well as knowledge-based, limitations in detecting the full spectrum of disease-causing variants. Given the small number of individuals affected by each specific condition, data sharing across centers and networks is crucial. By aggregating individual genomic and clinical data, researchers and clinicians can improve variant interpretation, uncover disease mechanisms, and accelerate progress toward precise diagnostics and personalized care and treatments. Importantly, there is an intimate relationship between clinical diagnostics and research in rare diseases, where new discoveries often emerge from studying individual cases. The active involvement of individuals living with rare diseases in research initiatives is essential, not only to improve diagnostic and therapeutic care at the individual level, but also to advance collective knowledge through responsible data sharing and collaboration (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eInformed consent\u003c/strong\u003e\u003cp\u003eis a fundamental principle in both research and medical practice, designed to safeguard participants' autonomy by ensuring that they voluntarily participate with a clear understanding of the associated risks, benefits, and procedures. The American Psychological Association (APA) defines informed consent as \"the process by which researchers explain their study to human participants and obtain their approval based on their understanding of the research's methods and objectives\" (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). The Declaration of Helsinki emphasizes that voluntary informed consent must be obtained before enrolling participants in research (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Similarly, the Council for International Organizations of Medical Sciences (CIOMS) highlights the importance of respecting participants' autonomy and their right to withdraw at any time without negative consequences (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e\u003c/p\u003e\u003cp\u003eIn the context of genetic and genomic research, informed consent must address specific considerations such as the inability to make data anonymous, possibility of incidental findings, implications for biological relatives, long-term data storage, and future secondary use of genomic data. Participants should also be informed about the potential benefits, such as receiving a diagnosis or contributing to the development of targeted therapies. Given the sensitive and enduring nature of genomic information, clear communication about data privacy and sharing is essential (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eInformed consent\u003c/strong\u003e\u003cp\u003ehas traditionally relied on paper-based processes, but electronic consent (eConsent) platforms are creating new opportunities for participant engagement. eConsent offers a flexible, participant-centered approach that uses interactive and digital tools to enhance understanding (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). This innovation is particularly relevant in an era of growing demands for transparency, faster research cycles, and remote or decentralized study designs (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Participant comprehension is a known challenge in consent procedures, and integrating clear communication strategies and interactive elements into eConsent platforms may help address this issue (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Furthermore, dynamic consents, a more flexible, patient-centered model, can foster long-term engagement and accommodate evolving preferences and study needs (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). However, it is important to acknowledge that some individuals may face difficulties navigating electronic systems (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e) or may lack access to digital tools, emphasizing the need for accessible and inclusive design in eConsent implementation.\u003c/p\u003e\u003c/p\u003e\u003cp\u003eGenetic data is particularly sensitive due to its uniquely identifiable nature, its potential to reveal disease predispositions, and its implications not only for the individual but also for their biological relatives. As the reuse of genetic data becomes more common in research, concerns about privacy and autonomy have grown, highlighting the importance of broad consent frameworks and established ethical guidelines in safeguarding participants. Such frameworks are essential not only to protect participants but also to ensure the continued trust of patients, demonstrating our commitment to safeguarding their data and privacy as we share and utilize genetic information (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). Nevertheless, people living with rare diseases have generally shown a high willingness to share their genetic data (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eGenomic Medicine Sweden (GMS), initiated in 2017, aims to integrate genomics-based diagnostics in routine healthcare and build a sustainable national infrastructure for precision medicine (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). As of 2025,WGS is offered as a clinical diagnostic test at four of Sweden\u0026rsquo;s seven university hospital laboratories, with more than 30,000 individuals tested within the Swedish healthcare system (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eIn this article, we describe our experiences with informing and consenting individuals with rare diseases, who face diverse medical, cognitive, or practical challenges, using an electronic consent process. We focus on the benefits and challenges encountered during implementation and highlight the importance of flexible systems that support participant understanding, trust, and informed decision-making regardless of individual abilities, circumstances, or mode of consent.