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Clinical Manifestations, Mutational Analysis, and Immunological Phenotype in Patients with RAG1/2 Mutations: First Cases Series from Mexico and Description of Two Novel Mutations

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Abstract

Mutations in recombinase activating genes 1 and 2 (RAG1/2) result in human severe combined immunodeficiency (SCID). The products of these genes are essential for V(D)J rearrangement of the antigen receptors during lymphocyte development. Mutations resulting in null-recombination activity in RAG1 or RAG2 are associated with the most severe clinical and immunological phenotypes, whereas patients with hypomorphic mutations may develop leaky SCID, including Omenn syndrome (OS). A group of previously unrecognized clinical phenotypes associated with granulomata and/or autoimmunity have been described as a consequence of hypomorphic mutations. Here, we present six patients from unrelated families with missense variants in RAG1 or RAG2. Phenotypes observed in these patients ranged from OS to severe mycobacterial infections and granulomatous disease. Moreover, we report the first evidence of two variants that had not been associated with immunodeficiency. This study represents the first case series of RAG1- or RAG2-deficient patients from Mexico and Latin America.

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Acknowledgements

The authors would like to thank the patients and their families for participating in this study.

Funding

MECM is supported by Consejo Nacional de Ciencia y Tecnología (CONACYT 281854).

LDN is supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.

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MECM and SEP conceived the study. MECM, SORL, and NP wrote the manuscript. SORL, JN, SDR, and LDN performed, analyzed, and interpreted the genetics. NP performed and analyzed the protein modeling. EGS and LBR performed proliferation assays and provided flow cytometry data. CAV, CMG, LLFL, and KCS provided the in silico analysis and classification of RAG1/2 variants. MAYN, SSM, GW, MENN, APMR, ATSB, and EVM took care of the patients and provided clinical data. PG and JAY performed genetic studies. IMD provided their expertise on congenital disorders. All authors critically reviewed the manuscript and approved the final version.

Corresponding authors

Correspondence to Sara Espinosa-Padilla or Mario Ernesto Cruz-Munoz.

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The original online version of this article was revised: Had typos in the last names of two authors.

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Lugo-Reyes, S.O., Pastor, N., González-Serrano, E. et al. Clinical Manifestations, Mutational Analysis, and Immunological Phenotype in Patients with RAG1/2 Mutations: First Cases Series from Mexico and Description of Two Novel Mutations. J Clin Immunol 41, 1291–1302 (2021). https://doi.org/10.1007/s10875-021-01052-0

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