Narcolepsy-cataplexy syndrome

disease

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Also known as Gelineau diseaseGelineau syndromeGelineau's syndromeGélineau diseasenarcolepsy type 1narcolepsy with cataplexynarcoleptic syndrome

Summary

Narcolepsy-cataplexy syndrome (MONDO:0016158) is a disease with 21 cohort genes (49 GWAS associations across 10 studies) and 49 clinical trials. Top therapeutic interventions include pitolisant, sodium oxybate, and clarithromycin.

At a glance

Prevalence: 1-5 / 10 000 (Europe) [Orphanet-validated]
Cohort genes: 21
GWAS associations: 49
ClinVar variants: 4
Phenotypes (HPO): 30
Clinical trials: 49

Clinical features

Epidemiology

Prevalence records

7 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000	30	Europe	Validated
Annual incidence	1-9 / 1 000 000	0.74	United States	Validated
Point prevalence	1-5 / 10 000	22	Norway	Validated
Point prevalence	1-5 / 10 000	26	Finland	Validated
Point prevalence	1-5 / 10 000	34	China	Validated
Point prevalence	1-5 / 10 000	40	United Kingdom	Validated
Point prevalence	1-5 / 10 000	28.9	United States	Not yet validated

Signs & symptoms

Clinical features (HPO)

30 HPO clinical features (Orphanet curated; top 30 by frequency):

HPO ID	Term	Frequency
HP:0000738	Hallucinations	Very frequent (80-99%)
HP:0001262	Excessive daytime somnolence	Very frequent (80-99%)
HP:0002360	Sleep abnormality	Very frequent (80-99%)
HP:0002524	Cataplexy	Very frequent (80-99%)
HP:0010534	Transient global amnesia	Very frequent (80-99%)
HP:0007018	Attention deficit hyperactivity disorder	Frequent (30-79%)
HP:0007686	Abnormal pupillary function	Frequent (30-79%)
HP:0012452	Restless legs	Frequent (30-79%)
HP:0025235	Non-rapid eye movement parasomnia	Frequent (30-79%)
HP:0030014	Female sexual dysfunction	Frequent (30-79%)
HP:0040307	Male sexual dysfunction	Frequent (30-79%)
HP:0000017	Nocturia	Frequent (30-79%)
HP:0000739	Anxiety	Frequent (30-79%)
HP:0000822	Hypertension	Frequent (30-79%)
HP:0000975	Hyperhidrosis	Frequent (30-79%)
HP:0002019	Constipation	Frequent (30-79%)
HP:0002307	Drooling	Frequent (30-79%)
HP:0002494	Abnormal rapid eye movement sleep	Frequent (30-79%)
HP:0002519	Hypnagogic hallucinations	Frequent (30-79%)
HP:0006896	Hypnopompic hallucinations	Frequent (30-79%)
HP:0000711	Restlessness	Occasional (5-29%)
HP:0000716	Depression	Occasional (5-29%)
HP:0000826	Precocious puberty	Occasional (5-29%)
HP:0001279	Syncope	Occasional (5-29%)
HP:0001350	Slurred speech	Occasional (5-29%)
HP:0001513	Obesity	Occasional (5-29%)
HP:0002076	Migraine	Occasional (5-29%)
HP:0010535	Sleep apnea	Occasional (5-29%)
HP:0025233	Sleep paralysis	Occasional (5-29%)
HP:0000709	Psychosis	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	narcolepsy-cataplexy syndrome
Mondo ID	MONDO:0016158
Orphanet	2073
ICD-10-CM	G47.4, G47.411
ICD-11	1851015159
UMLS	C0751362
MedGen	199638
GARD	0007162
MedDRA	10028713
Is cancer (heuristic)	no

Also known as: Gelineau disease · Gelineau syndrome · Gelineau’s syndrome · Gélineau disease · narcolepsy type 1 · narcolepsy with cataplexy · narcolepsy-cataplexy syndrome · narcoleptic syndrome

Data availability: 4 ClinVar variants · 49 GWAS associations (10 studies).

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › narcolepsy-cataplexy syndrome

Subtypes (3): narcolepsy 1, narcolepsy 3, narcolepsy 7

Genetics & variants

GWAS landscape

49 GWAS associations across 10 studies. Top hits map to 24 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs1154155	7e-86	TRAJ10 - TRAJ9	G	0.48
rs9271117	6e-14	HLA-DRB1 - HLA-DQA1	?	1.75
rs2096464	7e-14	IL10RB - IFNAR1	T	0.17
rs7458379	9e-13	TRBV7-1 - TRBV4-2	T	0.16
rs10995245	3e-12	LINC02929	A	0.15
rs9270965	5e-12	HLA-DRB1 - HLA-DQA1	?	1.72
rs3815556	7e-11	CD207	G	0.25
rs34593439	8e-11	CTSH	A	0.23
rs72917118	1e-10	NEMP2-DT	T	0.21
rs1551570	4e-10	PPAN-P2RY11, PPAN	?	1.32
rs11171731	5e-10	RPS26 - ERBB3	T	0.15
rs2289702	1e-09	CTSH	?	1.34
rs12131588	1e-09	DENND1B	A	0.17
rs7112455	1e-09	CTSC	A	0.25
rs6034239	3e-09	SIRPG-AS1, SIRPG	A	0.13
rs78325861	3e-09	PALD1	G	0.33
rs7744020	8e-09	HLA-DQA1 - HLA-DQB1	A	1.9
rs198811	1e-08	H2AC6	A	1.69
rs2834188	2e-08	IL10RB - IFNAR1	?	1.3
rs9274477	2e-08	HLA-DQB1	G	1.82
rs10158467	2e-08	GOT2P2 - TNFSF4	G	0.16
rs2858884	3e-08	HLA-DQB3 - HLA-DQA2	A	1.79
rs17212223	3e-08	HLA-DQB1 - MTCO3P1	T	1.95
rs2854536	4e-08	TRBV7-2 - TRBV8-1	?	1.28
rs7553711	4e-08	TNFSF4	C	1.33
rs5770917	6e-08	CHKB-CPT1B	C	1.63
rs2859998	1e-07	UBXN2B	?	4.41
rs12425451	2e-07	TEAD4 - RPL13AP24	?	6.79
rs10915020	5e-07	MIR552 - SMIM12	A	1.32
rs17882041	1e-06	TMEM123 - MMP7	?	0.66

