Hypersomnia

Summary

Hypersomnia (MONDO:0005466) is a disease with 8 cohort genes (7 GWAS associations across 7 studies) and 24 clinical trials. Top therapeutic interventions include solriamfetol, modafinil, and flumazenil.

At a glance

• Cohort genes: 8
• GWAS associations: 7
• Clinical trials: 24

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypersomnia
Mondo ID	MONDO:0005466
EFO	EFO:0005246
ICD-10-CM	G47.1
NCIT	C78346
SNOMED CT	77692006
UMLS	C0917799
MedGen	214588
Is cancer (heuristic)	no

Also known as: hypersomnia · hypersomnia (disease)

Data availability: 7 GWAS associations (7 studies) · 1 HPO phenotype.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by developmental or physiological process › sleep disorder › sleep-wake disorder › hypersomnia

Related subtypes (11): bruxism, recurrent hypersomnia, sleep apnea syndrome, periodic limb movement disorder, REM sleep behavior disorder, autosomal dominant cerebellar ataxia, deafness and narcolepsy, hereditary sensory neuropathy-deafness-dementia syndrome, autoimmune encephalopathy with parasomnia and obstructive sleep apnea, narcolepsy, circadian rhythm sleep disorder, sleep disorder, initiating and maintaining sleep

Subtypes (1): idiopathic hypersomnia

Genetics & variants

GWAS landscape

7 GWAS associations across 7 studies. Top hits map to 4 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs10988217	8e-09	PTPA	G	2.63
rs16826005	1e-07	NCKAP5	G	3.52
rs16966389	7e-07	LINC02895	G	2.73
rs359268	1e-06	RNA5SP94 - MIR4432HG	C	2.81
rs7725217	1e-06	LINC02112	C	2.66
rs1553441	6e-06	PLD5 - RSL24D1P4	?	2.44

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90477482	Verma A	2024	3,542	437,197	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90477481	Verma A	2024	1,097	117,257	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90481060	Verma A	2024	1,097	117,257	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90481856	Verma A	2024	469	57,764	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST003016	Cho CH	2015	263	0	CDH13 and HCRTR2 May Be Associated with Hypersomnia Symptom of Bipolar Depression: A Genome-Wide Functional Enrichment Pathway Analysis.
GCST001971	Khor SS	2013	125	0	Genome-wide association study of HLA-DQB1*06:02 negative essential hypersomnia.
GCST007191	Miyagawa T	2018	119	1,582	A variant at 9q34.11 is associated with HLA-DQB1*06:02 negative essential hypersomnia.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	6

MAF distribution

Bucket	Variants
common (>=0.05)	6
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	3
intergenic_variant	3

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs10988217	9	129125837	A>G	0.244	intron_variant	PTPA	8e-09	Tier 4: intronic/intergenic
rs16826005	2	133508430	A>C,G,T	0.319	intron_variant	NCKAP5	1e-07	Tier 4: intronic/intergenic
rs16966389	15	38172673	G>A,C	0.358	intergenic_variant	LINC02895	7e-07	Tier 4: intronic/intergenic
rs359268	2	60232671	T>A,C	0.431	intergenic_variant	RNA5SP94 - MIR4432HG	1e-06	Tier 4: intronic/intergenic
rs7725217	5	9756217	A>C	0.223	intron_variant	LINC02112	1e-06	Tier 4: intronic/intergenic
rs1553441	1	242546741	A>T	0.05	intergenic_variant	PLD5 - RSL24D1P4	6e-06	Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BCL11A	Orphanet:251380	Hereditary persistence of fetal hemoglobin-sickle cell disease syndrome
BCL11A	Orphanet:619233	Hereditary persistence of fetal hemoglobin-intellectual disability syndrome
SPRED1	Orphanet:137605	Legius syndrome

