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We aimed to investigate the polygenic origins of VEO-IBD in a cohort with a high proportion of Hispanic patients.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Patients with VEO-IBD who underwent whole exome sequencing at our center were included. Genes were categorized as genes of interest (GOIs) (129 genes previously described to be associated with VEO-IBD) or non-GOIs. VEO-IBD \u201csusceptibility\u201d single nucleotide variants (SNVs) were identified through enrichment compared with gnomAD (Genome Aggregation Database) and ALFA (Allele Frequency Aggregator) and were scored by Combined Annotation Dependent Depletion for deleteriousness. Gene networks carrying susceptibility SNVs were created. Myosin 5b immunofluorescence was also studied.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Fifty-six patients met inclusion criteria, and 32.1% identified as Hispanic. Monogenic disease was infrequent (8.9%). Significant enrichment of GOI susceptibility SNVs was observed, notably in MYO5B, especially in Hispanics. MEFV, TNFAIP3, SH3TC2, and NCF2 were also central participants in the GOI networks. Myosin 5b immunofluorescence in colonic mucosa was significantly reduced in those with MYO5B susceptibility SNVs compared with control subjects. Seven genes (ESRRA, HLA-DQ1, RETSAT, PABPC1, PARP4, CCDC102A, and SUSD2) were central participants in the non-GOI networks.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Our results support the polygenic nature of VEO-IBD, in which key participants, like MYO5B, were identified through network analytics. Rare variant load within susceptibility genes may be relevant not only for the genetic origins of inflammatory bowel disease, but also for the age of disease onset. Our findings could guide future work in precision medicine.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/ibd\/izae169","type":"journal-article","created":{"date-parts":[[2024,8,3]],"date-time":"2024-08-03T15:19:50Z","timestamp":1722698390000},"page":"189-199","source":"Crossref","is-referenced-by-count":9,"title":["<i>MYO5B<\/i> and the Polygenic Landscape of Very Early-Onset Inflammatory Bowel Disease in an Ethnically Diverse Population"],"prefix":"10.1093","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6272-466X","authenticated-orcid":false,"given":"Ashleigh","family":"Watson","sequence":"first","affiliation":[{"name":"Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Texas Children\u2019s Hospital, Baylor College of Medicine , Houston, TX ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R Alan","family":"Harris","sequence":"additional","affiliation":[{"name":"Human Genome Sequencing Center, Baylor College of Medicine , Houston, TX ,","place":["USA"]},{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine , Houston, TX ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy C","family":"Engevik","sequence":"additional","affiliation":[{"name":"Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina , Charleston, SC ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Numan","family":"Oezguen","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Baylor College of Medicine , Houston, TX ,","place":["USA"]},{"name":"Texas Children\u2019s Microbiome Center, Texas Children\u2019s Hospital , Houston, TX ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maribeth R","family":"Nicholson","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Vanderbilt University School of Medicine , Nashville, TN ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Dooley","sequence":"additional","affiliation":[{"name":"Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina , Charleston, SC ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Stubler","sequence":"additional","affiliation":[{"name":"Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina , Charleston, SC ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa Forbes","family":"Satter","sequence":"additional","affiliation":[{"name":"Department of Pediatric Allergy and Immunology, William T. Shearer Center for Human Immunobiology, Texas Children\u2019s Hospital, Baylor College of Medicine , Houston, TX ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina B","family":"Karam","sequence":"additional","affiliation":[{"name":"Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Texas Children\u2019s Hospital, Baylor College of Medicine , Houston, TX ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4146-1335","authenticated-orcid":false,"given":"Richard","family":"Kellermayer","sequence":"additional","affiliation":[{"name":"Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Texas Children\u2019s Hospital, Baylor College of Medicine , Houston, TX ,","place":["USA"]},{"name":"Children\u2019s Nutrition and Research Center, U.S. Department of Agriculture Agricultural Research Service , Houston, TX 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