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST005522	Faraco J	2013	1,886	10,421	ImmunoChip study implicates antigen presentation to T cells in narcolepsy.
GCST002260	Han F	2013	1,189	1,997	Genome wide analysis of narcolepsy in China implicates novel immune loci and reveals changes in association prior to versus after the 2009 H1N1 influenza pandemic.
GCST011662	Ouyang H	2020	903	1,982	Constructing gene network for type 1 narcolepsy based on genome-wide association study and differential gene expression analysis (STROBE).
GCST002259	Han F	2013	893	0	Genome wide analysis of narcolepsy in China implicates novel immune loci and reveals changes in association prior to versus after the 2009 H1N1 influenza pandemic.
GCST000385	Hallmayer J	2009	807	1,074	Narcolepsy is strongly associated with the T-cell receptor alpha locus.
GCST001909	Luca G	2013	585	0	Clinical, polysomnographic and genome-wide association analyses of narcolepsy with cataplexy: a European Narcolepsy Network study.
GCST000771	Hor H	2010	562	0	Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy.
GCST002912	Toyoda H	2015	409	1,562	A polymorphism in CCR1/CCR3 is associated with narcolepsy.
GCST000236	Miyagawa T	2008	222	0	Variant between CPT1B and CHKB associated with susceptibility to narcolepsy.
GCST90293089	Ollila HM	2023	213	1,747	Narcolepsy risk loci outline role of T cell autoimmunity and infectious triggers in narcolepsy.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	2
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	40

MAF distribution

Bucket	Variants
common (>=0.05)	41
low_freq (0.01-0.05)	1
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intergenic_variant	21
intron_variant	19
missense_variant	1
stop_gained	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs1154155	14	22533736	G>A,T	0.05	intergenic_variant	TRAJ10 - TRAJ9	7e-86	Tier 4: intronic/intergenic
rs9271117	6	32609018	C>T	0.05	intergenic_variant	HLA-DRB1 - HLA-DQA1	6e-14	Tier 4: intronic/intergenic
rs2096464	21	33313744	G>A,T	0.05	intergenic_variant	IL10RB - IFNAR1	7e-14	Tier 4: intronic/intergenic
rs7458379	7	142338339	C>A,G,T	0.05	intergenic_variant	TRBV7-1 - TRBV4-2	9e-13	Tier 4: intronic/intergenic
rs10995245	10	62631615	G>A,C	0.05	intron_variant	LINC02929	3e-12	Tier 4: intronic/intergenic
rs9270965	6	32605694	A>C,G	0.05	intergenic_variant	HLA-DRB1 - HLA-DQA1	5e-12	Tier 4: intronic/intergenic
rs3815556	2	70832022	A>G	0.05	intron_variant	CD207	7e-11	Tier 4: intronic/intergenic
rs34593439	15	78942615	G>A,C	0.05	intron_variant	CTSH	8e-11	Tier 4: intronic/intergenic
rs72917118	2	190621355	C>T	0.05	intron_variant	NEMP2-DT	1e-10	Tier 4: intronic/intergenic
rs1551570	19	10107354	C>G,T	0.458	intron_variant	PPAN-P2RY11, PPAN	4e-10	Tier 4: intronic/intergenic
rs11171731	12	56049558	C>A,G,T	0.05	intergenic_variant	RPS26 - ERBB3	5e-10	Tier 4: intronic/intergenic
rs2289702	15	78944951	C>T	0.05	missense_variant	CTSH	1e-09	Tier 1: coding
rs12131588	1	197696981	G>A	0.05	intron_variant	DENND1B	1e-09	Tier 4: intronic/intergenic
rs7112455	11	88318125	T>A	0.05	intron_variant	CTSC	1e-09	Tier 4: intronic/intergenic
rs6034239	20	1635491	G>A,C,T	0.05	stop_gained	SIRPG-AS1, SIRPG	3e-09	Tier 1: coding
rs78325861	10	70618733	C>G	0.05	intergenic_variant	PALD1	3e-09	Tier 4: intronic/intergenic
rs7744020	6	32658353	G>A	0.272	intergenic_variant	HLA-DQA1 - HLA-DQB1	8e-09	Tier 4: intronic/intergenic
rs198811	6	26128218	C>G,T	0.19	intron_variant	H2AC6	1e-08	Tier 4: intronic/intergenic
rs2834188	21	33316948	A>C,G,T	0.295	intergenic_variant	IL10RB - IFNAR1	2e-08	Tier 4: intronic/intergenic
rs9274477	6	32665936	A>G,T	0.292	intron_variant	HLA-DQB1	2e-08	Tier 4: intronic/intergenic
rs10158467	1	173162354	A>G,T	0.05	intergenic_variant	GOT2P2 - TNFSF4	2e-08	Tier 4: intronic/intergenic
rs2858884	6	32732306	A>C,G,T	0.19	intergenic_variant	HLA-DQB3 - HLA-DQA2	3e-08	Tier 4: intronic/intergenic
rs17212223	6	32683763	C>T	0.191	intergenic_variant	HLA-DQB1 - MTCO3P1	3e-08	Tier 4: intronic/intergenic
rs2854536	7	142357119	C>A,G,T	0.292	intergenic_variant	TRBV7-2 - TRBV8-1	4e-08	Tier 4: intronic/intergenic
rs7553711	1	173162769	T>A,C	0.285	intergenic_variant	TNFSF4	4e-08	Tier 4: intronic/intergenic
rs5770917	22	50578924	T>C,G	0.17	intron_variant	CHKB-CPT1B	6e-08	Tier 4: intronic/intergenic
rs2859998	8	58411603	G>A,C,T	0.05	intron_variant	UBXN2B	1e-07	Tier 4: intronic/intergenic
rs12425451	12	3055757	C>G,T	0.05	intron_variant	TEAD4 - RPL13AP24	2e-07	Tier 4: intronic/intergenic
rs10915020	1	34692115	T>A	0.084	intergenic_variant	MIR552 - SMIM12	5e-07	Tier 4: intronic/intergenic
rs17882041	11	102519612	G>A,T	0.05	intergenic_variant	TMEM123 - MMP7	1e-06	Tier 4: intronic/intergenic

