Approaches to patients with variants in RAG genes: from diagnosis to timely treatment

ABSTRACT

Introduction: Patients with primary immunodeficiency secondary to abnormal recombinase activating genes (RAG) can present with broad clinical phenotypes ranging from early severe infections to autoimmune complications and inflammation. Immunological phenotype may also vary from T⁻B⁻ severe combined immunodeficiency to combined immunodeficiency or antibody deficiencies with near-normal T and B cell counts and even preserved specific antibody response to pathogens. It is not uncommon that RAG variants of uncertain significance are identified by serendipity during a broad genetic screening process and pathogenic RAG variants are increasingly recognized among all age groups, including adults. Establishing the pathogenicity and clinical relevance of novel RAG variants can be challenging since RAG genes are highly polymorphic. This review paper aims to summarize clinical phenotypes of RAG deficiencies and provide practical guidance for confirming the direct link between specific RAG variants and clinical disease. Lastly, we will review the current understanding of treatment option for patients with varying severity of RAG deficiencies.

Area covered: This review discusses the different phenotypes and immunological aspects of RAG deficiencies, the diagnosis dilemma facing clinicians, and an overview of current and advancement in treatments.

Expert opinion: A careful analysis of immunological and clinical data and their correlation with genetic findings helps to determine the significance of the genetic polymorphism. Advances in functional assays, as well as anti-cytokine antibodies, make it easier to resolve the diagnostic dilemma.

KEYWORDS:

• RAG deficiencies
• immunodeficiency
• RAG deficiency phenotypes
• RAG deficiency diagnosis
• RAG deficiency management
• hematopoietic stem cell transplant

Article highlights

• RAG deficiency is an autosomal recessive disease that can present with a wide variety of clinical phenotypes (infections and autoimmunity) partly secondary to variability in remnant recombinase activity (phenotype–genotype correlation) and influence of epigenetic modifiers (such as infections).

• RAG genes are highly polymorphic, and variants of uncertain significance (VUS) may be discovered among patients during broad genetic screening.

• The causative link between the VUS in RAG genes and clinical phenotype should be established by a rigorous diagnostic approach.

• Functional evaluation of RAG activity among patients with VUS in RAG genes may include in vitro recombinase assays and/or B and T cell receptor repertoire studies.

• Patients with homozygous or compound heterozygous pathogenic RAG variants and clinical features of autoimmunity may fail conventional treatment approach and can be eligible for hematopoietic stem cell transplant.

Acknowledgments

We thank Dr. Svetlana Sharapova (Belarusian Research Centre for Pediatric Oncology, Hematology and Immunology, Minsk, Belarus) for contribution of original images (Figures 2 and 3). We thank Dr. Ignacio Gonzalez-Gomez (Molecular Pathology, Johns Hopkins All Children’s Hospital, St. Petersburg, Florida) for interpretation of granuloma images (Figure 3).

Declaration of interest

JE Walter has been an advisory board member and speaker for Shire (Takeda), and has received an investigator-initiated grant from X4 Pharmaceutics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This work was partly supported by the Jeffrey Modell Foundation, Robert A. Good Endowment at University of South Florida and NIAID sub-R01AI100887-05 (J.E.W.).