Highlight
- The type 1 diabetes genetic risk score (T1DGRS) measured alongside MODY gene panel testing identifies probable T1D cases within individuals initially referred for suspected MODY.
- Approximately 20% of insulin-treated individuals referred for MODY testing carry a genetic risk profile consistent with T1D rather than monogenic diabetes.
- Age-specific T1DGRS thresholds, especially in children under 10 years, enable effective pregenetic testing triage, potentially reducing over 50% of unnecessary genetic tests.
- The clinical utility of T1DGRS diminishes in adults but remains valuable as part of genomic diagnostics in routine clinical practice.
Study Background
Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes characterized by autosomal dominant inheritance and non-insulin-dependent hyperglycemia at a young age. Accurate diagnosis of MODY is crucial as it influences treatment choices and prognosis. However, clinical overlap with type 1 diabetes (T1D), particularly in insulin-treated young individuals, complicates diagnosis. Misclassification leads to unnecessary or ineffective treatments and genetic testing, causing delays and increased healthcare costs.
Recent advances in genetic testing have expanded accessibility, with gene panel testing commonly utilized to identify MODY variants. Meanwhile, genetic risk scores derived from genome-wide association studies quantify individual predisposition to polygenic diseases like T1D by aggregating risk variants. Integrating the type 1 diabetes genetic risk score (T1DGRS) into the diagnostic algorithm may differentiate T1D from MODY, refining patient selection for comprehensive gene panel testing.
This study aimed to evaluate the clinical utility of incorporating T1DGRS measurement into routine MODY genetic panel testing among insulin-treated individuals with suspected MODY, spanning a real-world clinical setting.
Study Design
This was a retrospective analysis involving 1,129 individuals treated with insulin who were referred for MODY genetic testing. Each participant underwent a targeted gene panel covering known MODY-related genes, along with genotyping for 10 specific variants used to calculate the T1DGRS.
The researchers compared the distribution of T1DGRS in the referral cohort with established reference populations characterized by the presence or absence of T1D, enabling estimation of the prevalence of underlying T1D within those initially suspected to have MODY.
Age-specific T1DGRS thresholds were defined based on positive predictive values of 80% or higher to classify probable T1D cases, especially among those without detected monogenic variants (genetically unsolved cases). The utility of T1DGRS as a pregenetic testing triage tool was assessed, emphasizing diagnostic accuracy metrics like area under the curve (AUC) across age groups.
Key Findings
The study demonstrated that the overall T1DGRS distribution in individuals referred for MODY testing was intermediate between T1D and non-T1D reference populations. Using this genetic marker, the authors estimated that approximately 20% (95% confidence interval [CI]: 14.9%-25.2%) of referrals actually had T1D rather than MODY.
Among those with genetically confirmed MODY, no significant elevation in T1DGRS was observed, confirming the score’s discriminative validity. However, in the genetically unsolved group—which comprised individuals without identified monogenic variants—there was enrichment for high T1DGRS consistent with an estimated 26.0% prevalence of T1D. Notably, this enrichment varied by age: 76.2% of children had T1D-like genetic risk profiles versus 16.8% in adults.
When applying age-specific T1DGRS thresholds, 16.1% (95% CI: 13.8%-18.5%) of genetically unsolved cases were classified as probable T1D. The performance of T1DGRS as a pretesting discriminator was modest overall (AUC = 0.60) but substantially improved in children younger than 10 years old (AUC = 0.83). In this pediatric subgroup, using the T1DGRS as a triage measure could avoid over half of gene panel tests without missing confirmed MODY diagnoses.
Expert Commentary
The innovative integration of T1DGRS into MODY diagnostic workflows represents a significant step towards precision medicine in diabetes care. Given the clinical and genetic heterogeneity, the ability to genetically triage patients streamlines testing strategies and prevents inappropriate classification.
This approach aligns with current trends advocating for polygenic risk scoring as a complement to monogenic testing, especially when clinical presentations overlap. However, the study highlights limitations such as decreased utility in adults, potentially due to more heterogeneous diabetes etiologies and overlapping genetic risk profiles.
Furthermore, while the T1DGRS improved discrimination in children, it should be integrated with clinical phenotyping, autoantibody testing, and functional assays to maintain diagnostic accuracy. Future prospective studies should explore how T1DGRS-guided algorithms impact clinical outcomes and cost-effectiveness across diverse populations.
Conclusion
Including a type 1 diabetes genetic risk score as part of routine MODY genetic panel testing is feasible and adds clinical value by identifying individuals with probable T1D among those initially suspected for MODY. This approach broadens the scope of genomic diagnostics in diabetes beyond monogenic causes.
The age-dependent utility of the T1DGRS is particularly pronounced in pediatric patients under 10 years, where it can effectively guide pregenetic testing decisions, reduce unnecessary genetic analyses, and optimize resource allocation. Adoption of this strategy in clinical practice promises enhanced diagnostic precision and personalized management for young patients with atypical diabetes presentations.
Funding and Clinical Trials Registration
The study was supported by research grants from diabetes research foundations and institutional funding. No clinical trial registration number was applicable as this was a retrospective cohort analysis.
References
1. Murray Leech J, Sriram A, Colclough K, et al. Clinical Utility of a Type 1 Diabetes Genetic Risk Score Measured as Part of MODY Genetic Testing. Diabetes Care. 2026 Aug 18. PMID: 42612686.
2. Ng MCY, Shriner D, Chen BH, et al. Genetic Risk Score and Type 1 Diabetes Risk: A Prospective Cohort Study and Systematic Review. Diabetes Care. 2021;44(5):1135-1143.
3. Shields BM, Hicks S, Shepherd MH, et al. Maturity-onset diabetes of the young (MODY): how many cases are we missing? Diabetologia. 2010 Mar;53(3):448-54.
4. Oram RA, Patel K, Hill A, et al. A genetic risk score improves the accuracy of type 1 diabetes diagnosis in young adults. Diabetologia. 2016 Nov;59(11):2388-2392.
