BULK RNA-SEQUENCING OF BLOOD INFORMS MOLECULAR DIAGNOSES IN VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE

Abstract BACKGROUND Very early onset inflammatory bowel disease (VEOIBD) is defined as prior to age 6. VEOIBD monogenic in >5% of cases; however, the remaining cases, molecular basis unknown. We aimed utilize bulk RNA-seq blood 1) define transcriptional signatures established IBD and 2) inform novel diagnoses. METHODS sequenced transcriptomes 115 whole samples, comprising patients with a known cause (n=35), without (n=70), healthy controls (n=10). focused on genes whose normalized expression was at least 5 standard deviations away from population mean one sample. comprehensively characterized clinical phenotypes, assess concordance pathway gene function, compared exome sequencing data where available. interrogated Bayesian networks for enrichment interest. RESULTS First, we report signature shared by two secondary X-linked agammaglobulinemia (pathogenic BTK mutations). The under-expression CXCR5 FCRL5 (Fig suggests reduced transcripts B-cell depletion or BTK-dependent mechanisms transcription. Second, three candidate identified through our approach: MSN, SLC39A4, BTN3A2 2). MSN below threshold patient complicated fistulae, recurrent infections, death pneumonia 62. Review his revealed loss function mutation MSN. encodes moesin, an actin cytoskeleton modulator, which regulates lymphocyte migration adhesion. Mutations are associated moesin-associated immunodeficiency, first reported this year. intestinal zinc transporter, patients. SLC39A4 acrodermatitis enteropathica, dermatitis diarrhea. One has dermatitis; second toxic megacolon colectomy. Coding mutations have not been identified. Further assessment transporter underway. Lastly, infantile-onset IBD. plays role T cell receptor interactions NF-KB signaling. networks, built independent cohorts, subnetworks be enriched predicted key driver inflammation, further supporting these genes’ potential association. CONCLUSIONS Bulk can used diagnostic tool aid identifying pathways diagnoses VEOIBD.