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eGMS-RD Project and Ethical Approval\u003c/h2\u003e\u003cp\u003e The national multicenter project \u0026ldquo;GMS-RD: Identification of Novel Causes of Rare Genetic Diseases\u0026rdquo; was registered and approved by the Swedish Ethical Review Authority in December 2019 (Ref no 2019\u0026ndash;04746). In brief, the study allows for clinical, functional and psychosocial studies of patients as well as sharing of genomic data with national and international research initiatives such as the \u0026ldquo;Beyond 1\u0026nbsp;Million Genomes\u0026rdquo; initiative (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e) and the European Health Data Space (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). The study is the foundation of national data sharing within GMS-RD where data will be stored in the National Genomics Platform (NGP), a high compute cluster that enables both storage and computation (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eSwedish healthcare has historically relied on paper-based informed consents, but an eConsent system was introduced to facilitate data sharing and research participation in the era of genomic medicine. The eConsent platform, minforskning.se, was further developed and tailored to the specific needs of the GMS-RD project through a collaboration between GMS and Uppsala University. The platform implementation commenced with the first participant enrollment on September 27, 2023.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eInclusion sites and clinical cohorts\u003c/h3\u003e\n\u003cp\u003eThe eConsent platform was piloted in a clinical routine setting at three Genomic Medicine Centers (GMC) in Sweden located at Sahlgrenska University Hospital (GMC West, Gothenburg), Karolinska University Hospital (GMC-K, Stockholm) and Sk\u0026aring;ne University Hospital (GMC South, Lund). All sites offer WGS as part of their clinical genetic diagnostics programs and analyses are performed as both trios and singletons and both with panel and whole-genome interpretation. eConsent evaluation included trio consent cohorts (affected child with both parents having also analyzed samples) and singleton consent cases (affected child or adult). eConsent was also separately evaluated for the nationwide Undiagnosed Diseases Network Sweden (UDN Sweden) initiative, which includes trio sample investigations of individuals with intellectual disability (ID) or ID syndromes who remain undiagnosed after short-read WGS.\u003c/p\u003e\n\u003ch3\u003eTechnical solution for an electronic consent database and data collection\u003c/h3\u003e\n\u003cp\u003eWe used the solution minforskning.se, originally developed as part of a research study at Uppsala University, but later commercialized in the company MinForskning AB (Uppsala, Sweden) (\u003cspan additionalcitationids=\"CR24\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). The system has been used in seven additional studies, including studies with and without the co-signature of a physician, studies where participants are recruited via social media without the need for a co-signature, clinical drug trials requiring a physician's co-signature and, one study where the legal guardians provide consent on behalf of their minor children. Minforskning.se provides public access to relevant study information, participant consent forms, and contact details via BankID, the largest Swedish electronic identification system that has a usage rate of 94% among smartphone users in Sweden (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e) and is an accepted identification solution by national authorities. BankID is administered by Finansiell ID-Teknik BID AB, which is owned by several Swedish and Scandinavian banks. In minforskning.se, personal information is accessible only after logging in with BankID. Participants can view and download signed eConsents and access withdrawal instructions. Anyone can create a profile to receive study offers and studies can send secure, individualized messages through the platform. Participants can independently consent to studies, or, for studies requiring a physician\u0026rsquo;s co-signature, the system ensures that signatures occur in the correct sequence in the same session. Through real-time checks with the Swedish Population Register, the system allows legal guardians to consent for minors, and mandates all (one or two) guardians to consent before an eConsent is considered valid. The system tracks eConsent status in real-time, and manual paper consents can be recorded to obtain a complete eConsent database for a study. In addition, an Application Programming Interface (API) solution makes it possible to ask questions about valid eConsents from other authorized systems, such as genomic databases. The platform complies with key international standards for clinical research and electronic data management. These include the Good Automated Manufacturing Practice 5 (GAMP 5) (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e), the International Council for Harmonisation Guideline for Good Clinical Practice E6 (ICH E6), the international Good Clinical Practice (GCP) guideline for clinical trials involving human participants (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e), the U.S. Food and Drug Administration Code of Federal Regulations (FDA CRF) 21 Part 11, which defines the use of electronic records and electronic signatures in FDA-regulated environments (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e), and EudraLex Annex 11, outlining the European Union\u0026rsquo;s requirements for computerized systems in pharmaceutical manufacturing and clinical trials (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). All personal data is securely stored in Sweden in compliance with the General Data Protection Regulation (GDPR), with MinForskning AB acting as the designated data processor. Registered patient consents and other study-specific data is owned by the respective research institutions, while MinForskning AB holds intellectual property rights for the technical platform.