Whole exome sequencing for identifying rare genetic variants related to idiopathic granulomatous mastitis.

backgroundsTo reveal rare genetic factors that cause susceptibility to idiopathic granulomatous mastitis (IGM).

methodsWhole exome sequencing (WES) was performed in 30 patients with histopathologically diagnosed idiopathic granulomatous mastitis. WES analysis mainly focused on 317 genes linked to autoimmunity, autoinflammation, and immune dysregulation.

resultsA total of 141 variants were detected in 100 genes. The 40% (12/30) of patients had pathogenic or likely pathogenic variants. The pathogenic/likely pathogenic variants were 10.6% of all variants, and the rest of the variants (89.4%) were classified as VUS. Most of the variants were heterozygous (97.2%) only 4 variants (2.8%) were homozygous. Pathogenic/likely pathogenic variants were detected in FCGR1A, MPO, F5, IL36RN, CLUH, C9, NAXD, PROC, THRB, IFI30, COQ2, RNASEH2B, and SLC29A3 genes. The highest number of variants were detected in UNC13D, VPS13B, EPHB4, NLRP12, TCIRG1, TOM1, IRF9, and PIK3CG.

conclusionUp to date, our study is the first whole exome sequencing study of IGM patients which aims to find out the rare variants related to etiopathogenesis of the disease. We identified 141 single nucleotide variants of 100 genes, and most of these variants were found in innate immunity-related genes. The current study provides clues for identifying the etiologic factors and designing further functional studies in this rare disease with unknown etiopathogenesis. Key Points •Autoimmunity/autoinflammation-related genetic factors are blamed for etiopathogenesis of idiopathic granulomatous mastitis (IGM). •Mutation in genes related to innate immunity, especially in macrophage functions and phagocytosis, may lead to IGM susceptibility. •Potential candidate genes for genetic susceptibility to IGM may shed light for new treatment options.