title: Brief Report: IFIH1 Mutation Causes Systemic Lupus Erythematosus With Selective IgA Deficiency.
abstract: OBJECTIVE
  To identify the underlying genetic defect in a 16-year-old girl with severe early-onset and refractory systemic lupus erythematosus (SLE), IgA deficiency, and mild lower limb spasticity without neuroradiologic manifestations.
  
  
  METHODS
  Whole-exome sequencing and extensive immunologic analysis were performed on samples from the index patient.
  
  
  RESULTS
  We identified a de novo p.R779H IFIH1 gain-of-function mutation in a patient with severe early-onset SLE, selective IgA deficiency, and mild lower limb spasticity. The same mutation in IFIH1 was recently identified in patients with Aicardi-Goutières syndrome, a rare neuroimmunologic disorder associated with elevated levels of type I interferon (IFN). IFN induced with helicase C domain 1 functions as an intracellular innate immune receptor that senses viral nucleic acids and leads to the induction of type I IFN and proinflammatory cytokines. Despite systemic immunosuppressive treatment, disease activity persisted in the patient and was associated with elevated serum levels of IFNα and up-regulation of IFIH1 itself.
  
  
  CONCLUSIONS
  This finding adds a new genetic causation for Mendelian lupus and greatly extends the disease spectrum associated with mutations in IFIH1 (ranging from inflammatory encephalopathy to prototypic systemic autoimmune disease). This marked phenotypic heterogeneity, despite an identical mutation, demonstrates the importance of modifying factors in type I IFN-dependent pathologies caused by mutations in IFIH1.
authors.affiliation: VIB and University of Leuven, Leuven, Belgium.
authors.forename: Lien
authors.initials: L
authors.lastname: Van Eyck
authors.affiliation: University Hospitals Leuven, Leuven, Belgium.
authors.forename: Lien
authors.initials: L
authors.lastname: De Somer
authors.affiliation: VIB and University of Leuven, Leuven, Belgium.
authors.forename: Diana
authors.initials: D
authors.lastname: Pombal
authors.affiliation: VIB and University of Leuven, Leuven, Belgium.
authors.forename: Simon
authors.initials: S
authors.lastname: Bornschein
authors.affiliation: University of Leuven, Leuven, Belgium.
authors.forename: Glynis
authors.initials: G
authors.lastname: Frans
authors.affiliation: VIB and University of Leuven, Leuven, Belgium.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Humblet-Baron
authors.affiliation: University of Leuven, Leuven, Belgium.
authors.forename: Leen
authors.initials: L
authors.lastname: Moens
authors.affiliation: University Hospitals Leuven and University of Leuven, Leuven, Belgium.
authors.forename: Francis
authors.initials: F
authors.lastname: de Zegher
authors.affiliation: University of Leuven, Leuven, Belgium.
authors.forename: Xavier
authors.initials: X
authors.lastname: Bossuyt
authors.affiliation: University Hospitals Leuven and University of Leuven, Leuven, Belgium.
authors.forename: Carine
authors.initials: C
authors.lastname: Wouters
authors.affiliation: VIB and University of Leuven, Leuven, Belgium.
authors.forename: Adrian
authors.initials: A
authors.lastname: Liston
mesh_terms: D000293:Adolescent; D053487:DEAD-box RNA Helicases / Q000235:genetics*; D005260:Female; D006801:Humans; D017098:IgA Deficiency / Q000150:complications / Q000235:genetics*; D000072640:Interferon-Induced Helicase, IFIH1; D008180:Lupus Erythematosus, Systemic / Q000150:complications / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: C452815:IFIH1 protein, human; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1