{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:01:03Z","timestamp":1792789263693,"version":"4.5.0"},"reference-count":24,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T00:00:00Z","timestamp":1787961600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002855","name":"Ministry of Science and Technology of the People\u2019s Republic of China","doi-asserted-by":"publisher","award":["2023YFC2706501"],"award-info":[{"award-number":["2023YFC2706501"]}],"id":[{"id":"10.13039\/501100002855","id-type":"DOI","asserted-by":"publisher"}]},{"award":["2023YFC2706501"],"award-info":[{"award-number":["2023YFC2706501"]}],"id":[{"id":"https:\/\/ror.org\/027s68j25","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Science and Technology Commission of Shanghai Municipality","award":["23Y11905100"],"award-info":[{"award-number":["23Y11905100"]}],"id":[{"id":"https:\/\/ror.org\/03kt66j61","id-type":"ROR","asserted-by":"crossref"}]},{"award":["23Y11905100"],"award-info":[{"award-number":["23Y11905100"]}],"id":[{"id":"https:\/\/ror.org\/03kt66j61","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: RELA encodes the p65 subunit of NF-\u03baB and plays a critical role in immune regulation, epithelial protection, and anti-apoptotic signaling. Pathogenic RELA variants cause monogenic immune dysregulation with heterogeneous clinical manifestations. However, genotype\u2013phenotype relationships and optimal treatment strategies remain incompletely defined. Methods: We conducted a comprehensive literature-based analysis of reported individuals with RELA variants and additionally described a family carrying a RELA c.706C&gt;T (p.R236*) variant, including a clinically affected proband and his variant-positive father with isolated vitiligo. Clinical, immunological, genetic, endoscopic, and therapeutic data were extracted and summarized using a module-based phenotypic framework. Exploratory analyses were performed to examine potential genotype\u2013phenotype patterns and reported treatment responses. Results: A total of 72 individuals with RELA variants, including the proband and his variant-positive father from the present family, were analyzed. RELA-associated disease exhibited marked clinical heterogeneity, encompassing mucocutaneous, systemic inflammatory, autoimmune, gastrointestinal, hematologic, allergic\/eosinophilic, and infection-related manifestations. Exploratory analyses suggested that truncating or splice-site variants were more frequently observed among individuals with mucocutaneous lesions, whereas missense variants appeared to be more common among those with autoimmune manifestations. Tumor necrosis factor (TNF) inhibitors were among the therapies associated with favorable reported responses. In the present family, the proband presented with early-onset Beh\u00e7et-like intestinal inflammation and achieved clinical and endoscopic remission after thalidomide and dose-escalated infliximab treatment. Conclusions: This study expands the clinical spectrum of RELA-associated disease and highlights preliminary variant-related clinical patterns that require confirmation in larger independent cohorts. The available treatment experience suggests that TNF blockade may be considered as a therapeutic option in selected patients, although comparative efficacy cannot be established from the available data.<\/jats:p>","DOI":"10.3390\/genes17091043","type":"journal-article","created":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T02:08:58Z","timestamp":1788142138000},"page":"1043","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Clinical Insights into RELA-Associated Disease: From Genotype to Phenotype and Exploring Treatment"],"prefix":"10.3390","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, No. 399 Wanyuan Road, Minhang District, Shanghai 201102, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]},{"given":"Cuifang","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center, No. 399 Wanyuan Road, Minhang District, Shanghai 201102, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"}]},{"given":"Yuhuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center, No. 399 Wanyuan Road, Minhang District, Shanghai 201102, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Jieru","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center, No. 399 Wanyuan Road, Minhang District, Shanghai 201102, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Lin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center, No. 399 Wanyuan Road, Minhang District, Shanghai 201102, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Ying","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Children\u2019s Hospital of Fudan University, National Children\u2019s Medical Center, No. 399 Wanyuan Road, Minhang District, Shanghai 201102, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2195","DOI":"10.1101\/gad.1228704","article-title":"Signaling to NF-\u03baB","volume":"18","author":"Hayden","year":"2004","journal-title":"Genes Dev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2321","DOI":"10.1101\/gad.909001","article-title":"NF-\u03baB signaling pathways in mammalian and insect innate immunity","volume":"15","author":"Silverman","year":"2001","journal-title":"Genes Dev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2599","DOI":"10.1128\/JVI.02213-10","article-title":"Distinct Roles for the NF-\u03baB RelA Subunit during Antiviral Innate Immune Responses","volume":"85","author":"Basagoudanavar","year":"2011","journal-title":"J. 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