\u003c/p\u003e\n\u003ch3\u003eGeneral eConsent process\u003c/h3\u003e\n\u003cp\u003e Individuals were invited to participate in the GMS-RD study through a letter in Swedish containing brief information about the study, the eConsent platform, and practical steps for consenting (examples of letter templates used translated to English are available as Supplementary materials (Additional file 1: Document S1)). In brief, for a singleton adult case, the process includes creation of a profile, choosing a study site, reading the informed consent and then signing with an electronic ID (BankID) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). For a singleton pediatric case, legal guardians (one or two) need to sign for the child. For a pediatric trio case, a complete trio consent is needed, where both biological parents need to sign for the child and also can choose to separately sign for themselves since their samples also has been collected.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\n\u003ch3\u003eExperiences and questions\u003c/h3\u003e\n\u003cp\u003eData were derived from participant inquiries and researcher notes, focusing on the practical and logistical challenges encountered during the consent process.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003eCohorts evaluated for eConsent\u003c/h2\u003e\u003cp\u003e For the clinical cohort in total, 709 adult singletons, 448 pediatric singletons, and 1087 individuals belonging to trios (369 affected affected individuals and 718 healthy relatives, most often parents) were invited by letter to participate by registering eConsent in the GMS-RD study. Consents were obtained for 197 adult singletons, 65 pediatric singletons, and 61 trios (155 individuals), respectively. In average, this represented a consent rate of 18,6%, albeit with large differences between subgroups. For the UDN cohort the corresponding consent rate was 94%. (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eConsent evaluation clinical cohorts and acceptance rates\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCohort\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCohort Type*\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSite\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eApproached individuals\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eeConsented individuals\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eeConsent rate (%)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"7\" rowspan=\"8\"\u003e\u003cp\u003eClinical cohorts\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTrio\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eGMC South\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e420\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e72\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e17.1%\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTrio\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eGMC Karolinska\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e120\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2.5%\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTrio\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eGMC West\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e547\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e80\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e14.6%\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSingleton pediatric\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eGMC South\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e248\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e38\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e15.3%\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSingleton pediatric\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eGMC West\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e200\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e27\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e13,5%\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSingleton adult\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eGMC South\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e226\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e62\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e27.4%\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSingleton adult\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eGMC Karolinska\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e340\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e105\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e30.9%\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSingleton adult\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eGMC West\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e143\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e21,0%\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUDN\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTrio\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eUDN Sweden\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e303\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e285\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e94%\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e * For trios, consent was obtained from the child as well as from each parent, resulting in three individual consents in most families.