{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T17:53:36Z","timestamp":1791309216301,"version":"4.3.1"},"posted":{"date-parts":[[2026,10,2]]},"group-title":"Allergy and Immunology","reference-count":40,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T00:00:00Z","timestamp":1790899200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.medrxiv.org\/about\/FAQ#license"}],"funder":[{"award":["ZIA AI001222"],"award-info":[{"award-number":["ZIA AI001222"]}],"id":[{"id":"https:\/\/ror.org\/043z4tv69","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01AI153830"],"award-info":[{"award-number":["R01AI153830"]}],"id":[{"id":"https:\/\/ror.org\/043z4tv69","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01AI153827"],"award-info":[{"award-number":["R01AI153827"]}],"id":[{"id":"https:\/\/ror.org\/043z4tv69","id-type":"ROR","asserted-by":"publisher"}]},{"award":["U24 HD104590"],"award-info":[{"award-number":["U24 HD104590"]}],"id":[{"id":"https:\/\/ror.org\/04byxyr05","id-type":"ROR","asserted-by":"publisher"}]},{"name":"National Key R&D Program of China","award":["2022YFE0132100"],"award-info":[{"award-number":["2022YFE0132100"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,10,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Partially preserved function of recombination-activating genes (RAG) 1 and 2 can be linked to divergent and hard-to-predict clinical and immunological phenotypes, even among close relatives. It is unclear how intrinsic RAG hypomorphism interacts with extrinsic environmental pressures to shape clinical trajectory. We dissect this phenomenon in a unique cohort of 18 Old Order Mennonite individuals with a novel missense founder\n                  <jats:italic>RAG1<\/jats:italic>\n                  variant (p.C176F) with 25.8% recombinase activity of wild-type protein. After studying a myriad of markers, we demonstrate varying severity and progression of clinical disease (predominantly in females) that paralleled decline in CMV-specific immune competence, break in tolerance with hallmark presence of antibodies to IFN\u03b1, a TH1\/IFN\u03b3-driven inflammatory milieu with elevated serum markers (CXCL9\/10), expansion of follicular helper T cells and clonal B cells enriched for autoreactive-prone VH4.34 B cell receptor. BCR and TCR repertoires carry the fingerprints of both extrinsic and RAG-driven intrinsic changes. Through this \u2018experiment of nature\u2019, our cohort demonstrated that partial RAG deficiency (pRD) is not a monolithic disease but the result of compounded RAG intrinsic and extrinsic events. Overall, this study uses multi-omics approaches to dissect the contribution of a hypomorphic RAG variant to variable severity of clinical disease and immunological dysregulation at cellular and molecular level. Emerging biomarkers of a multi-omic roadmap should allow monitoring of progression of clinical disease and guide who and when to treat with hematopoietic stem cell transplant in pRD.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>One sentence summary<\/jats:title>\n                  <jats:p>A unique cohort of pediatric and adult US Mennonite patients with shared novel partial RAG defect and variable penetrance of disease allow correlation of clinical severity with RAG-intrinsic and extrinsic factors driving plasticity in T and B cell competence to eliminate infections and tolerance to self.