Abstract
Proteins expressed by recombination activating genes 1 and 2 (RAG1/2) are essential in the process of V(D)J recombination that leads to generation of the T and B cell repertoires. Clinical and immunological phenotypes of patients with RAG deficiencies correlate well to the degree of impaired RAG activity and this has been expanding to variants of combined immunodeficiency (CID) or even milder antibody deficiency syndromes. Pathogenic variants that severely impair recombinase activity of RAG1/2 determine a severe combined immunodeficiency (SCID) phenotype, whereas hypomorphic variants result in leaky (partial) SCID and other immunodeficiencies. We report a patient with novel pathogenic compound heterozygous RAG2 variants that result in a CID phenotype with two distinctive characteristics: late-onset progressive hypogammaglobulinemia and highly elevated B cell count. In addition, the patient had early onset of infections, T cell lymphopenia and expansion of lymphocytes after exposure to herpes family viruses. This case highlights the importance of considering pathogenic RAG variants among patients with preserved B cell count and CID phenotype.
Highlights
RAG1 and RAG2 proteins combine to form a heterotetrameric complex which acts as an endonuclease
We present a patient with combined immunodeficiency (CID) associated with novel compound heterozygous RAG2 variants
The patient does not meet the criteria for leaky SCID (LS) or Omenn syndrome (OS) as mitogen proliferation are preserved, and has higher relative RAG activity [16% in combined variants (Figure 2)] compared to LS/OS patients
Summary
RAG1 and RAG2 proteins combine to form a heterotetrameric complex which acts as an endonuclease. A 14-year-old female with chronic rhinosinusitis and lung disease with bronchiectasis was referred for immunologic investigation in São Paulo, Brazil She had a history of chronic cough with recurrent wheezing since birth with prolonged use of antimicrobials for lower and upper respiratory tract infections, oral candidiasis and stomatitis. At 13 years of age, she was hospitalized with bilateral pneumonia and stomatitis with positive polymerase chain reaction (PCR) for herpes simplex virus (HSV) on oral lesion biopsy. She responded well to intravenous antibiotics and acyclovir. Genetic studies using targeted sequencing of 16 SCID genes identified a heterozygous compound variant in RAG2 (c.509A > G: p.E170G and c.829insT, p.Y277fs) in the coding regions. There is no matched sibling available and we await results of human leukocyte antigen testing to search for a matched unrelated donor
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