European Autism GEnomics Registry (EAGER): Protocol for a multicentre cohort study and registry

Introduction Autism is a common neurodevelopmental condition with a complex genetic aetiology that includes contributions from monogenic and polygenic factors. Many autistic people have unmet healthcare needs that could be served by genomics-informed research and clinical trials. The primary aim of the European Autism GEnomics Registry (EAGER) is to establish a registry of participants with a diagnosis of autism or an associated rare genetic condition who have undergone whole-genome sequencing. The registry can facilitate recruitment for future clinical trials and research studies, based on genetic, clinical, and phenotypic profiles, as well as participant preferences. The secondary aim of EAGER is to investigate the association between mental and physical health characteristics and participants’ genetic profiles. Methods and analysis EAGER is a European multisite cohort study and registry and is part of the AIMS-2-TRIALS consortium. EAGER was developed with input from the AIMS-2-TRIALS Autism Representatives and representatives from the rare genetic conditions community. 1,500 participants with a diagnosis of autism or an associated rare genetic condition will be recruited at 13 sites across 8 countries. Participants will give a blood or saliva sample for whole-genome sequencing and answer a series of online questionnaires. Participants may also consent for the study to access pre-existing clinical data. Participants will be added to the EAGER registry. Data will be shared via the Autism Sharing Initiative, a new international collaboration aiming to create a federated system for autism data sharing. Ethics and dissemination EAGER has received full ethical approval from ethics committees in the UK (REC 23/SC/0022), Germany (S-375/2023), Portugal (CE-085/2023) and Spain (HCB/2023/0038, PIC-164-22). Approvals are in the process of being obtained from committees in Italy, Sweden, Ireland, and France. Findings will be disseminated via scientific publications and conferences, but also beyond to participants and the wider community (e.g., the AIMS-2-TRIALS website, stakeholder meetings, newsletters). STRENGHTS AND LIMITATIONS OF THIS STUDY ### Competing Interest Statement In the past 3 years TC has served as a paid consultant to F. Hoffmann-La Roche Ltd. and Servier and has received royalties from Sage Publications and Guilford Publications. DM has received funding for a PhD studentship from Compass, and for consulting from Jaguar Therapeutics and Hoffman Le Roche. GM receives funding for an investigator-initiated study from Compass Pathways; no financial or other conflict of interest with the present study. SB discloses that he has in the last 3 years acted as an author, consultant, or lecturer for Medice, Roche, and Linus Biotechnology. SB receives royalties for textbooks and diagnostic tools from Hogrefe, UTB, Ernst Reinhardt, Kohlhammer, and Liber, and is a partner at NeuroSupportSolutions International AB. CC is a full-time employee of Genentech and owns stocks or RSUs in Roche Holdings, Ltd. MA is the UK chief investigator for a trial sponsored by Roche (a phase II, randomised, double-blind, placebo-controlled, parallel group study to evaluate the safety, efficacy, and pharmacodynamics of 52 weeks of treatment with basmasanil in participants aged 2 to 14 years old with dup15q syndrome followed by a 2-year optional open-label extension). LB served on an advisory board to Kingdom therapeutics in 2022. ### Funding Statement This work has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 777394 for the project AIMS-2-TRIALS. This Joint Undertaking receives support from the European Union Horizon 2020 research and innovation programme and EFPIA and AUTISM SPEAKS, Autistica, SFARI and from Horizon Europe \[grant agreement no. 101057385] and from Horizon Europe [grant agreement no. 101057385] and from UK Research and Innovation (UKRI) under the UK government's Horizon Europe funding guarantee [grant no.10039383\] (R2D2-MH). The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. Any views expressed are those of the author(s) and not necessarily those of the funders. In addition, SB receives funding from Swedish Research Council and Region Stockholm. CT receives funding from Epilepsy Research UK, Autistica, the Baily Thomas Charitable Fund and the Tuberous Sclerosis Association. LG receives funding from Horizon Europe: Risk and Resilience in Developmental Diversity and Mental Health (R2D2-MH). CPS receives funding from Foundation of Prader-Willi Research, European Joint Program for Rare Diseases, Illumina, German Children's Cancer Foundation, and the German Ministry of Education and Research. RB, RM, SC, BM receive funding from the Italian Ministry of Health (Ricerca Corrente and 5x1000 to IRCCS Fondazione Stella Maris). Genomic data utilised here will be sequenced in part/whole through the financial contribution of F Hoffmann La-Roche. This paper represents independent research part-funded by the NIHR Maudsley Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics and dissemination: EAGER has received full ethical approval from ethics committees in the UK (REC 23/SC/0022), Germany (S-375/2023), Portugal (CE-085/2023) and Spain (HCB/2023/0038, PIC-164-22). Approvals are in the process of being obtained from committees in Italy, Sweden, Ireland, and France. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Not applicable as this is a protocol paper