ClinVar germline variants

4 retrieved; paginated sample, class counts are floors:

4 association

ClinVar	Variant (HGVS)	Gene	Classification	Review
180728	NM_002566.4(P2RY11):c.*638G>A	EIF3G	association	no assertion criteria provided
180730	NM_003755.5(EIF3G):c.596-260T>C	EIF3G	association	no assertion criteria provided
180725	NM_020230.7(PPAN):c.190-151C>T	PPAN	association	no assertion criteria provided
180727	NM_002566.4(P2RY11):c.-203A>G	PPAN	association	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 10 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 4

Dual-evidence genes (GWAS + Mendelian — highest-confidence targets)

Gene	HGNC	Evidence routes
ZNF365	ZNF365	GWAS, Orphanet
CTSH	CTSH	GWAS, Orphanet
DNMT1	DNMT1	GWAS, Orphanet
P2RY11	P2RY11	GWAS, Orphanet

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
THRB	Orphanet:566243	Resistance to thyroid hormone due to a mutation in thyroid hormone receptor beta
TRA	Orphanet:99861	Precursor T-cell acute lymphoblastic leukemia
CCR1	Orphanet:117	Behçet disease
ZNF365	Orphanet:2073	Narcolepsy type 1
ZNF365	Orphanet:83465	Narcolepsy type 2
CTSH	Orphanet:2073	Narcolepsy type 1
DNMT1	Orphanet:314404	Autosomal dominant cerebellar ataxia-deafness-narcolepsy syndrome
DNMT1	Orphanet:456318	Hereditary sensory neuropathy-deafness-dementia syndrome
IL10RB	Orphanet:238569	Immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections syndrome
P2RY11	Orphanet:2073	Narcolepsy type 1

