A Systematic Review of the use of Precision Diagnostics in Monogenic Diabetes

Monogenic forms of diabetes present opportunities for precision medicine as identification of the underlying genetic cause has implications for treatment and prognosis. However, genetic testing remains inconsistent across countries and health providers, often resulting in both missed diagnosis and misclassification of diabetes type. One of the barriers to deploying genetic testing is uncertainty over whom to test as the clinical features for monogenic diabetes overlap with those for both type 1 and type 2 diabetes. In this review, we perform a systematic evaluation of the evidence for the clinical and biochemical criteria used to guide selection of individuals with diabetes for genetic testing and review the evidence for the optimal methods for variant detection in genes involved in monogenic diabetes. In parallel we revisit the current clinical guidelines for genetic testing for monogenic diabetes and provide expert opinion on the interpretation and reporting of genetic tests. We provide a series of recommendations for the field informed by our systematic review, synthesizing evidence, and expert opinion. Finally, we identify major challenges for the field and highlight areas for future research and investment to support wider implementation of precision diagnostics for monogenic diabetes. Plan Language Summary Since monogenic diabetes misclassification can occur and lead to missed opportunities for optimal management, and several diagnostic technologies are available, we systematically review the yield of monogenic diabetes using different criteria to select people with diabetes for genetic testing and the technologies used. ### Competing Interest Statement RM has received honoraria for consulting activities for Lilly and Boeringer Ingelheim. SM has Investigator initiated funding from DexCom and serves on the Board of Trustees for the Diabetes Research & Wellness Foundation (UK). LKB received honoraria for consulting activities for Novo Nordisk, Bayer, Lilly, Xeris, and Sanofi which are unrelated to this present work. ALG spouse holds stock options in Roche and is an employee of Genentech. ### Funding Statement P.R.N. was supported by grants from the European Research Council (AdG #293574), Stiftelsen Trond Mohn Foundation (Mohn Center of Diabetes Precision Medicine), the University of Bergen, Haukeland University Hospital, the Research Council of Norway (FRIPRO grant #240413), the Western Norway Regional Health Authority (Strategic Fund Personalised Medicine for Children and Adults), and the Novo Nordisk Foundation (grant #54741). J.M.I. was supported by a grant from the National Institute of Health (K08DK133676). S.E.F. is supported by a Wellcome Trust Senior Research Fellowship (Grant Number 223187/Z/21/Z). ALG is a Wellcome Trust Senior Fellow (200837/Z/16/Z) and is also supported by NIDDK (UM-1DK126185). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes 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 No original data is present in this manuscript it is a systematic review.