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eExperiences from the national UDN Sweden study\u003c/h3\u003e\n\u003cp\u003eThe 101 children with undiagnosed rare ID and ID syndromes that met the inclusion criteria for the national UDN Sweden project had already spent years in the diagnostic odyssey. They were recruited mainly through patient organizations for undiagnosed individuals with rare diseases (Wilhelm Foundation and Anonymous) which spread information about the study as well as about the eConsent platform. Several information sessions were held where families also had the possibility to ask questions. In the end, digital consents were obtained from 94% trios (95/101 trios).\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eRegistration of paper consents in the eConsent database\u003c/h2\u003e\u003cp\u003eIn addition to primary electronic consents, a total of 2,178 paper consents (2,100 from Lund, 76 from Stockholm, 2 from Gothenburg) were registered retrospectively by study personnel in the eConsent database. These registrations are excluded from the above reported dataset.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eParticipant experiences\u003c/h2\u003e\u003cp\u003eIn the different groups, data from participant inquiries and researcher notes, focusing on the practical and logistical challenges encountered during the consent process was compiled.\u003c/p\u003e\u003cp\u003eLetters describing the GMS-RD study and the eConsent platform were sent to 40 pediatric trio families in the GMC Karolinska cohort. Four families responded electronically, but only one successfully completed the digital consent for all family members. The remaining families either provided consent for only one parent and the child, or, in one case, for the parents only. Parents reported that the trio process was time-consuming and burdensome, as each parent or legal guardian was required to create separate accounts for themselves and for each child. Based on this feedback, we adopted a different approach for subsequent outreach, which was not included in the overall statistics for the initial pilot. In this adapted approach, 210 additional families were contacted by phone and offered the option to provide paper-based consent in addition to using the eConsent platform. Of note, among the families contacted using this modified strategy, all who chose to participate provided consent on paper. Many families called back multiple times, as one parent often wished to discuss participation with the other before making a decision. In several cases, families requested a callback the following day after internal discussions. In total, 148 of the 250 families opted to participate (60%).\u003c/p\u003e\u003cp\u003eThe uptake of correct electronic consent in the GMC South pediatric (trio and singleton) cohort was considerably higher than for GMC Karolinska (17.1% and 15.3%, respectively). Almost all these families handled the registration without problem. One participant sent an email to ask if they had managed to register the consent for all three individuals in the trio, but in this case, everything was already in order. In addition, six emails and five phone calls were registered where the legal guardian had general questions about the project, but none of these questions were related specifically to the consenting process on the eConsent platform.\u003c/p\u003e\u003cp\u003eThe uptake in the GMC West cohorts was similar to GMC South for the singleton pediatric and trio cohort. All three sites had higher up-take for the adult cohorts (21,0%, 27,4% and 30,4% for GMC West, GMC South and GMC Karolinska respectively). The GMC West cohort consisted almost exclusively of participants with a negative genetic screening result and hence differed in composition compared to the other sites. The most frequent reason of correspondence and questions raised at this site (19 contacts) was about the offer of study inclusion in it-self (9 contacts) rather than problems with the eConsent platform (4 contacts).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003ePhone calls, e-mails and experiences\u003c/h2\u003e\u003cp\u003e In all clinical cohorts, incoming questions from potential research participants were monitored following the distribution of invitation letters. In the GMC South singleton adult cohort (226 individuals approached), one email and five phone calls were received. In the GMC Karolinska adult cohort (340 individuals approached), 25 phone calls were received, and in the Sahlgrenska cohort (890 individuals approached), 19 emails were received. Most inquiries related to difficulties navigating the eConsent platform or clarifying the reason for inclusion. In one case, a letter had been sent to a deceased individual, underscoring the importance of cross-referencing participant lists with national registries to prevent distress to families. The following challenges were reported:\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003eLogin difficulties\u003c/h2\u003e\u003cp\u003eEighteen individuals had difficulties logging into the platform. Of note, in total nine elderly participants struggled with the eConsent platform and frequently required additional guidance. Two individuals from Stockholm and two from Lund lacked a digital identity verification system such as Bank-ID and could therefore not login to the system.