Monogenic Diabetes: Next Generation Diagnosis, Treatment and Complications

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ABSTRACT Diabetes mellitus affects close to 30 million people in the United States, causing significant morbidity and mortality and economic burden to the healthcare system. A critical aspect of addressing this burden is optimizing glycemic outcomes through accurate diabetes classification and management. This concept is most precisely applied to monogenic diabetes, where genetic diagnosis directs gene-targeted therapy resulting in improved clinical outcomes and will inform the implementation of similar future approaches to type 1 and type 2 diabetes. Monogenic diabetes remains the best example of personalized medicine in diabetes, yet it is usually misdiagnosed and therefore inappropriately treated. Over the last four years, enrollment in the University of Chicago Monogenic Diabetes Registry has surged to over 1000 with causal genetic variants, including 344 individuals whose diagnosis was made possible only through our research funding in the last four years. We are the largest registry of monogenic diabetes in the Western Hemisphere and we have detailed the clinical and cost-effectiveness of diabetes precision medicine in over 30 publications. Our overarching goals continue to be: to accelerate efficient diagnosis, to advance progress in understanding, and to inform clinical guidelines in the management of monogenic forms of diabetes, through cumulative longitudinal follow-up and pragmatic cohort studies from our Registry. We propose to bolster our innovative efforts by establishing a genetic testing algorithm that accurately identifies appropriate individuals for single gene Sanger sequencing and prioritizes massively parallel sequencing for those who would otherwise require iterative gene screening. Additionally, we will adapt the Registry platform to improve engagement via a participant-facing portal and ensure sustainability through adaptive change garnered from Registry insights. Finally, we will engage current Registry participants to identify barriers to sharing positive monogenic diabetes results with relatives, which will guide the development of a structured approach to cascade genetic testing, as well as cost-effectiveness analyses, to improve enrollment of family members for genetic testing. These projects will have a broad direct impact by improving healthcare provider and commercial genetic testing laboratory practices in the cost-effective diagnosis of monogenic diabetes. We aim to decrease participant burden and improve data quality and completeness while advancing the evaluation and surveillance infrastructure of the Registry to allow accurate conclusions about the benefits of targeted gene therapy in monogenic diabetes. Furthermore, we aim to develop improved strategies to extend the benefits of precision medicine through cascade testing. The Monogenic Diabetes Registry will continue to play a prominent role in bridging evidence gaps in monogenic diabetes to ultimately improve patient outcomes and be a model for precision diagnosis and treatment for all forms of diabetes.