Cohort genes → proteins

21 cohort genes, 19 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	19
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TEAD4	HGNC:11717	ENSG00000197905	Q15561	Transcriptional enhancer factor TEF-3	gwas
THRB	HGNC:11799	ENSG00000151090	P10828	Thyroid hormone receptor beta	gwas
TRA	HGNC:12027		P0DSE1	M1-specific T cell receptor alpha chain	gwas
TRAJ10	HGNC:12038	ENSG00000211879		T cell receptor alpha joining 10	gwas
CCR1	HGNC:1602	ENSG00000163823	P32246	C-C chemokine receptor type 1	gwas
CCR3	HGNC:1604	ENSG00000183625	P51677	C-C chemokine receptor type 3	gwas
ZNF365	HGNC:18194	ENSG00000138311	Q70YC4	Talanin	gwas
CPT1B	HGNC:2329	ENSG00000205560	Q92523	Carnitine O-palmitoyltransferase 1, muscle isoform	gwas
A1CF	HGNC:24086	ENSG00000148584	Q9NQ94	APOBEC1 complementation factor	gwas
CTSH	HGNC:2535	ENSG00000103811	P09668	Pro-cathepsin H	gwas
UBXN2B	HGNC:27035	ENSG00000215114	Q14CS0	UBX domain-containing protein 2B	gwas
DNMT1	HGNC:2976	ENSG00000130816	P26358	DNA (cytosine-5)-methyltransferase 1	gwas
EIF3G	HGNC:3274	ENSG00000130811	O75821	Eukaryotic translation initiation factor 3 subunit G	clinvar
MIR552	HGNC:32808	ENSG00000207941		microRNA 552	gwas
GJB5	HGNC:4287	ENSG00000189280	O95377	Gap junction beta-5 protein	gwas
H2AC6	HGNC:4733	ENSG00000180573	Q93077	Histone H2A type 1-C	gwas
HLA-DQA2	HGNC:4943	ENSG00000237541	P01906	HLA class II histocompatibility antigen, DQ alpha 2 chain	gwas
IL10RB	HGNC:5965	ENSG00000243646	Q08334	Interleukin-10 receptor subunit beta	gwas
P2RY11	HGNC:8540	ENSG00000244165	Q96G91	P2Y purinoceptor 11	gwas
PPAN	HGNC:9227	ENSG00000130810	Q9NQ55	Suppressor of SWI4 1 homolog	clinvar
PKN2	HGNC:9406	ENSG00000065243	Q16513	Serine/threonine-protein kinase N2	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TEAD4	Transcriptional enhancer factor TEF-3	Transcription factor which plays a key role in the Hippo signaling pathway, a pathway involved in organ size control and tumor suppression by restricting proliferation and promoting apoptosis.
THRB	Thyroid hormone receptor beta	Nuclear hormone receptor that can act as a repressor or activator of transcription.
TRA	M1-specific T cell receptor alpha chain	The alpha chain of TRAV2701J4201C01/TRBV1901J2S701C02 alpha-beta T cell receptor (TR) clonotype that is specific for HLA-A*02:01-restricted M/matrix protein 1 immunodominant epitope GILGFVFTL of influenza A virus (IAV).
CCR1	C-C chemokine receptor type 1	Chemokine receptor that plays a crucial role in regulating immune cell migration, inflammation, and immune responses.
CCR3	C-C chemokine receptor type 3	G protein-coupled receptor (GPCR) that plays a key role in the immune system by regulating the migration and activation of white blood cells in response to chemokines.
ZNF365	Talanin	May play a role in uric acid excretion.
CPT1B	Carnitine O-palmitoyltransferase 1, muscle isoform	Catalyzes the transfer of the acyl group of long-chain fatty acid-CoA conjugates onto carnitine, an essential step for the mitochondrial uptake of long-chain fatty acids and their subsequent beta-oxidation in the mitochondrion.
A1CF	APOBEC1 complementation factor	Essential component of the apolipoprotein B mRNA editing enzyme complex which is responsible for the postranscriptional editing of a CAA codon for Gln to a UAA codon for stop in APOB mRNA.
CTSH	Pro-cathepsin H	Important for the overall degradation of proteins in lysosomes.
UBXN2B	UBX domain-containing protein 2B	Adapter protein required for Golgi and endoplasmic reticulum biogenesis.
DNMT1	DNA (cytosine-5)-methyltransferase 1	DNA methyltransferase that methylates CpG residues.
EIF3G	Eukaryotic translation initiation factor 3 subunit G	RNA-binding component of the eukaryotic translation initiation factor 3 (eIF-3) complex, which is required for several steps in the initiation of protein synthesis.
GJB5	Gap junction beta-5 protein	One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell.
H2AC6	Histone H2A type 1-C	Core component of nucleosome.
HLA-DQA2	HLA class II histocompatibility antigen, DQ alpha 2 chain	Binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells.
IL10RB	Interleukin-10 receptor subunit beta	Shared cell surface receptor required for the activation of five class 2 cytokines: IL10, IL22, IL26, IL28, and IFNL1.
P2RY11	P2Y purinoceptor 11	Receptor for ATP and ADP coupled to G-proteins that activate both phosphatidylinositol-calcium and adenylyl cyclase second messenger systems.
PPAN	Suppressor of SWI4 1 homolog	May have a role in cell growth.
PKN2	Serine/threonine-protein kinase N2	PKC-related serine/threonine-protein kinase and Rho/Rac effector protein that participates in specific signal transduction responses in the cell.

Protein-family classification

Druggable: 10 · Difficult: 2 · Unknown: 9 · Druggable fraction: 0.48

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Nuclear receptor	1	18.4×	0.147
Antibody/Immunoglobulin	3	4.2×	0.147
GPCR	3	3.4×	0.147
Protease	1	1.7×	0.861
Kinase	1	1.3×	0.861
Transcription factor	2	0.8×	0.921
Other/Unknown	9	0.8×	0.921
Enzyme (other)	1	0.6×	0.921

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TEAD4	Other/Unknown	no		TEA/ATTS_dom, TEF_metazoa, TEF-3
THRB	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt
TRA	Antibody/Immunoglobulin	yes		Ig_sub, Ig-like_dom, Ig_V-set
TRAJ10	Other/Unknown	no
CCR1	GPCR	yes		GPCR_Rhodpsn, Chemokine_rcpt, Chemokine_CCR1
CCR3	GPCR	yes		GPCR_Rhodpsn, Chemokine_rcpt, Chemokine_CCR3
ZNF365	Transcription factor	no		GenomicStab_NeuMorph_Reg, FBX41/ZN365_Znf-C2H2
CPT1B	Enzyme (other)	yes	2.3.1.21	Carn_acyl_trans, CAT-like_dom_sf, CPT_N
A1CF	Other/Unknown	no		RRM_dom, HnRNP_R/Q_splicing_fac, Nucleotide-bd_a/b_plait_sf
CTSH	Protease	yes	3.4.22.16	Pept_cys_AS, Peptidase_C1A_C, Peptidase_C1A
UBXN2B	Other/Unknown	no		UBX_dom, SEP_domain, Ubiquitin-like_domsf
DNMT1	Transcription factor	no	2.1.1.37	BAH_dom, C5_MeTfrase, Znf_CXXC
EIF3G	Other/Unknown	no		RRM_dom, Nucleotide-bd_a/b_plait_sf, eIF3_g
MIR552	Other/Unknown	no
GJB5	Other/Unknown	no		Connexin, Connexin311, Connexin_N
H2AC6	Other/Unknown	no		Histone_H2A, H2A/H2B/H3, Histone-fold
HLA-DQA2	Antibody/Immunoglobulin	yes		MHC_II_a_N, Ig/MHC_CS, Ig_C1-set
IL10RB	Antibody/Immunoglobulin	yes		FN3_dom, Ig-like_fold, Interferon/interleukin_rcp_dom
P2RY11	GPCR	yes		GPCR_Rhodpsn, GPCR_Rhodpsn_7TM, P2Y11_rcpt
PPAN	Other/Unknown	no		Brix, PPAN-like
PKN2	Kinase	yes	2.7.11.13	C2_dom, Prot_kinase_dom, AGC-kinase_C

Expression context

Cohort genes with no expression data: 1.

