title: Whole-Exome Sequencing Reveals Mutations in Genes Linked to Hemophagocytic Lymphohistiocytosis and Macrophage Activation Syndrome in Fatal Cases of H1N1 Influenza.
abstract: BACKGROUND
  Severe H1N1 influenza can be lethal in otherwise healthy individuals and can have features of reactive hemophagocytic lymphohistiocytosis (HLH). HLH is associated with mutations in lymphocyte cytolytic pathway genes, which have not been previously explored in H1N1 influenza.
  
  
  METHODS
  Sixteen cases of fatal influenza A(H1N1) infection, 81% with histopathologic hemophagocytosis, were identified and analyzed for clinical and laboratory features of HLH, using modified HLH-2004 and macrophage activation syndrome (MAS) criteria. Fourteen specimens were subject to whole-exome sequencing. Sequence alignment and variant filtering detected HLH gene mutations and potential disease-causing variants. Cytolytic function of the PRF1 p.A91V mutation was tested in lentiviral-transduced NK-92 natural killer (NK) cells.
  
  
  RESULTS
  Despite several lacking variables, cases of influenza A(H1N1) infection met 44% and 81% of modified HLH-2004 and MAS criteria, respectively. Five subjects (36%) carried one of 3 heterozygous LYST mutations, 2 of whom also possessed the p.A91V PRF1 mutation, which was shown to decrease NK cell cytolytic function. Several patients also carried rare variants in other genes previously observed in MAS.
  
  
  CONCLUSIONS
  This cohort of fatal influenza A(H1N1) infections confirms the presence of hemophagocytosis and HLH pathology. Moreover, the high percentage of HLH gene mutations suggests they are risk factors for mortality among individuals with influenza A(H1N1) infection.
authors.affiliation: Division of Pediatric Rheumatology, Cincinnati Children's Hospital Medical Center, Ohio.
authors.forename: Grant S
authors.initials: GS
authors.lastname: Schulert
authors.affiliation: Division of Pediatric Rheumatology, Children's Hospital of Alabama/University of Alabama at Birmingham.
authors.forename: Mingce
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Division of Pediatric Rheumatology, Cincinnati Children's Hospital Medical Center, Ohio.
authors.forename: Ndate
authors.initials: N
authors.lastname: Fall
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Ohio.
authors.forename: Ammar
authors.initials: A
authors.lastname: Husami
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Ohio.
authors.forename: Diane
authors.initials: D
authors.lastname: Kissell
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor.
authors.forename: Andrew
authors.initials: A
authors.lastname: Hanosh
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Ohio.
authors.forename: Kejian
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor.
authors.forename: Kristina
authors.initials: K
authors.lastname: Davis
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Jentzen
authors.affiliation: Department of Surgery, University of Michigan Medical School, Ann Arbor.
authors.forename: Lena
authors.initials: L
authors.lastname: Napolitano
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor.
authors.forename: Javed
authors.initials: J
authors.lastname: Siddiqui
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor.
authors.forename: Lauren B
authors.initials: LB
authors.lastname: Smith
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor Department of Dermatology, University of Michigan Medical School, Ann Arbor Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Harms
authors.affiliation: Division of Pediatric Rheumatology, Cincinnati Children's Hospital Medical Center, Ohio.
authors.forename: Alexei A
authors.initials: AA
authors.lastname: Grom
authors.affiliation: Division of Pediatric Rheumatology, Children's Hospital of Alabama/University of Alabama at Birmingham.
authors.forename: Randy Q
authors.initials: RQ
authors.lastname: Cron
mesh_terms: D015331:Cohort Studies; D059472:Exome; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype; D007251:Influenza, Human / Q000235:genetics* / Q000401:mortality; D007694:Killer Cells, Natural / Q000502:physiology; D051359:Lymphohistiocytosis, Hemophagocytic / Q000235:genetics*; D055501:Macrophage Activation Syndrome / Q000235:genetics*; D008297:Male; D009154:Mutation; D054353:Perforin / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA
chemical_list: D054353:Perforin
keywords: H1N1 influenza; LYST; cytolytic pathway; hemophagocytosis; macrophage activation syndrome; perforin