Genetic Variants in Early-Onset Inflammatory Bowel Disease: Monogenic Causes and Clinical Implications

<b>Background/Objectives:</b> This study aims to identify genetic variants associated with early-onset inflammatory bowel disease (IBD) and to improve diagnostic and therapeutic approaches. In selected monogenic IBD cases, treatment included colchicine, interleukin-1 inhibitors, and hematopoietic stem cell transplantation. <b>Methods:</b> This study included patients with early-onset IBD, defined as IBD diagnosed before the age of 10, who were under follow-up at the Department of Pediatric Gastroenterology, Hacettepe University, and agreed to participate between December 2018 and April 2021. Whole-exome sequencing (WES) was performed prospectively in patients without a prior diagnosis of monogenic disease, while clinical and laboratory data were reviewed retrospectively. Identified variants were evaluated for pathogenicity using standard bioinformatics tools. <b>Results:</b> A total of 47 patients were enrolled, including 33 boys (70.2%) and 14 girls (29.8%). The median age at symptom onset was 36 months (IQR: 10-72), and the median age at diagnosis was 3.7 years (IQR: 1.5-7.6). Crohn's disease was diagnosed in 53.2% (<i>n</i> = 25), ulcerative colitis in 38.3% (<i>n</i> = 18), and unclassified IBD in 8.5% (<i>n</i> = 4). Monogenic IBD was identified in 36.2% (<i>n</i> = 17) of patients, including nine with Familial Mediterranean Fever and others with glycogen storage disease type 1b (<i>n</i> = 2), XIAP deficiency, chronic granulomatous disease, DOCK8 deficiency, IL10 receptor alpha defect, LRBA deficiency, and NFKB2 deficiency (<i>n</i> = 1 each). A novel SLC29A3 gene variant (c.480_481delTGinsCA, p.V161I) (transcript ID: ENST00000479577.2) was identified in 76.6% (<i>n</i> = 36) of patients. <b>Conclusions:</b> This study underscores the importance of genetic variants in early-onset IBD, particularly MEFV and the novel NFKB2. The frequent detection of the SLC29A3 variant may suggest its potential involvement in the pathogenesis of the disease.