Cohort genes → proteins

8 cohort genes, 8 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	8

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BCL11A	HGNC:13221	ENSG00000119866	Q9H165	BCL11 transcription factor A	gwas
TAS2R1	HGNC:14909	ENSG00000169777	Q9NYW7	Taste receptor type 2 member 1	gwas
SPRED1	HGNC:20249	ENSG00000166068	Q7Z699	Sprouty-related, EVH1 domain-containing protein 1	gwas
CRAT	HGNC:2342	ENSG00000095321	P43155	Carnitine O-acetyltransferase	gwas
CARTPT	HGNC:24323	ENSG00000164326	Q16568	Cocaine- and amphetamine-regulated transcript protein	gwas
PLD5	HGNC:26879	ENSG00000180287	Q8N7P1	Inactive phospholipase D5	gwas
NCKAP5	HGNC:29847	ENSG00000176771	O14513	Nck-associated protein 5	gwas
PTPA	HGNC:9308	ENSG00000119383	Q15257	Serine/threonine-protein phosphatase 2A activator	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BCL11A	BCL11 transcription factor A	Transcription factor.
TAS2R1	Taste receptor type 2 member 1	Receptor that may play a role in the perception of bitterness and is gustducin-linked.
SPRED1	Sprouty-related, EVH1 domain-containing protein 1	Tyrosine kinase substrate that inhibits growth-factor-mediated activation of MAP kinase.
CRAT	Carnitine O-acetyltransferase	Catalyzes the reversible transfer of acyl groups from carnitine to coenzyme A (CoA) and regulates the acyl-CoA/CoA ratio.
CARTPT	Cocaine- and amphetamine-regulated transcript protein	Satiety factor closely associated with the actions of leptin and neuropeptide Y; this anorectic peptide inhibits both normal and starvation-induced feeding and completely blocks the feeding response induced by neuropeptide Y and regulated…
PTPA	Serine/threonine-protein phosphatase 2A activator	PPIases accelerate the folding of proteins.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 6 · Druggable fraction: 0.12

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
Enzyme (other)	1	1.5×	0.644
Other/Unknown	6	1.3×	0.644
Transcription factor	1	1.0×	0.644

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BCL11A	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, Dev/Hematopoietic_TF
TAS2R1	Other/Unknown	no		TAS2R
SPRED1	Other/Unknown	no		WH1/EVH1_dom, Sprouty, PH-like_dom_sf
CRAT	Enzyme (other)	yes	2.3.1.7	Carn_acyl_trans, CAT-like_dom_sf, Cho/carn_acyl_trans_1_2
CARTPT	Other/Unknown	no		CART, CART_C_sf
PLD5	Other/Unknown	no		PLipase_D/transphosphatidylase, PLDc_3, Diverse_PLD-related
NCKAP5	Other/Unknown	no		Nckap5l, NCKAP5_C
PTPA	Other/Unknown	no		Phstyr_phstse_ac, PTPA_sf, PTPA_C_lid

Expression context

Cohort genes with no expression data: 0.

7 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)	0
broad (>20)	8
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left testis	2
ventricular zone	2
cortical plate	1
ganglionic eminence	1
primary visual cortex	1
palpebral conjunctiva	1
right testis	1
calcaneal tendon	1
mucosa of sigmoid colon	1
male germ cell	1
sperm	1
hypothalamus	1
male germ line stem cell (sensu Vertebrata) in testis	1
middle temporal gyrus	1
descending thoracic aorta	1
pigmented layer of retina	1
thoracic aorta	1
cerebellar vermis	1
corpus callosum	1
Brodmann (1909) area 10	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BCL11A	247	ubiquitous	marker	cortical plate, ganglionic eminence, primary visual cortex
TAS2R1	48		yes	right testis, left testis, palpebral conjunctiva
SPRED1	248	ubiquitous	marker	ventricular zone, mucosa of sigmoid colon, calcaneal tendon
CRAT	289	ubiquitous	marker	sperm, male germ cell, left testis
CARTPT	156	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, hypothalamus, middle temporal gyrus
PLD5	167	broad	marker	pigmented layer of retina, descending thoracic aorta, thoracic aorta
NCKAP5	132	broad	marker	corpus callosum, cerebellar vermis, ventricular zone
PTPA	289	ubiquitous	marker	endometrium epithelium, Brodmann (1909) area 10, apex of heart

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CARTPT	3,160
SPRED1	2,744
BCL11A	2,389
PTPA	1,198
CRAT	1,056
PLD5	640
TAS2R1	614
NCKAP5	610

Structural data

PDB: 5 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BCL11A	Q9H165	17
PTPA	Q15257	6
SPRED1	Q7Z699	3
CRAT	P43155	3
CARTPT	Q16568	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PLD5	Q8N7P1	83.26
TAS2R1	Q9NYW7	80.07
NCKAP5	O14513	43.93

