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Study Objectives: To identify potential rare alleleicallelic variants and evaluate the distribution of HLA alleles in narcolepsy patients with hypocretin (orexin,HCRT) deficiency but lacking the DQB1*06:02 susceptibility alleleTo examine the occurrence of rare allele variants and evaluate the distribution of HLA alleles in narcolepsy patients negative for the susceptibility allele DQB1*06:02 and with hypocretin (orexin, HCRT) deficiency.Settings: China (Peking University Peoples Hospital), Czech Republic (Charles University), Denmark (Golstrup Hospital), Italy(University of Bologna), Korea (Catholic University) and USA (Stanford University).Design: CSF hypocretin-1, DQB1*06:02, clinical and polysomnographic data were collected in narcolepsy patients (552 with, and 144 without cataplexy) from 4 sites.Numbers of cases with and without DQB1*06:02 and low CSF Hypocretin-1 levels were compiled.HLA class Ⅰ (A, B, C), class Ⅱ (DRBs, DQA1, DQB1 but not DP, DPA1and 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.CSF hypocretin-1, DQB1*06:02, clinical and polysomnographic data was collected in narcolepsy patients at 4 sites, after exclusion of secondary cases, totaling 522 cases with and 144 without cataplexy.The number of cases with and without low CSF hypocretin-1 and with and without DQB1*06:02 was compiled.HLA class Ⅰ (A, B, C), class Ⅱ (DRBs, DQ A1, DQB1, DPA1 and DPB1) and whole exome sequencing were conducted in 9 DQ B1*06:02 negative cases with low CSF hypocretin-1.As confirmation, Sanger sequencing of selected exons in DNMT1, HCRT and MOG was also performed to exclude known narcolepsy-associated mutations in these genes.Measurements and 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 0.5%-31.7%[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.Four 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.Hypocretin gene 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.In cases with and without cataplexy, 87.4% and 20.0% were DQB1*06:02 positive with low CSF hypocretin-1 respectively.Nine DQB1*06:02 negative cases with low CSF hypocretin-1 constituted 0.5% to 3% of cases with cataplexy (none without cataplexy) across sites.Four subjects had severe cataplexy, often occurring without any clear triggers.Subjects had diverse ethnic background and HLA alleles at all loci, suggesting no single secondary HLA association.Hypocretin gene sequencing did not reveal any new mutation beside a previously reported L to R substitution in the signal peptide of the preprohypcretin gene in a very early onset case.No new MOG or DNMT1 mutations were found, and these cases did not share suspicious rare or private variants in any given gene.Conclusions: HLA-DQB1*06:02 negative cases with hypocretin deficiency do not share another single HLA allele or special mutations.Hypocretin gene or MOG or DNMT1 mutations are exceptional findings in DQB1*06:02 negative cases with hypocretin deficiency.These cases represent particularly difficult diagnostic challenges.