Biallelic Pathogenic Variants in IL2RA Cause NeonatalOnset Monogenic Autoimmune Diabetes

Autoimmune diabetes presenting in infancy or with additional autoimmune disorders can be the result of highly penetrant variants in key immune homeostasis genes. An example of this is observed with biallelic pathogenic variants in IL2RA (CD25), which causes immunodeficiency 41 (IMD41). IL2RA encodes the α-chain of the interleukin-2 receptor, which helps regulate the growth and activity of T cells. The diabetes phenotype in IMD41 has not been systematically described. We sequenced IL2RA in 290 individuals with diabetes diagnosed <6 months and in 64 individuals diagnosed <10 years who had additional autoimmunity. We also reviewed all previously reported IMD41 cases. We identified five new unrelated individuals with biallelic pathogenic IL2RA variants. Four presented with diabetes in the first month of life with very low/absent C-peptide, and all were GAD antibody–positive. Of 17 previously reported cases, 9 had diabetes, yielding a total of 14 of 22 (64%) with early-onset diabetes. No relationship between variant location/type and diabetes development was observed. Autoimmune diabetes is therefore a common and early feature of IMD41. IL2RA should be included in genetic testing panels for neonatal and monogenic autoimmune diabetes. These findings highlight the important role of IL2RA in immune tolerance and β-cell protection.