{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T04:52:40Z","timestamp":1791175960731,"version":"4.1.0"},"reference-count":25,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T00:00:00Z","timestamp":1791158400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2023YFC2706501"],"award-info":[{"award-number":["2023YFC2706501"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82101953"],"award-info":[{"award-number":["82101953"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013105","name":"Shanghai Rising-Star Program","doi-asserted-by":"publisher","award":["22QA1401400"],"award-info":[{"award-number":["22QA1401400"]}],"id":[{"id":"10.13039\/501100013105","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100018625","name":"Science and Technology Innovation Plan Of Shanghai Science and Technology Commission","doi-asserted-by":"publisher","award":["23Y11905100"],"award-info":[{"award-number":["23Y11905100"]}],"id":[{"id":"10.13039\/501100018625","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Very early onset inflammatory bowel disease (VEOIBD) is frequently driven by monogenic defects. Pathogenic variants in the syntaxin-binding protein 3 (\n                      <jats:italic>STXBP3<\/jats:italic>\n                      ) gene have been implicated in VEOIBD; however, the relationship between specific variant types and clinical manifestations remains incompletely understood. This study aimed to identify the genetic cause in a patient with VEOIBD and explore the possible genotype-phenotype correlations of\n                      <jats:italic>STXBP3<\/jats:italic>\n                      -related disorders.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We performed trio-whole-exome sequencing (trio-WES) on a male infant presenting with VEOIBD, sensorineural hearing loss, and immunodeficiency. Functional consequences of the identified variant were investigated using RNA sequencing (RNA-seq), reverse transcription-polymerase chain reaction (RT-PCR), western blotting and co-immunoprecipitation (co-IP) assay. A systematic literature review was conducted to analyze clinical features and inheritance patterns across all reported\n                      <jats:italic>STXBP3<\/jats:italic>\n                      cases.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A novel heterozygous splice-site variant in\n                      <jats:italic>STXBP3<\/jats:italic>\n                      (c.1022_1029\u00a0+\u00a03del) was identified. RNA-seq and RT-PCR confirmed that this variant causes aberrant splicing, leading to the skipping of exon 12 and the production of a truncated protein. Co-IP showed that the aberrant protein reduced the ability to bind STX4. The comprehensive analysis of 13 patients revealed possible genotype-phenotype correlations: splice-site and frameshift variants were observed predominantly follow an autosomal dominant (AD) pattern associated with VEOIBD, sensorineural hearing loss, and immunodeficiency; conversely, missense variants generally follow an autosomal recessive (AR) pattern linked to VEOIBD, and congenital malformations. Given the small cohort, these comparisons were descriptive and were not intended to establish definitive genotype\u2013phenotype associations.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      We identified a novel pathogenic\n                      <jats:italic>STXBP3<\/jats:italic>\n                      variant and validated its impact on its function. The observed differences between AD and AR cases provided a preliminary, hypothesis-generating framework for understanding STXBP3-related disease, which require validation in larger cohorts.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1871633","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T04:31:23Z","timestamp":1791174683000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrated genetic and functional analyses reveal the pathogenic effects of a novel STXBP3 variant in very-early-onset inflammatory bowel disease with immunodeficiency"],"prefix":"10.3389","volume":"17","author":[{"given":"Chun","family":"Pan","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center","place":["Shanghai, 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China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haijiao","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center","place":["Shanghai, 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