Multi-omics approach to map a clinically diverse large cohort with homozygous founder RAG1 p.C176F variant among Old Order Mennonites
Year: 2026
Type: preprint
Study design: Observational Study
Abstract: 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 RAG1 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 IFNα, a TH1/IFNγ-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 ‘experiment of nature’, 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. One sentence summary 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.
Source: medRxiv
Authors: Evan Potts, Marta Toth, Karlla W. Brigatti, Erik G. Puffenberger, Paola R. Suhet, Mustafa Talib, Alanna E. Koehler, Zsuzsanna Gaál, Kellie A. Larsen, Rahim Z. Miller, Daryl J. Gibson, Philip Mendez, Zixiao An, Jeffrey J. Bednarski, Peter Blazso, Marita Bosticardo, Sharat Chandra, Ivan K. Chinn, Joelle W. Clark, Antonio Condino-Neto, Ottavia M. Delmonte, Dimana Dimitrova, Emily S. J. Edwards, Ganesh V. Halade, Jennifer R. Heimall, Ayal Hendel, Sarah E. Henrickson, Katherine E. Herman, Avni Joshi, Heather Kenney, Maleewan Kitcharoensakkul, Gloria Magro, Eliza C. Martin, Edgar B. Oliveira-Junior, Mei-Sing Ong, Oscar E. Ospina, Francesca Pala, Kady Palmer, Jason P. Raasch, Mathilde Salamon, Christopher D. Scharer, Christine M. Seroogy, Svetlana O. Sharapova, Raz Somech, Michael Teng, Timothy J. Thauland, Boglarka Ujhazi, James W. Verbsky, Brant R. Ward, Shengfeng Xu, Melis Yilmaz, Yuhang Zhang, Wei Zhao, Krisztian Csomos, Yu Nee Lee, David G. Schatz, Manish Butte, Nicholas L. Rider, Laura E. Poskitt, Luigi D. Notarangelo, Kevin A. Strauss, Jolan E. Walter
Institutions: University of South Florida, Clinic for Special Children, Johns Hopkins All Children's Hospital, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Washington University in St. Louis, University of Szeged, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Baylor College of Medicine, Universidade de São Paulo, National Cancer Institute, Monash University, Children's Hospital of Philadelphia, University of Pennsylvania, Bar-Ilan University, University of Rochester Medicine, University of Rochester, Mayo Clinic, St. Louis Children's Hospital, Yale University, Boston Children's Hospital, Medical University of South Carolina, Emory University, University of Wisconsin–Madison, Belarusian Research Center For Pediatric Oncology and Hematology, Tel Aviv University, Sheba Medical Center, Edmond and Lily Safra Children's Hospital, University of California, Los Angeles, Medical College of Wisconsin, Children's National, Shanghai Jiao Tong University, Virginia Commonwealth University, Virginia Commonwealth University Medical Center, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Carilion Clinic, Virginia Tech
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Funders: U.S. Department of Health and Human Services, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, University of South Florida, National Institutes of Health, National Institute of Allergy and Infectious Diseases, National Institute of Child Health and Human Development
Awards: G1063514041, G2856013597, Characterization of the cellular and molecular bases of inborn errors of immunity, Mechanisms driving extrafollicular polyreactive B cell lineages in partial RAG deficiency, Collaborative multi-site project to speed the identification and management of rare genetic immune diseases
OpenAlex ID: W7216444066