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003eInformation Gaps\u003c/h2\u003e\u003cp\u003eOther questions showed confusion about the purpose of the project (n\u0026thinsp;=\u0026thinsp;15), the need for additional sample collection (n\u0026thinsp;=\u0026thinsp;3) as well as concerns regarding the duration of consent validity but also positive feedback about the possibility to contribute to research and requests for inclusion.\u003c/p\u003e\u003cp\u003eMiscommunication led some participants to incorrectly believe they needed to provide new samples. We received feedback on information clarity and suggestions of allowing preferences for manual (paper-based) or oral consent (i.e., giving consent verbally rather than in writing).\u003c/p\u003e\u003cp\u003eA specific challenge is the inclusion of patient with a considerable time span between the performed analysis and the study inclusion, especially with negative results. They might not remember the performed analysis and hence question the offer to be included.\u003c/p\u003e\u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThis study outlines the experiences of GMS-RD in optimizing participant inclusion in a national multicenter rare disease project through the implementation of an electronic informed consent solution (eConsent) in addition to traditional paper-based consent (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Our findings indicate that the eConsent platform was more effective and practical for adult singleton cases than for pediatric scenarios (both singletons and trios), where additional logistical and communication challenges were encountered.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eIn rare disease research, data sharing is essential for fostering collaboration and accelerating discovery. Because rare diseases affect small and often dispersed populations, research findings are more valuable when shared across institutions and borders. Effective data sharing maximizes the utility of limited patient data, enabling researchers to identify patterns, refine diagnostic criteria, and advance treatment development, ultimately improving healthcare and quality of life for people living with rare diseases. Aggregating genetic and clinical data through shared resources also enables insights that would be difficult to achieve from smaller, isolated studies. However, the collection and sharing of sensitive health data raise important ethical and privacy concerns. It is essential that informed consent processes are robust and transparent, especially when data sharing is involved. Participants in rare disease studies must clearly understand how their data will be used, stored, and shared, with strong safeguards to protect their privacy. They should also be made aware of their right to withdraw from data-sharing initiatives at any time without negative consequences. Consent models that allow participants to manage and update their preferences over time, such as dynamic consent, offer a promising approach to addressing these concerns (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eIn the clinical cohorts, 28% (197/709) of adult singletons provided eConsent, compared to 14% (220/1,535) of pediatric patients and parents (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Although uptake was highest among adult singletons and lowest among pediatric trios, specific barriers differed between groups. Among elderly singleton participants, the most common challenges were login difficulties and low digital literacy, whereas in the pediatric trio scenario, the most frequently raised concern was the requirement for multiple guardian signatures to authorize participation. We predict that, even with an improved system, both of these scenarios will likely continue to benefit from personal guidance and support from trained personnel. Importantly, both the letters and the approved informed consent form were available only in Swedish, which limited inclusion of individuals with other language backgrounds.\u003c/p\u003e\u003cp\u003eThe consent rate for trios was considerably higher in the GMC South (17.1%) and GMC West (14.6) cohorts than in the GMC Karolinska cohort (2.5%), despite similar procedures for contacting the families, and the reason for this may be a subject for future studies. It should also be noted that the rate of acceptance in the national UDN study was much higher than for any of the other subgroups (95/101, 94%), probably due to the fact that the families in the UDN Sweden are highly motivated and typically have been actively searching for a diagnosis for years, often involving numerous contacts and discussions with healthcare providers, and also that patient associations were involved in the recruitment of these families and could provide support.\u003c/p\u003e\u003cp\u003e Improved communication may also enhance participation, especially in complex cases like pediatric studies. Clear and accessible materials that explain the study\u0026rsquo;s purpose, procedures, and benefits in simple terms help both participants and guardians better understand their role. In rare disease research, where medical concepts can be challenging, tailoring language and format to the audience is crucial. Future development of the eConsent platform should therefore focus not only on technical usability but also on improving information clarity.\u003c/p\u003e\u003cp\u003eFurthermore, for an adult population the eConsent platform provides an unprecedented possibility to join advanced rare disease research, where this study indicates that acceptance rates of about 30% may be expected after sending an invitation letter, minimizing the burden on the healthcare system. Additionally, the eConsent enables broad recruitment without geographic and disease group bias. The possibility to manually add paper-based informed consents to the secure eConsent database is an important functionality, since consent queries over API will then be able to cover all participants in a study, regardless of the mode of consent registration.