title: Identification of a pathogenic variant in TREX1 in early-onset cerebral systemic lupus erythematosus by Whole-exome sequencing.
abstract: Objective. Systemic lupus erythematosus (SLE) isa chronic and heterogeneous autoimmune disease. Both twin and sibling studies indicate a strong genetic contribution to lupus, but in the majority of cases the pathogenic variant remains to be identified. The genetic contribution to disease is likely to be greatest in cases with early onset and severe phenotypes. Whole-exome sequencing now offers the possibility of identifying rare alleles responsible for disease in such cases. This study was undertaken to identify genetic causes of SLE using whole-exome sequencing.Methods. We performed whole-exome sequencing in a 4-year-old girl with early-onset SLE and conducted biochemical analysis of the putative defect.Results. Whole-exome sequencing in a 4-year-old girl with cerebral lupus identified a rare, homozygous mutation in the three prime repair exonuclease 1 gene(TREX1) that was predicted to be highly deleterious.The TREX1 R97H mutant protein had a 20-fold reduction in exonuclease activity and was associated with an elevated interferon-alpha signature in the patient.The discovery and characterization of a pathogenic TREX1 variant in our proband has therapeutic implications.The patient is now a candidate for therapy. Conclusion. Our study is the first to demonstrate that whole-exome sequencing can be used to identify rare or novel deleterious variants as genetic causes of SLE and, through a personalized approach, improve therapeutic options.
authors.forename: Julia I
authors.initials: JI
authors.lastname: Ellyard
authors.forename: Rebekka
authors.initials: R
authors.lastname: Jerjen
authors.forename: Jaime L
authors.initials: JL
authors.lastname: Martin
authors.forename: Adrian Y S
authors.initials: AY
authors.lastname: Lee
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Field
authors.forename: Simon H
authors.initials: SH
authors.lastname: Jiang
authors.forename: Jean
authors.initials: J
authors.lastname: Cappello
authors.forename: Svenja K
authors.initials: SK
authors.lastname: Naumann
authors.forename: T Daniel
authors.initials: TD
authors.lastname: Andrews
authors.forename: Hamish S
authors.initials: HS
authors.lastname: Scott
authors.forename: Marco G
authors.initials: MG
authors.lastname: Casarotto
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Goodnow
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Chaitow
authors.forename: Virginia
authors.initials: V
authors.lastname: Pascual
authors.forename: Paul
authors.initials: P
authors.lastname: Hertzog
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Alexander
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Cook
authors.forename: Carola G
authors.initials: CG
authors.lastname: Vinuesa
mesh_terms: D002675:Child, Preschool; D005090:Exodeoxyribonucleases / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D005260:Female; D006720:Homozygote; D006801:Humans; D016898:Interferon-alpha / Q000032:analysis*; D020945:Lupus Vasculitis, Central Nervous System / Q000235:genetics*; D010375:Pedigree; D010750:Phosphoproteins / Q000235:genetics*
chemical_list: D016898:Interferon-alpha; D010750:Phosphoproteins; D005090:Exodeoxyribonucleases; C429526:three prime repair exonuclease 1