Identification of Patients with RAG Mutations Previously Diagnosed with Common Variable Immunodeficiency Disorders

Purpose 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 pre...

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Bibliographic Details
Published in:Journal of clinical immunology 2015-02, Vol.35 (2), p.119-124
Main Authors: Buchbinder, David, Baker, Rebecca, Lee, Yu Nee, Ravell, Juan, Zhang, Yu, McElwee, Joshua, Nugent, Diane, Coonrod, Emily M., Durtschi, Jacob D., Augustine, Nancy H., Voelkerding, Karl V., Csomos, Krisztian, Rosen, Lindsey, Browne, Sarah, Walter, Jolan E., Notarangelo, Luigi D., Hill, Harry R., Kumánovics, Attila
Format: Article
Language:English
Subjects:
Agammaglobulinemia - diagnosis
Agammaglobulinemia - etiology
Biomedical and Life Sciences
Biomedicine
Biopsy
Child, Preschool
Common Variable Immunodeficiency - complications
Common Variable Immunodeficiency - diagnosis
Common Variable Immunodeficiency - genetics
DNA Mutational Analysis
Fatal Outcome
Female
Homeodomain Proteins - genetics
Humans
Immunohistochemistry
Immunology
Infectious Diseases
Internal Medicine
Lung Diseases, Interstitial - diagnosis
Lung Diseases, Interstitial - etiology
Lymphopenia - diagnosis
Lymphopenia - etiology
Medical Microbiology
Mutation
Original Research
Tomography, X-Ray Computed
Young Adult
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Summary:Purpose 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. Methods 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. Results 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. Conclusion 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.
ISSN:0271-9142
1573-2592
DOI:10.1007/s10875-014-0121-5