title: Whole-exome sequencing identifies Coronin-1A deficiency in 3 siblings with immunodeficiency and EBV-associated B-cell lymphoproliferation.
abstract: BACKGROUND
  Primary immunodeficiencies are a rare group of inborn diseases characterized by a broad clinical and genetic heterogeneity. Substantial advances in the identification of the underlying molecular mechanisms can be achieved through the study of patients with increased susceptibility to specific infections and immune dysregulation. We evaluated 3 siblings from a consanguineous family presenting with EBV-associated B-cell lymphoproliferation at an early age (12, 7½, and 14 months, respectively) and profound naive T-cell lymphopenia.
  
  
  OBJECTIVE
  On the basis of the hypothesis of a rare inborn immunodeficiency of autosomal recessive inheritance, we sought to characterize the underlying genetic defect.
  
  
  METHODS
  We performed genome-wide homozygosity mapping, followed by whole-exome sequencing.
  
  
  RESULTS
  We identified a homozygous inherited missense mutation in the gene encoding Coronin-1A (CORO1A) in the 3 siblings. This mutation, p. V134M, results in the substitution of an evolutionarily conserved amino acid within the β-propeller domain, which abrogates almost completely the protein expression in the patients' cells. In addition to a significant diminution of naive T-cell numbers, we found impaired development of a diverse T-cell repertoire, near-to-absent invariant natural killer T cells, and severely diminished mucosal-associated invariant T cell numbers.
  
  
  CONCLUSIONS
  Our findings define a new clinical entity of a primary immunodeficiency with increased susceptibility to EBV-induced lymphoproliferation in patients associated with hypomorphic Coronin-1A mutation.
authors.affiliation: INSERM U768, Paris, France. despina.moshous@inserm.fr
authors.forename: Despina
authors.initials: D
authors.lastname: Moshous
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Martin
authors.forename: Wassila
authors.initials: W
authors.lastname: Carpentier
authors.forename: Annick
authors.initials: A
authors.lastname: Lim
authors.forename: Isabelle
authors.initials: I
authors.lastname: Callebaut
authors.forename: Danielle
authors.initials: D
authors.lastname: Canioni
authors.forename: Fabian
authors.initials: F
authors.lastname: Hauck
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.forename: Jeremy
authors.initials: J
authors.lastname: Schwartzentruber
authors.forename: Patrick
authors.initials: P
authors.lastname: Nitschke
authors.forename: Nicolas
authors.initials: N
authors.lastname: Sirvent
authors.forename: Pierre
authors.initials: P
authors.lastname: Frange
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.forename: Stéphane
authors.initials: S
authors.lastname: Blanche
authors.forename: Patrick
authors.initials: P
authors.lastname: Revy
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.forename: Sylvain
authors.initials: S
authors.lastname: Latour
authors.forename: Nada
authors.initials: N
authors.lastname: Jabado
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: de Villartay
mesh_terms: D000595:Amino Acid Sequence; D001402:B-Lymphocytes / Q000378:metabolism* / Q000821:virology; D001483:Base Sequence; D002648:Child; D003241:Consanguinity; D059472:Exome; D005260:Female; D015870:Gene Expression; D023061:Gene Order; D004854:Herpesvirus 4, Human / Q000276:immunology; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D007223:Infant; D008232:Lymphoproliferative Disorders / Q000235:genetics* / Q000473:pathology / Q000821:virology; D008297:Male; D008840:Microfilament Proteins / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics; D008958:Models, Molecular; D009154:Mutation; D010375:Pedigree; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D035781:Siblings
chemical_list: D008840:Microfilament Proteins; C072061:coronin proteins