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 34. Enrichment computed across 8 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
RAS signaling downstream of NF1 loss-of-function variants	1	407.9×	0.028	SPRED1
Beta-oxidation of pristanoyl-CoA	1	285.5×	0.028	CRAT
ALK mutants bind TKIs	1	237.9×	0.028	BCL11A
FGFRL1 modulation of FGFR1 signaling	1	219.6×	0.028	SPRED1
Signaling by FGFR1	1	203.9×	0.028	SPRED1
Diseases of signal transduction by growth factor receptors and second messengers	2	28.4×	0.028	BCL11A, SPRED1
Peroxisomal lipid metabolism	1	167.9×	0.028	CRAT
Formation of the embryonic stem cell BAF (esBAF) complex	1	150.3×	0.028	BCL11A
Branched-chain amino acid catabolism	1	119.0×	0.030	CRAT
Formation of neuronal progenitor and neuronal BAF (npBAF and nBAF)	1	114.2×	0.030	BCL11A
Signaling by FGFR	1	86.5×	0.033	SPRED1
Sensory perception of taste	1	84.0×	0.033	TAS2R1
Class C/3 (Metabotropic glutamate/pheromone receptors)	1	73.2×	0.033	TAS2R1
Sensory perception of sweet, bitter, and umami (glutamate) taste	1	69.6×	0.033	TAS2R1
Signaling by ALK in cancer	1	68.0×	0.033	BCL11A
Oncogenic MAPK signaling	1	62.1×	0.034	SPRED1
Regulation of RAS by GAPs	1	48.4×	0.039	SPRED1
Protein localization	1	47.6×	0.039	CRAT
Peroxisomal protein import	1	43.3×	0.041	CRAT
Signaling by ALK fusions and activated point mutants	1	37.6×	0.045	BCL11A
MAPK1/MAPK3 signaling	1	32.8×	0.047	SPRED1
Fatty acid metabolism	1	32.8×	0.047	CRAT
Disease	2	6.5×	0.047	BCL11A, SPRED1
MAPK family signaling cascades	1	25.7×	0.054	SPRED1
Sensory Perception	1	23.8×	0.056	TAS2R1
Signal Transduction	2	5.1×	0.066	TAS2R1, SPRED1
GPCR ligand binding	1	16.0×	0.077	TAS2R1
RAF/MAP kinase cascade	1	15.3×	0.078	SPRED1
Signaling by Receptor Tyrosine Kinases	1	12.9×	0.088	SPRED1
GPCR downstream signalling	1	10.9×	0.101	TAS2R1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of systemic arterial blood pressure by neurotransmitter	1	2407.4×	0.006	CARTPT
positive regulation of epinephrine secretion	1	2407.4×	0.006	CARTPT
response to corticotropin-releasing hormone	1	2407.4×	0.006	CARTPT
negative regulation of neuron remodeling	1	2407.4×	0.006	BCL11A
negative regulation of branching morphogenesis of a nerve	1	2407.4×	0.006	BCL11A
regulation of circadian sleep/wake cycle, wakefulness	1	1203.7×	0.006	CARTPT
negative regulation of locomotion	1	1203.7×	0.006	CARTPT
regulation of circadian sleep/wake cycle, REM sleep	1	1203.7×	0.006	CARTPT
somatostatin secretion	1	1203.7×	0.006	CARTPT
regulation of locomotion involved in locomotory behavior	1	1203.7×	0.006	CARTPT
negative regulation of relaxation of smooth muscle	1	1203.7×	0.006	CARTPT
regulation of heart rate by chemical signal	1	802.5×	0.006	CARTPT
carnitine metabolic process, CoA-linked	1	802.5×	0.006	CRAT
negative regulation of protein homooligomerization	1	802.5×	0.006	BCL11A
regulation of circadian sleep/wake cycle, non-REM sleep	1	802.5×	0.006	CARTPT
short-chain fatty acid metabolic process	1	802.5×	0.006	CRAT
vasculogenesis involved in coronary vascular morphogenesis	1	802.5×	0.006	SPRED1
negative regulation of glucagon secretion	1	802.5×	0.006	CARTPT
detection of chemical stimulus involved in sensory perception of pain	1	601.9×	0.007	CARTPT
regulation of lipid catabolic process	1	601.9×	0.007	CARTPT
negative regulation of dendrite extension	1	601.9×	0.007	BCL11A
positive regulation of type B pancreatic cell proliferation	1	481.5×	0.008	CARTPT
regulation of lipid biosynthetic process	1	401.2×	0.009	CARTPT
medium-chain fatty acid metabolic process	1	401.2×	0.009	CRAT
negative regulation of lens fiber cell differentiation	1	401.2×	0.009	SPRED1
negative regulation of eating behavior	1	401.2×	0.009	CARTPT
operant conditioning	1	343.9×	0.009	CARTPT
positive regulation of transmission of nerve impulse	1	343.9×	0.009	CARTPT
negative regulation of intracellular signal transduction	1	300.9×	0.010	SPRED1
negative regulation of dendrite development	1	300.9×	0.010	BCL11A

Therapeutics

Drugs indicated for this disease

0 approved, 1 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Armodafinil	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Clarithromycin, Solriamfetol.