\u003c/p\u003e\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\u003ch2\u003eRecommendations for Improvement\u003c/h2\u003e\u003cp\u003e\u003cem\u003eTo optimize eConsent processes in rare disease research, several strategies should be considered\u003c/em\u003e:\u003c/p\u003e\u003cp\u003e\u003col\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eEnhancing Usability: The complexity of digital consent systems can be a barrier for some participants, especially elderly and others with limited digital literacy and lack of access to digital solutions. Developing step-by-step guides with visuals and simplifying the login process can make the system more user-friendly, ensuring that participants can easily navigate through consent procedures without feeling overwhelmed.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eImproving Communication: Tailoring study materials to ensure clarity about the purpose, procedures, risks, and benefits of the research is crucial. For rare disease studies, simplifying complex medical language and using clear, concise messaging can help participants better understand their role in the research and how it might benefit both them and others with the same condition.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eStrengthening Data Accuracy: Ensuring that participant data is accurate is critical for both research integrity and ethical compliance. Implementing automatic checks for duplicate registrations and deceased participants can reduce errors and ensure that consent remains valid and up to date.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eFacilitating Long-term Data Sharing: The rare disease community relies on long-term data sharing to accelerate research. eConsent systems should enable participants to manage their consent preferences over time, allowing them to update or withdraw consent if their views or circumstances change.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003c/ol\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eIn conclusion, electronic consent systems hold significant promise for improving the informed consent process, particularly in rare disease research. By making the process more accessible, transparent, and user-friendly, eConsent platforms can enhance participant understanding, encourage data sharing, and streamline administrative tasks. The recommendations discussed, i.e. enhancing usability, improving communication, and strengthening data accuracy, are essential steps in ensuring that the consent process is ethical, robust and effective. This study offers valuable insights for optimizing eConsent processes, with implications not only for genomic research in rare diseases but also for broader adoption in clinical and epidemiological studies.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAPA; American Psychological Association\u003c/p\u003e\n\u003cp\u003eAPI; Application Programming Interface\u003c/p\u003e\n\u003cp\u003eBankID; Swedish electronic identification system\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCIOMS; Council for International Organizations of Medical Sciences\u003c/p\u003e\n\u003cp\u003eeConsent; Electronic informed consent\u003c/p\u003e\n\u003cp\u003eERN; European Reference Network\u003c/p\u003e\n\u003cp\u003eERN-ITHACA; European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability\u003c/p\u003e\n\u003cp\u003eFDA CRF 21 Part 11; U.S. Food and Drug Administration Code of Federal Regulations Title 21 Part 11\u003c/p\u003e\n\u003cp\u003eGAMP 5; Good Automated Manufacturing Practice version 5\u003c/p\u003e\n\u003cp\u003eGMC; Genomic Medicine Center\u003c/p\u003e\n\u003cp\u003eGMS; Genomic Medicine Sweden\u003c/p\u003e\n\u003cp\u003eGMS-RD; Genomic Medicine Sweden – Rare Diseases\u003c/p\u003e\n\u003cp\u003eICH E6; International Council for Harmonisation Guideline for Good Clinical Practice E6\u003c/p\u003e\n\u003cp\u003eID; Intellectual Disability\u003c/p\u003e\n\u003cp\u003eNGP; National Genomic data Platform\u003c/p\u003e\n\u003cp\u003eUDN Sweden; Undiagnosed Diseases Network Sweden\u003c/p\u003e\n\u003cp\u003eVUS; Variant of Uncertain Significance\u003c/p\u003e\n\u003cp\u003eWGS; Whole Genome Sequencing\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was conducted within the Genomic Medicine Sweden Rare Disease Working Group and supported by Genomic Medicine Sweden. We gratefully acknowledge the contributions of all participants. Several authors are members of the European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability (ERN-ITHACA) [EU Framework Partnership Agreement ID: 3HP-HP-FPA ERN-01-2016/739516].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe eConsent project was supported by Vinnova (2021-04229). AL and AN were supported by grants from the Swedish Research Council and the Swedish Brain Foundation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data is available in the article files.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor´s contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAL, HE, MJS, SJ, AN, CIM and MF conceptualized the study. HE, JS, MS and CJ designed the electronic consent platform. KE, AA, LL, EE, FT and ME collected data and performed formal analysis. AL, MJS, CIM, AN, LLo and HE drafted the GMS ethical application. KE, AA, HE, AL, and AN wrote the first draft. FT made the figures. All authors read, edited and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJS, MS and CJ are direct or indirect shareholders of MinForskning AB, the legal entity supplying the eConsent system discussed in this article.