title: HLA DQB1*06:02 negative narcolepsy with hypocretin/orexin deficiency.
abstract: OBJECTIVE
  To identify rare allelic variants and HLA alleles in narcolepsy patients with hypocretin (orexin, HCRT) deficiency but lacking DQB1*06:02.
  
  
  METHODS
  China (Peking University People's Hospital), Czech Republic (Charles University), Denmark (Golstrup Hospital), Italy (University of Bologna), Korea (Catholic University), and USA (Stanford University).
  
  
  METHODS
  CSF hypocretin-1, DQB1*06:02, clinical and polysomnographic data were collected in narcolepsy patients (552 with and 144 without cataplexy) from 6 sites. Numbers of cases with and without DQB1*06:02 and low CSF hypocretin-1 were compiled. HLA class I (A, B, C), class II (DRBs, DQA1, DQB1, DPA1, and DPB1), and whole exome sequencing were conducted in 9 DQB1*06:02 negative cases with low CSF hypocretin-1. Sanger sequencing of selected exons in DNMT1, HCRT, and MOG was performed to exclude mutations in known narcolepsy-associated genes.
  
  
  RESULTS
  Classic narcolepsy markers DQB1*06:02 and low CSF hypocretin-1 were found in 87.4% of cases with cataplexy, and in 20.0% without cataplexy. Nine cases (all with cataplexy) were DQB1*06:02 negative with low CSF hypocretin-1, constituting 1.7% [0.8%-3.4%] of all cases with cataplexy and 1.8% [0.8%-3.4%] of cases with low CSF hypocretin independent of cataplexy across sites. Five HLA negative subjects had severe cataplexy, often occurring without clear triggers. Subjects had diverse ethnic backgrounds and HLA alleles at all loci, suggesting no single secondary HLA association. The rare subtype DPB1*0901, and homologous DPB1*10:01 subtype, were present in 5 subjects, suggesting a secondary association with HLA-DP. Preprohypocretin sequencing revealed no mutations beyond one previously reported in a very early onset case. No new MOG or DNMT1 mutations were found, nor were suspicious or private variants in novel genes identified through exome sequencing.
  
  
  CONCLUSIONS
  Hypocretin, MOG, or DNMT1 mutations are exceptional findings in DQB1*06:02 negative cases with hypocretin deficiency. A secondary HLA-DP association may be present in these cases. These represent particularly difficult diagnostic challenges.
authors.affiliation: Department of Pulmonary Medicine, the Peking University People's Hospital, Beijing, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Han
authors.affiliation: Center for Sleep Sciences and Medicine, and Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA.
authors.forename: Ling
authors.initials: L
authors.lastname: Lin
authors.affiliation: Institute of Human Genetics, Technische Universität München, Munich, Germany and Institute of Human Genetics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Schormair
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna and IRCCS Institute of Neurological Sciences, Bologna, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Pizza
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna and IRCCS Institute of Neurological Sciences, Bologna, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Plazzi
authors.affiliation: Center for Sleep Sciences and Medicine, and Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA.
authors.forename: Hanna M
authors.initials: HM
authors.lastname: Ollila
authors.affiliation: Department of Neurology, Charles University in Prague, 1st Faculty of Medicine, Czech Republic.
authors.forename: Sona
authors.initials: S
authors.lastname: Nevsimalova
authors.affiliation: Danish Center for Sleep Medicine, Department of Clinical Neurophysiology, Glostrup Hospital, University of Copenhagen, Denmark.
authors.forename: Poul
authors.initials: P
authors.lastname: Jennum
authors.affiliation: Danish Center for Sleep Medicine, Department of Clinical Neurophysiology, Glostrup Hospital, University of Copenhagen, Denmark and Norwegian Resource Center for ADHD, TS and Narcolepsy (NK), Oslo University Hospital, Ullevål, Norway.
authors.forename: Stine
authors.initials: S
authors.lastname: Knudsen
authors.affiliation: Center for Sleep Sciences and Medicine, and Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA and Institute of Human Genetics, Technische Universität München, Munich, Germany and Institute of Human Genetics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Winkelmann
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA.
authors.forename: Cristin
authors.initials: C
authors.lastname: Coquillard
authors.affiliation: Stanford Genome Technology Center, Stanford University, Palo Alto, CA.
authors.forename: Farbod
authors.initials: F
authors.lastname: Babrzadeh
authors.affiliation: Institute of Human Genetics, Technische Universität München, Munich, Germany and Institute of Human Genetics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.affiliation: Stanford Genome Technology Center, Stanford University, Palo Alto, CA.
authors.forename: Chunlin
authors.initials: C
authors.lastname: Wang
authors.affiliation: Stanford Genome Technology Center, Stanford University, Palo Alto, CA.
authors.forename: Michael
authors.initials: M
authors.lastname: Mindrinos
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Fernandez Vina
authors.affiliation: Center for Sleep Sciences and Medicine, and Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Mignot
mesh_terms: D000483:Alleles; D002385:Cataplexy / Q000235:genetics; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D059866:HLA-DQ beta-Chains / Q000235:genetics*; D006801:Humans; D038622:Internationality; D047908:Intracellular Signaling Peptides and Proteins / Q000134:cerebrospinal fluid / Q000172:deficiency* / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000235:genetics; D009290:Narcolepsy / Q000235:genetics*; D009479:Neuropeptides / Q000134:cerebrospinal fluid / Q000172:deficiency* / Q000235:genetics*; D000068797:Orexins; D012097:Repressor Proteins / Q000235:genetics
chemical_list: C411744:DMAP1 protein, human; C000596229:HCRT protein, human; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D047908:Intracellular Signaling Peptides and Proteins; C571326:MOG protein, human; D063308:Myelin-Oligodendrocyte Glycoprotein; D009479:Neuropeptides; D000068797:Orexins; D012097:Repressor Proteins
keywords: DNMT1; HLA; MHC; MOG; cataplexy; exome sequencing; hypocretin; narcolepsy; orexin