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

Expert Rev Clin Immunol. 2019 Oct;15(10):1033-1046. doi: 10.1080/1744666X.2020.1670060. Epub 2019 Oct 10.


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; RAG deficiency diagnosis; RAG deficiency management; RAG deficiency phenotypes; hematopoietic stem cell transplant; immunodeficiency.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Autoimmune Diseases / etiology
  • DNA-Binding Proteins / genetics*
  • Genetic Variation*
  • Homeodomain Proteins / genetics*
  • Humans
  • Nuclear Proteins / genetics*
  • Severe Combined Immunodeficiency / diagnosis
  • Severe Combined Immunodeficiency / immunology
  • Severe Combined Immunodeficiency / therapy*


  • DNA-Binding Proteins
  • Homeodomain Proteins
  • Nuclear Proteins
  • RAG2 protein, human
  • RAG-1 protein