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.09.29.26363255","type":"posted-content","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T23:20:23Z","timestamp":1790983223000},"source":"Crossref","is-referenced-by-count":0,"title":["Multi-omics approach to map a clinically diverse large cohort with homozygous founder RAG1 p.C176F variant among Old Order Mennonites"],"prefix":"10.64898","author":[{"given":"Evan","family":"Potts","sequence":"first","affiliation":[{"name":"Division of Allergy and Immunology, Department of Pediatrics, University of South Florida Morsani College of Medicine; Tampa, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1007-0232","authenticated-orcid":false,"given":"Marta","family":"Toth","sequence":"additional","affiliation":[{"name":"Division of Allergy and Immunology, Department of Pediatrics, University of South Florida Morsani College of Medicine; Tampa, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karlla W.","family":"Brigatti","sequence":"additional","affiliation":[{"name":"Clinic for Special Children; Gordonville, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik G.","family":"Puffenberger","sequence":"additional","affiliation":[{"name":"Clinic for Special Children; Gordonville, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0758-6879","authenticated-orcid":false,"given":"Paola R.","family":"Suhet","sequence":"additional","affiliation":[{"name":"Division of Allergy and Immunology, Department of Pediatrics, University of South Florida Morsani College of Medicine; Tampa, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mustafa","family":"Talib","sequence":"additional","affiliation":[{"name":"Division of Allergy and Immunology, Department of Pediatrics, University of South Florida Morsani College of Medicine; Tampa, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alanna E.","family":"Koehler","sequence":"additional","affiliation":[{"name":"Clinic for Special Children; Gordonville, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zsuzsanna","family":"Ga\u00e1l","sequence":"additional","affiliation":[{"name":"Division of Allergy and Immunology, Department of Pediatrics, University of South Florida Morsani College of Medicine; Tampa, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kellie A.","family":"Larsen","sequence":"additional","affiliation":[{"name":"Division of Allergy and Immunology, Department of Pediatrics, University of South Florida Morsani College of Medicine; 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Van Dongen , M. Van Der Burg , Similar recombination-activating gene (RAG) mutations result in similar immunobiological effects but in different clinical phenotypes. Journal of Allergy and Clinical Immunology 133 (2014).","DOI":"10.1016\/j.jaci.2013.11.028"},{"key":"2026100610300766000_2026.09.29.26363255v1.10","doi-asserted-by":"crossref","unstructured":"R. Castagnoli , F. Pala , P. Subramanian , C. Oguz , B. Schwarz , A. I. Lim , A. S. Burns , E. Fontana , M. Bosticardo , C. Corsino , A. Angelova , O. M. Delmonte , H. Kenney , D. Riley , G. Smith , L. Ott de Bruin , V. Oikonomou , L. Dos Santos Dias , D. Fink , E. Bohrnsen , C. D. Kimzey , G. L. Marseglia , G. Alva-Lozada , J. R. E. Bergerson , A. Brett , K. W. Brigatti , D. Dimitrova , C. M. Dutmer , A. F. Freeman , H. Ale , S. M. Holland , F. Licciardi , S. Pasic , L. E. Poskitt , D. E. Potts , J. F. Dasso , S. O. Sharapova , K. A. Strauss , B. R. Ward , M. Yilmaz , D. B. Kuhns , M. S. Lionakis , S. R. Daley , H. H. Kong , J. A. Segre , A. Villa , S. Pittaluga , J. E. Walter , I. Vujkovic-Cvijin , Y. Belkaid , L. D. Notarangelo , Immunopathological and microbial signatures of inflammatory bowel disease in partial RAG deficiency. J. Exp. Med. 222 (2025).","DOI":"10.1084\/jem.20241993"},{"key":"2026100610300766000_2026.09.29.26363255v1.11","doi-asserted-by":"crossref","unstructured":"M. Bosticardo , K. Dobbs , O. M. Delmonte , A. J. Martins , F. Pala , T. Kawai , H. Kenney , G. Magro , L. B. Rosen , Y. Yamazaki , H. H. Yu , E. Calzoni , Y. N. Lee , C. Liu , J. Stoddard , J. Niemela , D. Fink , R. Castagnoli , M. Ramba , A. Cheng , D. Riley , V. Oikonomou , E. Shaw , B. Belaid , S. Keles , W. Al-Herz , C. Cancrini , C. Cifaldi , S. Baris , S. Sharapova , C. Schuetz , A. R. Gennery , A. F. Freeman , R. Somech , S. Choo , S. C. Giliani , T. G\u00fcng\u00f6r , D. Drozdov , I. Meyts , D. Moshous , B. Neven , R. S. Abraham , A. El-Marsafy , M. Kanariou , A. King , F. Licciardi , M. E. Cruz-Mu\u00f1oz , P. Palma , C. 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