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 7

Druggability breadth: 4 of 8 evidence-associated genes (50%) 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
TAS2R1	ISOPROTERENOL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TAS2R1	1	4
BCL11A	0	0
SPRED1	0	0
CRAT	0	0
CARTPT	0	0
PLD5	0	0
NCKAP5	0	0
PTPA	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ISOPROTERENOL	4	TAS2R1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
TAS2R1	30	Functional:28, Binding:2
PTPA	17	Binding:16, ADMET:1
CRAT	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CRAT	2.3.1.7	carnitine O-acetyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 8; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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)
ISOPROTERENOL	4	TAS2R1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	TAS2R1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	CRAT
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	6	BCL11A, SPRED1, CARTPT, PLD5, NCKAP5, PTPA

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
BCL11A	0	—
SPRED1	0	—
CRAT	2	—
CARTPT	0	—
PLD5	0	—
NCKAP5	0	—
PTPA	17	—

Clinical trials & evidence

Clinical trials

Clinical trials: 24.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	18
PHASE2	3
PHASE3	1
PHASE1/PHASE2	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03682185	PHASE3	COMPLETED	The Healthy Patterns Sleep Study
NCT06404099	PHASE2	ACTIVE_NOT_RECRUITING	RECOVER-SLEEP: Platform Protocol, Appendix_A (Hypersomnia)
NCT01146600	PHASE2	COMPLETED	Clarithromycin for the Treatment of Hypersomnia
NCT01183312	PHASE1/PHASE2	COMPLETED	Flumazenil for the Treatment of Primary Hypersomnia
NCT06404086	PHASE2	COMPLETED	RECOVER-SLEEP: Platform Protocol
NCT03626727	EARLY_PHASE1	WITHDRAWN	Evaluation of the Efficacy of Sodium Oxybate (Xyrem®) in Treatment of Post-traumatic Narcolepsy and Post-traumatic Hypersomnia
NCT05850676	Not specified	RECRUITING	Disentangling the Role of Depression in Hypersomnia
NCT00001664	Not specified	COMPLETED	Sleep Disorders of Patients With Diseases of the Nervous System
NCT00427323	Not specified	SUSPENDED	Light Exposure to Treat Sleep Disruption in Older People
NCT00916253	Not specified	COMPLETED	Method of Assessment of Driving Ability in Patients Suffering From Wakefulness Pathologies
NCT01544465	Not specified	TERMINATED	Structured Physical Activity for Sleep Quality and Daytime Sleepiness in Patients With Parkinson’s Disease
NCT01764035	Not specified	COMPLETED	Mindfulness Therapy on Disrupted Sleep in Bipolar Disorder
NCT01877616	Not specified	COMPLETED	Sleep Disorders and Their Cardiovascular Correlates in Atahualpa.
NCT03198156	Not specified	TERMINATED	Transcranial Direct Current Stimulation Therapy for Central Hypersomnia Without Cataplexy
NCT03459300	Not specified	COMPLETED	Importance of Sleep Deprivation in Differential Diagnosis of Primary Hypersomnia (Actisom dépistage)
NCT04157244	Not specified	COMPLETED	The Music, Sleep and Dementia Study
NCT04201392	Not specified	UNKNOWN	Sleep in Psychiatric Inpatients
NCT04300166	Not specified	UNKNOWN	Telemedicine and Humidification for Cpap IN Osas Key Treatment (THINK Study)
NCT05183464	Not specified	COMPLETED	Analysis of New Salivary Biomarkers to Evaluate Excessive Diurnal Sleepiness in Children With Hypersomnia
NCT05230394	Not specified	SUSPENDED	Patient Outcomes in Unattended and In- Lab Polysomnography
NCT05443373	Not specified	UNKNOWN	A Multi-Signal Based Monitoring System for CNS Hypersomnias
NCT05627388	Not specified	WITHDRAWN	Feasibility Study of At-Home EEG Monitoring for Hypersomnia
NCT05983731	Not specified	UNKNOWN	A Pilot Observational Study to Assess the Ability of Continuous ‘Home’ EEG to Accurately Diagnose Narcolepsy and Demonstrate Response to Treatment
NCT06531876	Not specified	COMPLETED	Efficacy of the Dreem 3S Ambulatory Sleep Monitoring Device for the Evaluation of Narcolepsy

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
SOLRIAMFETOL	4	6
MODAFINIL	4	3
FLUMAZENIL	4	1