ESPE Abstracts (2019) 92 S8.2

Monogenic Forms of Autoimmune Diabetes: Challenges and Opportunities

Sarah Flanagan


University of Exeter Medical School, Exeter, United Kingdom


Monogenic autoimmune diabetes results from a single highly penetrant mutation that causes autoimmunity leading to destruction of the beta-cells. Identifying monogenic autoimmune diabetes can be a challenge; early-onset type 1 diabetes (T1D) can cluster with additional autoimmune diseases due to shared polygenic risk, particularly from the HLA DR3 and DR4 alleles, and islet and other organ specific autoantibodies are present in patients with both monogenic and polygenic aetiologies. Gene discovery approaches based on phenotype and family structure have had some success in monogenic autoimmune diabetes, with 11 genes described to date. Integration of genetic risk scores shows promise to improve the yield of gene discovery by removing more common clustering of T1D and additional autoimmunity.

Identifying novel causes of monogenic autoimmune diabetes provides insights into pathways of autoimmunity which can improve understanding of more common polygenic autoimmune disease. For patients, a diagnosis of monogenic autoimmune diabetes is important as it can have treatment implications, with specific therapies for some subtypes (e.g. Abatacept in LRBA deficiency) and optimal immunosuppression in others (e.g. Sirolimus in IPEX syndrome). Furthermore, a genetic diagnosis is desirable before undertaking stem cell transplantation which can be curative but carries high risk. Families can also benefit from knowledge of recurrence risk and the availability of prenatal testing.

In 2014 we identified gain of function STAT3 mutations as a cause of autoimmune diabetes with onset in the neonatal period. In 2017 we reported that recessively inherited LRBA mutations can cause autoimmune neonatal diabetes and more recently demonstrated that trisomy 21 can cause diabetes before 6 months that is autoimmune but not HLA associated. This suggests that there is a unique subset of diabetes caused by trisomy 21 amongst the more common co-incidence of T1D and Down syndrome.

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