Clinical utility of a type 1 diabetes genetic risk score measured as part of MODY genetic testing

<jats:p>&lt;p dir="ltr"&gt;Objective&lt;/p&gt;&lt;p dir="ltr"&gt;To evaluate the clinical utility of incorporating a type 1 diabetes genetic risk score (T1DGRS) into monogenic diabetes gene panel testing for individuals referred with suspected maturity-onset diabetes of the young (MODY) from routine clinical practice.&lt;/p&gt;&lt;p dir="ltr"&gt;Research Design and Methods&lt;/p&gt;&lt;p dir="ltr"&gt;We studied 1,129 insulin-treated individuals referred for MODY genetic testing. All underwent gene panel testing including 10 variants to calculate T1DGRS. We compared T1DGRS distributions with reference populations to estimate the T1D prevalence within referrals. We defined age-specific T1DGRS thresholds to identify probable T1D (positive predictive value ≥80%) and applied them in genetically unsolved individuals to assess its utility as a pre-genetic testing triage tool.&lt;/p&gt;&lt;p dir="ltr"&gt;Results&lt;/p&gt;&lt;p dir="ltr"&gt;T1DGRS in MODY referrals was intermediate between T1D and non-T1D reference populations, consistent with an estimated 20% (95% CI 14.9–25.2) T1D in this real-world setting. After genetic testing, no excess T1DGRS was observed in solved-MODY whereas unsolved-MODY cases showed enrichment consistent with 26.0% T1D, highest in children (76.2%) and lowest in adults (16.8%). Age-specific T1DGRS thresholds identified 16.1% (95% CI 13.8–18.5%) of genetically unsolved as probable T1D. As a pre-testing tool, T1DGRS showed limited discrimination overall (AUC 0.60), but performed well in children under 10years (AUC 0.83), where &gt;50% of tests could be avoided without missing MODY.&lt;/p&gt;&lt;p&gt;&lt;br&gt;&lt;/p&gt;&lt;p dir="ltr"&gt;Conclusions&lt;/p&gt;&lt;p dir="ltr"&gt;Incorporating a T1DGRS into routine MODY gene panel referrals is feasible and clinically valuable. This approach broadens genomic diagnostics beyond monogenic disease by identifying T1D in genetically unsolved cases. Pre-genetic testing utility is age dependent and may reduce unnecessary testing in paediatric patients.&lt;/p&gt;&lt;p&gt;&lt;br&gt;&lt;/p&gt;</jats:p>