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

Methods

A 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.

Results

Applying 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.

Conclusions

Using 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 Context

• What is already known about this subject?

  • Diagnosing 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.

  • Individuals with type 1 diabetes and monogenic diabetes have a different genetic risk for type 1 diabetes.

  • The genetic risk score for type 1 diabetes (T1D GRS) can be computed from disease-associated polymorphisms.

• What is the key question?

  • What is the utility of T1D GRS as a tool for the prioritisation of cases for genetic testing of monogenic diabetes?

• What are the new findings?

  • More 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.

  • The 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.

  • Low T1D GRS can draw interest to cases that would otherwise not be suspected of having monogenic diabetes.

• How might this affect clinical practice in the foreseeable future?

  • Children and adolescents with confirmed diabetes and normal BMI, negative autoantibodies and low T1D GRS can be prioritised for genetic testing soon after diabetes diagnosis.