T1D GRS: a tool for identifying children and adolescents with monogenic diabetes

The aim of this study was to determine the effectiveness of the Type 1 Diabetes Genetic Risk Score (T1D GRS) for the prioritisation of children with newly diagnosed hyperglycaemia for genetic testing of monogenic diabetes. MethodsA cohort of 808 children and adolescents with newly diagnosed hyperglycaemia were collected. All underwent standard clinical follow-up and genetic testing based on the knowledge and means accessible at the time. In this cohort and in 189 control subjects (165 monogenic diabetes patients and 24 healthy individuals), we assessed the T1D GRS2 and 10 SNP GRS scores. We assessed the T1D GRS2 cut-off in our cohort and investigated its utility in addition to negative autoantibody status for the prioritisation of cases for genetic testing for monogenic diabetes. Genetic testing included Sanger sequencing, panel sequencing and MLPA. ResultsApplying T1D GRS2 in addition to negative autoantibodies on the newly diagnosed hyperglycaemia cohort substantially decreased the number of unnecessarily tested cases. The pick-up rate was increased three-fold, while the sensitivity of the prioritisation decreased only slightly from 77.8% to 72.2% when compared with autoantibodies alone. The majority of monogenic diabetes cases that escaped this prioritisation for genetic testing had low levels of a single autoantibody and were most probably false positives in the autoantibody testing. The monogenic cases that would not be prioritised using GRS2 and autoantibodies were diagnosed based on clinical phenotype. On the other hand, two monogenic diabetes cases with HNF1B-MODY were not originally diagnosed and were identified only thanks to their low GRS2 value. ConclusionsUsing T1D GRS in combination with autoantibody testing is effective in decreasing the number of unnecessarily genetically tested cases. This approach, used in addition to the standard clinical evaluation, can be a valuable tool in the early selection of suitable candidates for molecular testing for monogenic diabetes. Research in ContextO_LIWhat is already known about this subject? O_LIDiagnosing monogenic diabetes is important, because gene-tailored treatment is available. In children and adolescents, monogenic diabetes has to be differentiated mostly from type 1 diabetes. C_LIO_LIIndividuals with type 1 diabetes and monogenic diabetes have a different genetic risk for type 1 diabetes. C_LIO_LIThe genetic risk score for type 1 diabetes (T1D GRS) can be computed from disease-associated polymorphisms. C_LI C_LIO_LIWhat is the key question? O_LIWhat is the utility of T1D GRS as a tool for the prioritisation of cases for genetic testing of monogenic diabetes? C_LI C_LIO_LIWhat are the new findings? O_LIMore than half of the children with diabetes with negative autoantibodies (type 2 diabetes excluded) and T1D GRS2 below a cut-off was confirmed genetically as having monogenic diabetes. C_LIO_LIThe combination of T1D GRS2 + negative autoantibodies increased the pick-up rate by genetic testing three-fold compared with negative autoantibodies alone, with only small decrease in sensitivity of the prioritisation. C_LIO_LILow T1D GRS can draw interest to cases that would otherwise not be suspected of having monogenic diabetes. C_LI C_LIO_LIHow might this affect clinical practice in the foreseeable future? O_LIChildren and adolescents with confirmed diabetes and normal BMI, negative autoantibodies and low T1D GRS can be prioritised for genetic testing soon after diabetes diagnosis. C_LI C_LI