Background. Accurately classifying pediatric diabetes can be challenging for providers, and misclassification can result in suboptimal care. In recent years, type 1 diabetes (T1D) polygenic scores, which quantify one's genetic risk for T1D based on T1D risk allele burden, have been developed with good discriminating capacity between T1D and not-T1D. These tools have the potential to improve significantly diagnostic provider accuracy if used in clinic. Methods. We applied T1D polygenic scores to a group of pediatric patients (n=1846) with genetic data available in the Boston Children's Hospital PrecisionLink Biobank, including 96 individuals diagnosed with T1D. Results. Patients with a clinical diagnosis of T1D had higher T1D polygenic scores compared to controls (Wilcoxon rank-sum P<0.0001). Sixty-nine of the 74 individuals with diabetes and a T1D polygenic score exceeding an externally validated cutoff for distinguishing T1D from non-T1D were confirmed to have T1D. There were multiple cases where T1D polygenic scores would have clinical utility. An elevated T1D polygenic score suggested T1D in a pancreatic autoantibody (PAA)- negative individual with negative MODY genetic testing and a phenotype matching T1D. A low T1D polygenic score accurately indicated atypical diabetes in an individual found to have HNF1B-MODY. One individual had positive PAA, but the provider noted that the patient may not have classic T1D, as later suggested by a low T1D polygenic score. Conclusion. T1D polygenic scores already have clinical utility to aid in the accurate diagnosis of pediatric diabetes. Efforts are now needed to advance their use in clinical practice.

MSU and JCF have received grant support from Novo Nordisk (unrelated to this manuscript). MSU has received royalties for contributions to UptoDate, Inc. JCF has participated on an advisory board for Alveus Therapeutics.

This work was supported in part by Cooperative Agreement from the National Center for Advancing Translational Sciences/NIH and the PrecisionLink Project at Boston Children's Hospital [U01TR002623]. RJK is supported by NIH NIDDK [T32DK007699-41]. AJD is supported by NIH NIDDK [F32 DK137487 and K23 DK140643]. MSU is supported by the Doris Duke Foundation [Clinical Scientist Development Award 2022063].

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

IRB of Boston Children's Hospital gave ethical approval for this work (protocol numbers - P00000159 and P00044203).

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The data that support the findings of this study are available from Boston Children's Hospital PrecisionLink Biobank. Restrictions apply to the availability of these data, which were used under license for this study. Data are available from the author(s) with the permission of Boston Children's Hospital PrecisionLink Biobank.