14 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	1
broad (>20)	19
unknown	1

Top tissues across cohort

Tissue	Cohort genes
granulocyte	5
blood	4
monocyte	4
leukocyte	3
secondary oocyte	3
gastrocnemius	2
Brodmann (1909) area 23	2
middle temporal gyrus	2
vermiform appendix	2
mononuclear cell	2
oocyte	2
sural nerve	2
hindlimb stylopod muscle	1
muscle of leg	1
tibia	1
lateral nuclear group of thalamus	1
apex of heart	1
heart left ventricle	1
right atrium auricular region	1
ileal mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TEAD4	220	ubiquitous	marker	hindlimb stylopod muscle, gastrocnemius, muscle of leg
THRB	267	ubiquitous	marker	Brodmann (1909) area 23, middle temporal gyrus, tibia
TRA
TRAJ10	86		yes	granulocyte, vermiform appendix, blood
CCR1	244	broad	marker	monocyte, mononuclear cell, leukocyte
CCR3	100	tissue_specific	yes	secondary oocyte, blood, oocyte
ZNF365	206	broad	yes	middle temporal gyrus, lateral nuclear group of thalamus, Brodmann (1909) area 23
CPT1B	142	tissue_specific	yes	apex of heart, heart left ventricle, right atrium auricular region
A1CF	78	tissue_specific	marker	liver, jejunal mucosa, ileal mucosa
CTSH	290	ubiquitous	marker	cranial nerve II, nephron tubule, lower lobe of lung
UBXN2B	292	ubiquitous	marker	cortical plate, blood, ganglionic eminence
DNMT1	266	ubiquitous	marker	oocyte, secondary oocyte, sural nerve
EIF3G	301	ubiquitous	marker	granulocyte, body of pancreas, left ovary
MIR552	19		yes	monocyte, gastrocnemius, blood
GJB5	168	broad	marker	lower esophagus mucosa, skin of abdomen, esophagus mucosa
H2AC6	288	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
HLA-DQA2	127	broad	marker	granulocyte, vermiform appendix, male germ line stem cell (sensu Vertebrata) in testis
IL10RB	142	ubiquitous	marker	placenta, monocyte, leukocyte
P2RY11	134	broad	yes	granulocyte, right uterine tube, skin of leg
PPAN	239	ubiquitous	marker	sural nerve, granulocyte, mucosa of transverse colon
PKN2	300	ubiquitous	marker	tongue squamous epithelium, nipple, secondary oocyte

Protein interactions among cohort

Intra-cohort edges: 4.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DNMT1	7,179
EIF3G	3,482
CCR1	2,912
PKN2	2,710
PPAN	2,505
TEAD4	2,432
CTSH	2,087
THRB	2,044
H2AC6	1,960
CCR3	1,741

Intra-cohort edges

A	B	Sources
CCR1	CCR3	string_interaction
EIF3G	P2RY11	string_interaction
EIF3G	PPAN	string_interaction
P2RY11	PPAN	string_interaction

Structural data

PDB: 14 · AlphaFold-only: 5 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
THRB	P10828	34
DNMT1	P26358	27
H2AC6	Q93077	26
TEAD4	Q15561	23
EIF3G	O75821	19
TRA	P0DSE1	13
IL10RB	Q08334	5
PPAN	Q9NQ55	4
PKN2	Q16513	4
CCR1	P32246	3
CTSH	P09668	2
CCR3	P51677	1
A1CF	Q9NQ94	1
UBXN2B	Q14CS0	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CPT1B	Q92523	92.31
HLA-DQA2	P01906	89.29
P2RY11	Q96G91	81.11
GJB5	O95377	78.61
ZNF365	Q70YC4	30.21

