Whole-Exome Sequencing: Discovering Genetic Causes of Granulomatous Mastitis

Granulomatous mastitis (GM) is a rare, benign, but chronic and recurrent inflammatory breast disease that significantly impacts physical and psychological well-being. It often presents symptoms such as pain, swelling, and discharge, leading to diagnostic confusion with malignancy. The etiology of GM remains unclear, though autoimmune and multifactorial components are suspected. This study aimed to explore the genetic underpinnings of GM using whole-exome sequencing (WES) on 22 GM patients and 52 healthy controls to identify single nucleotide variants (SNVs) and copy number variations (CNVs) potentially linked to the disease. WES analysis revealed novel SNVs in six genes: BRCA2 (rs169547), CFTR (rs4727853), NCF1 (rs10614), PTPN22 (rs2476601), HLA-DRB1 (seven variants), and C3 (rs406514). Notably, most of these variants are associated with immune regulation and inflammatory pathways, supporting the hypothesis that GM is an autoimmune disease. However, all identified variants were classified as benign according to the American College of Medical Genetics and Genomics (ACMG) guidelines, necessitating further investigation into their potential functional effects. Despite conducting CNV analysis, no significant variations were identified. This study represents a foundational step in linking genetic predisposition to GM and highlights the need for integrating genetic, clinical, and functional data to better understand GM's pathophysiology. Future research should focus on larger cohorts, functional studies, and exploring multifactorial contributors to GM, including hormonal and environmental factors.