Abstract
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. ARTICLE HIGHLIGHTS: We report five new cases of neonatal or early childhood-onset diabetes caused by biallelic pathogenic variants in IL2RA. Autoimmune diabetes was the presenting feature in most individuals and occurs in 64% of all reported cases of immunodeficiency 41. Patients typically presented in infancy with diabetic ketoacidosis, low C-peptide, and GAD antibody positivity, highlighting an autoimmune etiology. The diabetes phenotype was consistent across cases but not linked to variant type or location. IL2RA should be included in genetic testing for neonatal diabetes and considered in children with diabetes plus immune dysregulation.