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 121. Enrichment computed across 21 evidence-associated genes (15 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 15 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Interleukin-10 signaling	2	31.1×	0.102	CCR1, IL10RB
Chemokine receptors bind chemokines	2	25.0×	0.102	CCR1, CCR3
DNA methylation	2	23.8×	0.102	DNMT1, H2AC6
Defective pyroptosis	2	20.9×	0.102	DNMT1, H2AC6
PRC2 methylates histones and DNA	2	20.3×	0.102	DNMT1, H2AC6
RUNX3 regulates YAP1-mediated transcription	1	95.2×	0.117	TEAD4
mRNA Editing: C to U Conversion	1	84.6×	0.117	A1CF
mRNA Editing	1	84.6×	0.117	A1CF
Formation of the Editosome	1	84.6×	0.117	A1CF
STAT3 nuclear events downstream of ALK signaling	1	69.2×	0.117	DNMT1
P2Y receptors	1	63.4×	0.117	P2RY11
Formation of axial mesoderm	1	54.4×	0.117	TEAD4
Carnitine shuttle	1	50.8×	0.117	CPT1B
YAP1- and WWTR1 (TAZ)-stimulated gene expression	1	50.8×	0.117	TEAD4
Maternal to zygotic transition (MZT)	1	47.6×	0.117	TEAD4
SUMOylation of DNA methylation proteins	1	44.8×	0.117	DNMT1
Zygotic genome activation (ZGA)	1	44.8×	0.117	TEAD4
Regulation of PD-L1(CD274) transcription	2	14.5×	0.117	TEAD4, H2AC6
NoRC negatively regulates rRNA expression	2	14.0×	0.117	DNMT1, H2AC6
MHC class II antigen presentation	2	11.9×	0.117	CTSH, HLA-DQA2
Class A/1 (Rhodopsin-like receptors)	2	9.9×	0.117	CCR1, CCR3
Peptide ligand-binding receptors	2	9.9×	0.117	CCR1, CCR3
GPCR ligand binding	2	8.6×	0.117	CCR1, CCR3
Translocation of ZAP-70 to Immunological synapse	1	42.3×	0.118	HLA-DQA2
Phosphorylation of CD3 and TCR zeta chains	1	36.2×	0.132	HLA-DQA2
Co-inhibition by PD-1	1	34.6×	0.133	HLA-DQA2
Other interleukin signaling	1	31.7×	0.139	IL10RB
Interleukin-20 family signaling	1	28.2×	0.151	IL10RB
Surfactant metabolism	1	24.6×	0.165	CTSH
Generation of second messenger molecules	1	23.1×	0.165	HLA-DQA2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 19 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cellular response to thyroid hormone stimulus	2	161.3×	0.004	THRB, CTSH
DNA-templated transcription	3	35.5×	0.004	TEAD4, THRB, DNMT1
immune response	5	12.4×	0.004	CCR1, CCR3, CTSH, HLA-DQA2, IL10RB
calcium-mediated signaling	3	28.9×	0.006	CCR1, CCR3, P2RY11
trophectodermal cell fate commitment	1	887.0×	0.020	TEAD4
cerebellar molecular layer morphogenesis	1	887.0×	0.020	ZNF365
epigenetic programming of gene expression	1	887.0×	0.020	DNMT1
dichotomous subdivision of terminal units involved in lung branching	1	887.0×	0.020	CTSH
regulation of DNA strand resection involved in replication fork processing	1	887.0×	0.020	ZNF365
embryo implantation	2	37.0×	0.020	TEAD4, A1CF
adaptive immune response	3	13.3×	0.020	TRA, CTSH, HLA-DQA2
chemokine-mediated signaling pathway	2	34.1×	0.021	CCR1, CCR3
neuropeptide catabolic process	1	443.5×	0.023	CTSH
labyrinthine layer morphogenesis	1	443.5×	0.023	GJB5
negative regulation of protein localization to centrosome	1	443.5×	0.023	UBXN2B
obsolete negative regulation of vascular associated smooth muscle cell differentiation involved in phenotypic switching	1	443.5×	0.023	DNMT1
detection of tumor cell	1	295.6×	0.023	TRA
T cell mediated cytotoxicity directed against tumor cell target	1	295.6×	0.023	TRA
female courtship behavior	1	295.6×	0.023	THRB
mRNA localization resulting in post-transcriptional regulation of gene expression	1	295.6×	0.023	A1CF
gamma-tubulin complex localization	1	295.6×	0.023	ZNF365
positive regulation of mitotic centrosome separation	1	295.6×	0.023	UBXN2B
retinal cone cell apoptotic process	1	295.6×	0.023	THRB
negative regulation of vascular associated smooth muscle cell apoptotic process	1	295.6×	0.023	DNMT1
thyroid hormone receptor signaling pathway	1	221.7×	0.025	THRB
positive regulation of thyroid hormone receptor signaling pathway	1	221.7×	0.025	THRB
carnitine shuttle	1	221.7×	0.025	CPT1B
chromosomal DNA methylation maintenance following DNA replication	1	221.7×	0.025	DNMT1
chromosomal 5-methylcytosine DNA demethylation pathway	1	221.7×	0.025	A1CF
cell chemotaxis	2	19.5×	0.025	CCR1, CCR3

Therapeutics

Drug target analysis

Approved (phase 4): 5 · Phase ≥3: 5 · Phased (≥1): 9 · Undrugged: 12

Druggability breadth: 11 of 21 evidence-associated genes (52%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
THRB	AMINOCAPROIC ACID
CCR1	ABAMETAPIR
DNMT1	DECITABINE
P2RY11	ADENOSINE PHOSPHATE
PKN2	AXITINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
THRB	117	4
PKN2	38	4
CCR1	8	4
DNMT1	6	4
TEAD4	3	2
P2RY11	3	4
CCR3	2	2
CPT1B	1	2
CTSH	1	2
TRA	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
AMINOCAPROIC ACID	4	THRB
INDIGOTINDISULFONATE	4	THRB
CHLORMADINONE ACETATE	4	THRB
AMOXAPINE	4	THRB
IDARUBICIN	4	THRB
DYCLONINE HYDROCHLORIDE	4	THRB
ISOSORBIDE	4	THRB
CLOMIPRAMINE HYDROCHLORIDE	4	THRB
CHLORMEZANONE	4	THRB
PHENOXYBENZAMINE HYDROCHLORIDE	4	THRB
METHYSERGIDE MALEATE	4	THRB
LIOTHYRONINE SODIUM	4	THRB
DYCLONINE	4	THRB
ROSE BENGAL FREE ACID	4	THRB
INAMRINONE	4	THRB
MOLSIDOMINE	4	THRB
METRONIDAZOLE	4	THRB
AMILORIDE HYDROCHLORIDE	4	THRB
ALTRETAMINE	4	THRB
BISOPROLOL FUMARATE	4	THRB
ATORVASTATIN	4	THRB
OXYTETRACYCLINE	4	THRB
LIOTHYRONINE	4	THRB
MECLOFENAMATE SODIUM	4	THRB
DAUNORUBICIN HYDROCHLORIDE	4	THRB
AMANTADINE HYDROCHLORIDE	4	THRB
ACETOHEXAMIDE	4	THRB
DEBRISOQUIN SULFATE	4	THRB
PHENYTOIN SODIUM	4	THRB
LEVOTHYROXINE	4	THRB