\u003c/p\u003e\n\u003cp\u003eJS also reports direct or indirect shareholdership in companies Anagram kommunikation AB, Sence Research AB, and Symptoms Europe AB, providing services to companies and authorities in the health sector including Amgen, AstraZeneca, Bayer, Boehringer, Eli Lilly, Gilead, GSK, Göteborg University, Itrim, Ipsen, Janssen, Karolinska Institutet, LIF, Linköping University, Novo Nordisk, Parexel, Pfizer, Region Stockholm, Region Uppsala, Sanofi, STRAMA, Takeda, TLV, Uppsala University, Vifor Pharma, WeMind.\u003c/p\u003e\n\u003cp\u003eThe other authors declare no conflicts of interest.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSupporting information\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAdditional File 1: Document S1.\u0026nbsp;Examples of letter templates sent to patients/families\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eFerreira, C. 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ICH Harmonised Guideline: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice E6(R2). 2016 11 July 2025.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eUS Food and Drug Administration. \u003cem\u003eCode of Federal Regulations Title 21, Part 11\u003c/em\u003e (Electronic Records; Electronic Signatures, 1997).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCommission E. EudraLex - Volume 4 - Good Manufacturing Practice (GMP) Guidelines: Annex 11 Computerised Systems. (2011).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMascalzoni, D. et al. Ten years of dynamic consent in the CHRIS study: informed consent as a dynamic process. \u003cem\u003eEur. J. Hum. Genet.\u003c/em\u003e \u003cb\u003e30\u003c/b\u003e (12), 1391\u0026ndash;1397 (2022).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"electronic informed consent (eConsent), whole-genome sequencing, rare diseases, genomics","lastPublishedDoi":"10.21203/rs.3.rs-7906738/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7906738/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eIn rare disease research, sharing of individual health data is essential for advancing diagnostics and therapies, requiring robust and ethically sound informed consent processes.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eWithin the Genomic Medicine Sweden Rare Diseases (GMS-RD) multicenter study, an electronic informed consent (eConsent) platform was developed to support data sharing, facilitate participation and enable research engagement. Tailored to the complex consent needs of rare disease contexts, the platform was piloted at three Genomic Medicine Centers in Sweden.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eA total of 2,244 individuals were invited in the clinical routine cohort, with an overall eConsent rate of 18.6%. Uptake was highest among adult singletons (27.8%) and lowest in trios (14.3%). In contrast, the Undiagnosed Diseases Network (UDN) Sweden cohort achieved a 94% consent rate, attributed to targeted communication and active patient organization involvement. Key challenges included technical accessibility limitations, digital literacy deficits, comprehension and language barriers, and the burden of multi-step processes, especially for families. Findings underscore the need to improve usability, strengthen communication, and implement flexible consent management over time.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eeConsent can broaden participation in genomic research and promote responsible data sharing. However, in rare diseases contexts, it must be designed with inclusivity, clarity, and adaptability to meet the diverse participant needs.\u003c/p\u003e","manuscriptTitle":"Implementing Electronic Informed Consent in Rare Disease Genomics","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-06 04:17:19","doi":"10.21203/rs.3.rs-7906738/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-11-17T14:36:02+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-15T15:44:03+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"153899351350138285708377545591287938942","date":"2025-11-15T12:02:30+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-14T10:31:23+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"9453770537049828429258907331391745574","date":"2025-10-27T09:11:50+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-10-24T08:56:52+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-24T08:48:09+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-10-24T08:22:58+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-10-22T14:41:09+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-10-22T13:01:15+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a8d16671-51f1-41e6-930b-44c2497d288a","owner":[],"postedDate":"November 6th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":57440379,"name":"Biological sciences/Computational biology and bioinformatics"},{"id":57440380,"name":"Biological sciences/Genetics"},{"id":57440381,"name":"Health sciences/Health care"},{"id":57440382,"name":"Health sciences/Medical research"}],"tags":[],"updatedAt":"2025-12-29T16:03:30+00:00","versionOfRecord":{"articleIdentity":"rs-7906738","link":"https://doi.org/10.1038/s41598-025-32740-1","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2025-12-23 15:58:28","publishedOnDateReadable":"December 23rd, 2025"},"versionCreatedAt":"2025-11-06 04:17:19","video":"","vorDoi":"10.1038/s41598-025-32740-1","vorDoiUrl":"https://doi.org/10.1038/s41598-025-32740-1","workflowStages":[]},"version":"v1","identity":"rs-7906738","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7906738","identity":"rs-7906738","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}