title: Identification of patients with RAG mutations previously diagnosed with common variable immunodeficiency disorders.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Pediatrics / Hematology, CHOC Children's Hospital-UC Irvine, Orange, CA, USA, dbuchbinder@choc.org.
authors.forename: David
authors.initials: D
authors.lastname: Buchbinder
authors.forename: Rebecca
authors.initials: R
authors.lastname: Baker
authors.forename: Yu Nee
authors.initials: YN
authors.lastname: Lee
authors.forename: Juan
authors.initials: J
authors.lastname: Ravell
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Joshua
authors.initials: J
authors.lastname: McElwee
authors.forename: Diane
authors.initials: D
authors.lastname: Nugent
authors.forename: Emily M
authors.initials: EM
authors.lastname: Coonrod
authors.forename: Jacob D
authors.initials: JD
authors.lastname: Durtschi
authors.forename: Nancy H
authors.initials: NH
authors.lastname: Augustine
authors.forename: Karl V
authors.initials: KV
authors.lastname: Voelkerding
authors.forename: Krisztian
authors.initials: K
authors.lastname: Csomos
authors.forename: Lindsey
authors.initials: L
authors.lastname: Rosen
authors.forename: Sarah
authors.initials: S
authors.lastname: Browne
authors.forename: Jolan E
authors.initials: JE
authors.lastname: Walter
authors.forename: Luigi D
authors.initials: LD
authors.lastname: Notarangelo
authors.forename: Harry R
authors.initials: HR
authors.lastname: Hill
authors.forename: Attila
authors.initials: A
authors.lastname: Kumánovics
mesh_terms: D000361:Agammaglobulinemia / Q000175:diagnosis / Q000209:etiology; D001706:Biopsy; D002675:Child, Preschool; D017074:Common Variable Immunodeficiency / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D004252:DNA Mutational Analysis; D017809:Fatal Outcome; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D017563:Lung Diseases, Interstitial / Q000175:diagnosis / Q000209:etiology; D008231:Lymphopenia / Q000175:diagnosis / Q000209:etiology; D009154:Mutation; D014057:Tomography, X-Ray Computed; D055815:Young Adult
chemical_list: D018398:Homeodomain Proteins; C064658:RAG-1 protein