Identification of Patients with RAG Mutations Previously Diagnosed with Common Variable Immunodeficiency Disorders
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Combined immunodeficiency (CID) presents a unique challenge to clinicians. Two patients presented with the prior clinical diagnosis of common variable immunodeficiency (CVID) disorder marked by an early age of presentation, opportunistic infections, and persistent lymphopenia. Due to the presence of atypical clinical features, next generation sequencing was applied documenting RAG deficiency in both patients.
Two different genetic analysis techniques were applied in these patients including whole exome sequencing in one patient and the use of a gene panel designed to target genes known to cause primary immunodeficiency disorders (PIDD) in a second patient. Sanger dideoxy sequencing was used to confirm RAG1 mutations in both patients.
Two young adults with a history of recurrent bacterial sinopulmonary infections, viral infections, and autoimmune disease as well as progressive hypogammaglobulinemia, abnormal antibody responses, lymphopenia and a prior diagnosis of CVID disorder were evaluated. Compound heterozygous mutations in RAG1 (1) c256_257delAA, p86VfsX32 and (2) c1835A>G, pH612R were documented in one patient. Compound heterozygous mutations in RAG1 (1) c.1566G>T, p.W522C and (2) c.2689C>T, p. R897X) were documented in a second patient post-mortem following a fatal opportunistic infection.
Astute clinical judgment in the evaluation of patients with PIDD is necessary. Atypical clinical findings such as early onset, granulomatous disease, or opportunistic infections should support the consideration of atypical forms of late onset CID secondary to RAG deficiency. Next generation sequencing approaches provide powerful tools in the investigation of these patients and may expedite definitive treatments.
KeywordsRAG1 RAG deficiency primary immunodeficiency severe combined immune deficiency common variable immunodeficiency disorder exome sequencing gene panel
We would like to acknowledge the support of the Intramural Research Program of the NIAID, NIH and the assistance of Julie Niemela for CLIA-confirming the mutation and Helen Matthews for clinical support. The authors are grateful to Helen Su, MD PhD for her clinical and laboratory support as well as her assistance in the preparation of this manuscript. This work was partly supported by the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH) (grant no. 5P01AI076210-04 and grant no. U54AI082973 to L.D.N.; grant no. 1K08AI103035-03 to J.E.W.), the Manton Foundation (to L.D.N.), the March of Dimes (grant no. 6-FY10-282 to L.D.N.), the Jeffrey Modell Foundation (to L.D.N.), the Division of Intramural Research, NIAID, NIH (to L.B.R. and S.K.B.), and by the ARUP Institute for Clinical and Experimental Pathology.
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