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 4.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
PKN2	327	Binding:326, Functional:1
CCR1	243	Binding:176, Functional:67
DNMT1	233	Binding:229, Functional:3, ADMET:1
CCR3	175	Binding:107, Functional:68
THRB	169	Binding:129, Functional:40
TEAD4	131	Binding:131
CTSH	58	Binding:58
P2RY11	45	Functional:31, Binding:14
CPT1B	7	Binding:7
EIF3G	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CPT1B	2.3.1.21	carnitine O-palmitoyltransferase
CTSH	3.4.22.16	cathepsin H
DNMT1	2.1.1.37	DNA (cytosine-5-)-methyltransferase
PKN2	2.7.11.13	protein kinase C

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
TEAD4	131
THRB	169
CCR1	243
CCR3	175
DNMT1	233
PKN2	327

Pharmacogenomics

Cohort genes with a PharmGKB record: 21; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
AMINOCAPROIC ACID	4	THRB
INDIGOTINDISULFONATE	4	THRB
CHLORMADINONE ACETATE	4	THRB
AMOXAPINE	4	THRB
IDARUBICIN	4	THRB
DYCLONINE HYDROCHLORIDE	4	THRB
ISOSORBIDE	4	THRB
CLOMIPRAMINE HYDROCHLORIDE	4	THRB
CHLORMEZANONE	4	THRB
PHENOXYBENZAMINE HYDROCHLORIDE	4	THRB
METHYSERGIDE MALEATE	4	THRB
LIOTHYRONINE SODIUM	4	THRB
DYCLONINE	4	THRB
ROSE BENGAL FREE ACID	4	THRB
INAMRINONE	4	THRB
MOLSIDOMINE	4	THRB
METRONIDAZOLE	4	THRB
AMILORIDE HYDROCHLORIDE	4	THRB
ALTRETAMINE	4	THRB
BISOPROLOL FUMARATE	4	THRB
ATORVASTATIN	4	THRB
OXYTETRACYCLINE	4	THRB
LIOTHYRONINE	4	THRB
MECLOFENAMATE SODIUM	4	THRB
DAUNORUBICIN HYDROCHLORIDE	4	THRB
AMANTADINE HYDROCHLORIDE	4	THRB
ACETOHEXAMIDE	4	THRB
DEBRISOQUIN SULFATE	4	THRB
PHENYTOIN SODIUM	4	THRB
LEVOTHYROXINE	4	THRB

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	5	THRB, CCR1, DNMT1, P2RY11, PKN2
B	Phased (≥1) drug, not yet approved	4	TEAD4, CCR3, CPT1B, CTSH
C	Druggable family + PDB, no drug	2	TRA, IL10RB
D	Druggable family + AlphaFold only, no drug	1	HLA-DQA2
E	Difficult family or no structure, no drug	9	TRAJ10, ZNF365, A1CF, UBXN2B, EIF3G, MIR552, GJB5, H2AC6, PPAN

