Novel Gene Mutations Regulating Immune Responses in Autoimmune Polyglandular Syndrome With an Atypical Course

CONTEXT: Autoimmune polyglandular syndrome (APS) is a cluster of endocrine disorders arising from immune dysregulation, often combined with damage to nonendocrine organs. There are 2 types of APS: type 1 and type 2 (APS-1 and APS-2, respectively). In clinical practice, an atypical course of APS is often observed. OBJECTIVE: This work aims to find a novel genetic predictor of APS. METHODS: We performed exome sequencing in 2 patients with an atypical clinical APS picture and members of their families. Patient A presented with a manifestation of APS-2 in early childhood and patient B with a late manifestation of the main components of APS-1. RESULTS: In patient B, we identified inherited compound mutations as a novel combination of the c.769C > T and c.821delG alleles of AIRE and genetic variation in the CIITA gene. No homozygous or compound mutations in AIRE were found in patient A, but we did reveal mutations in genes encoding regulatory proteins of innate and acquired immunity in this patient. CONCLUSION: Our data revealed novel combination of mutations in the AIRE gene in atypical APS and imply that mutations in immune-related genes may modify the clinical manifestation of APS in AIRE-mutation carriers and contribute to the development of autoimmune pathology in non-AIRE carriers with atypical APS.