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

Abstract

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.

Human RAG mutations: biochemistry and clinical implications

“…Following this description, several other cases of CID–G/AI with various auto immune manifestations (such as cytopaenias, vitiligo, psoriasis, myasthenia gravis and Guillain–Barré syndrome) have been reported 33–40 . Additional phenotypes that are associated with RAG deficiency include idiopathic CD4 + T cell lymphopaenia 41 , common variable immunodeficiency 40,42 , IgA deficiency 43,44 , selective deficiency of polysaccharide-specific antibody responses 44 , hyper-IgM syndrome 45 and sterile chronic multifocal osteomyelitis 46 . Overall, these observations have substantially broadened the clinical and immunological spectrum of human RAG deficiency and have identified immune dysregulation as a prominent manifestation of perturbed RAG function.…”

Granulomatous and lymphocytic interstitial lung disease: a spectrum of pulmonary histopathologic lesions in common variable immunodeficiency—histologic and immunohistochemical analyses of 16 cases

“…Recent studies show that pulmonary lesions similar to GLILD can also occur in primary immunodeficiencies other than CVID, for example, cytotoxic T lymphocyte antigen-4 (CTLA4) deficiency, lipopolysaccharide responsive beige-like anchor protein (LRBA) deficiency and hypomorphic mutations in the recombinase-activating gene 1 (Rag1) [37–40]. Importantly, hypogammaglobulinemia may be one of the immunological abnormalities found in these primary immunodeficiencies.…”

Understanding the genetic and epigenetic basis of common variable immunodeficiency disorder through omics approaches

“…The genes and the pathways identified in this study may be further pursued by studies with larger sample size and functional studies. In addition to whole genome-sequencing, recently exome-sequencing identified additional mutations that are related or causative in individual CVID patients, such as the newly identified mutations in genes NLRP12 [53], NFKB2 [54], ITPKB [55] and RAG1 [56]. A recent genetic study using whole exome-sequencing and comparative genomic hybridization array identified multiple heterozygous mutations and deletions in gene IKZF1 responsible for a form of CVID with drastically reduced number of B cells.…”