Genotype-phenotype correlations in autoimmune and autoinflammatory diseases: An NGS-based immunogenetic cohort study

ObjectiveAutoimmune and autoinflammatory diseases (AIDs) represent a heterogeneous group of immune-mediated disorders characterized by dysregulated innate and adaptive immune responses. This study aimed to investigate the immunogenetic background of AIDS by assessing the distribution of genetic variants identified by a targeted next-generation sequencing (NGS) panel and elucidating genotype-phenotype correlations in the context of systemic immune dysregulation.Materials and methodsA targeted NGS panel encompassing 19 genes involved in immune regulation, inflammatory signaling pathways, and immune tolerance was utilized to evaluate a cohort of 110 patients presenting with clinical manifestations suggestive of autoinflammatory disease. Clinical severity was quantitatively assessed using longitudinal serum C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) measurements across acute and baseline periods. Detected variants were classified according to the American College of Medical Genetics and Genomics (ACMG) guidelines and correlated with patient clinical phenotypes and established immunogenetic literature.ResultsA total of 55 genetic variants were identified across 41 patients. Alterations predominantly clustered in MEFV (38.2%), HFE (29.1%), and SLC29A3 (21.8%), followed by NOD2, MVK, CARD14, IL10RB, and PLCG2 (1.8% each). According to ACMG criteria, 61.8% of the variants were pathogenic, 25.5% were likely pathogenic, and 12.7% were VUS. Genotype-phenotype correlation analyses successfully linked rare variants (including PLCG2, IL10RB, and CARD14) and oligogenic combinations to specific laboratory profiles. These findings revealed unexpected penetrance, variable expressivity, and distinct biomarker disassociations, most notably highlighted by isolated ESR elevations reaching 91 mm/h.ConclusionOur findings underscore the immunogenetic heterogeneity of autoinflammatory diseases and substantiate the diagnostic value of NGS-based profiling in deciphering complex genotype-phenotype associations. The integration of specific quantitative biomarkers and downstream mechanisms highlights how non-HLA regulatory variants reshape the chronic inflammatory immune microenvironment, lowering the threshold for inflammasome activation and systemic autoimmunity.