Undrugged target profiles

12 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
PPAN	0	P2RY11
TRA	0	—
TRAJ10	0	—
ZNF365	0	—
A1CF	0	—
UBXN2B	0	—
EIF3G	1	—
MIR552	0	—
GJB5	0	—
H2AC6	0	—
HLA-DQA2	0	—
IL10RB	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 49.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	23
PHASE3	10
PHASE2	9
PHASE2/PHASE3	3
PHASE1	3
PHASE4	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02637076	PHASE4	COMPLETED	Xyrem and Brain Dopamine in Narcolepsy
NCT05816382	PHASE2/PHASE3	RECRUITING	A Study of TAK-861 for the Treatment of Selected Central Hypersomnia Conditions
NCT05914194	PHASE3	NOT_YET_RECRUITING	A Eight-Week Study of NLS-2 (Mazindol Extended Release) in Participants With Narcolepsy Type 1
NCT06767683	PHASE2/PHASE3	RECRUITING	A Long-Term Study of ALKS 2680 in Subjects With Narcolepsy and Idiopathic Hypersomnia
NCT07363720	PHASE3	RECRUITING	A Trial of TAK-861 for the Treatment of Narcolepsy With Cataplexy
NCT07455383	PHASE3	RECRUITING	A Study to Evaluate the Efficacy and Safety of ALKS 2680 in Adults With Narcolepsy Type 1
NCT07540897	PHASE3	RECRUITING	A Study to Evaluate the Efficacy, Safety and Tolerability of ALKS 2680 in Adults With Narcolepsy Type 1 (Brilliance NT1 - 304)
NCT07598708	PHASE2/PHASE3	NOT_YET_RECRUITING	A Study to Investigate the Effects of Cleminorexton Compared With Placebo in the Treatment of Participants With Central Disorders of Hypersomnolence
NCT01800045	PHASE3	COMPLETED	Pitolisant to Assess Weekly Frequency of Cataplexy Attacks and EDS in Narcoleptic Patients (HARMONY CTP)
NCT02221869	PHASE3	COMPLETED	A Multicenter Study of the Efficacy and Safety of Xyrem With an Open- Label Pharmacokinetic Evaluation and Safety Extension in Pediatric Subjects With Narcolepsy With Cataplexy
NCT02611687	PHASE3	COMPLETED	Efficacy and Safety of Pitolisant in Pediatric Narcoleptic Patients With or Without Cataplexy, Double-blind Study Followed by a Prolonged Open-label Period
NCT03030599	PHASE3	COMPLETED	A Study of the Efficacy and Safety of JZP-258 in Subjects With Narcolepsy With Cataplexy
NCT06470828	PHASE3	COMPLETED	A Study of TAK-861 for the Treatment of Narcolepsy Type 1
NCT06505031	PHASE3	COMPLETED	A Study of TAK-861 in People With Narcolepsy Type 1
NCT06752668	PHASE2	RECRUITING	A Study of ORX750 in Participants With Narcolepsy and Idiopathic Hypersomnia
NCT06809803	PHASE2	RECRUITING	Extended-release Sodium Oxybate in Children
NCT07096674	PHASE2	RECRUITING	A Long-term Extension Study of ORX750 in Participants With Narcolepsy and Idiopathic Hypersomnia
NCT04026958	PHASE2	COMPLETED	Clarithromycin Mechanisms in Hypersomnia Syndromes
NCT04096560	PHASE2	TERMINATED	A Study of TAK-994 in Adults With Type 1 and Type 2 Narcolepsy
NCT04820842	PHASE2	TERMINATED	A Study of TAK-994 in Adults With Narcolepsy
NCT05055024	PHASE2	COMPLETED	An Open Label Study of NLS-2 (Mazindol Extended Release) in Subjects With Narcolepsy
NCT05687903	PHASE2	COMPLETED	A Study of TAK-861 in Participants With Narcolepsy Type 1
NCT06358950	PHASE2	COMPLETED	A Study to Evaluate the Safety and Effectiveness of ALKS 2680 in Subjects With Narcolepsy Type 1 (ALKS 2680-201)
NCT07584434	PHASE1	NOT_YET_RECRUITING	A Phase 1, First-in-human Study of VX-433
NCT00345800	PHASE1	COMPLETED	Exploratory Clinical Study to Evaluate Sodium Oxybate (Xyrem) on Potential Endocrine Changes
NCT06462404	PHASE1	COMPLETED	A Study to Evaluate the Efficacy, Safety, and Tolerability of E2086 Compared to Placebo and Active Comparator in Adult Participants With Narcolepsy Type 1
NCT06292598	Not specified	RECRUITING	Bacterial Translocation and Gut Microbiota in Type 1 Narcolepsy Patients Versus a Control Population
NCT06336057	Not specified	RECRUITING	Mentalizating in Adults Suffering from Narcolepsy Type 1.
NCT06383806	Not specified	NOT_YET_RECRUITING	Decreasing Nightmares in Adults With Narcolepsy
NCT06457945	Not specified	RECRUITING	Mind-wandering and Predictive Processes in Narcolepsy: a Putative Mechanism Through Covert REM Intrusions
NCT06484348	Not specified	RECRUITING	Deciphering the Interactions Between Food Intake, Sleepiness, and Nighttime Sleep Quality in Patients With Type 1 Narcolepsy and Idiopathic Hypersomnia
NCT07006233	Not specified	RECRUITING	A Novel Approach to Manage Symptoms of Narcolepsy and Idiopathic Hypersomnia
NCT07299097	Not specified	RECRUITING	Epidemiology of Narcolepsy Type 1 and Type 2 in Spain
NCT07365566	Not specified	RECRUITING	Pain Assessment in Patients With Idiopathic Rapid Eye Movement (REM) Sleep Behaviour Disorder
NCT03433131	Not specified	NO_LONGER_AVAILABLE	Expanded Access Program to Provide Treatment With Pitolisant to Adult Patients in the U.S. With Excessive Daytime Sleepiness Associated With Narcolepsy With or Without Cataplexy
NCT04306952	Not specified	COMPLETED	Awareness and Self-Compassion Enhancing Narcolepsy Treatment
NCT04419792	Not specified	SUSPENDED	‘A Profile of Physical Performance Variables in an Out-patient Adult Population With Narcolepsy’
NCT04445129	Not specified	COMPLETED	Wake and Sleep State Transitions on a Portable Electroencephalogram (EEG) Device in Narcolepsy Type 1 (NT1) and Healthy Participants
NCT04483310	Not specified	UNKNOWN	Meditation-Relaxation (MR Therapy) for Sleep Paralysis.
NCT05314556	Not specified	COMPLETED	Group Psychotherapy in Narcolepsy Type 1

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
PITOLISANT	4	9
SODIUM OXYBATE	4	2
CLARITHROMYCIN	4	1
MAZINDOL	4	1

Cohort genes: TEAD4, THRB, TRA, CCR1, CCR3, ZNF365, CPT1B, A1CF, CTSH, UBXN2B, DNMT1, EIF3G, MIR552, GJB5, H2AC6, HLA-DQA2, IL10RB, P2RY11, PPAN, PKN2
Drugs: Pitolisant, Sodium Oxybate, Clarithromycin, Mazindol