Intestinal somatic mutations in inflammatory bowel disease patients are enriched in very early onset IBD and primary immunodeficiency genes

The genetic predisposition of Inflammatory bowel disease (IBD) in the germline is well-established, while the potential role of somatic mutations in IBD remains underexplored. We aim to identify somatic mutations in intestinal mucosa and study their potential role in IBD pathogenesis. We identified somatic mutations using 538 intestinal biopsies and 268 blood samples from 268 IBD patients and 51 intestinal biopsies from 19 non-IBD controls. Mutations were called from RNA-seq data and whole exome sequencing data using Mutect2 software. Pathogenicity of mutations was predicted using the Variant Interpretation Pipeline. Mutation frequency and patterns were compared between IBD and controls, and within IBD-subgroups, considering both inflammation status and tissue of origin. IBD-affected tissue exhibited a significantly higher burden of somatic mutations compared to controls (p=0.02), with a striking enrichment for predicted likely pathogenic or pathogenic (pLP-P) mutations (p=2.07e-09). Notably, within IBD biopsies, pLP-P mutations were enriched in very early onset-IBD (VEO-IBD) genes (p[≤]2.2e-16) and primary immune deficiency (PID) genes (p[≤]2.2e-16), showing a 5.5-fold increase compared to non-IBD. Inflamed tissue showed an increase in mutations in PID and IBD-GWAS associated genes. Additionally, we identified pathogenic mutations in many IBD genes, such as the stop-gained mutation (c.517C>T) in HPS1, and many pLP-P mutations across the JAK-STAT pathway. Our analysis reveals widespread accumulation of pLP-P somatic mutations in IBD-affected tissue compared to non-IBD controls, with significant enrichment in genes that cause monogenic VEO-IBD. These findings suggest that somatic mutations can contribute to the initiation and perpetuation of inflammation in IBD.