Familial sleep-related hypermotor epilepsy
diseaseOn this page
Also known as ADNFLEautosomal dominant nocturnal frontal lobe epilepsyepilepsy, nocturnal frontal lobe, familialfamilial sleep-related hyperkinetic epilepsyfamillial SHE
Summary
Familial sleep-related hypermotor epilepsy (MONDO:0000030) is a disease (an umbrella term covering 5 Mondo subtypes) caused by CHRNA4 (GenCC Definitive), with 14 cohort genes. The dominant Reactome pathway is Highly calcium permeable nicotinic acetylcholine receptors (3 cohort genes).
At a glance
- Prevalence: Unknown (Europe) [Orphanet-validated]
- Causal gene: CHRNA4 (GenCC Definitive)
- Umbrella term: 5 Mondo subtypes
- Cohort genes: 14
- ClinVar variants: 2,279
- Phenotypes (HPO): 22
Clinical features
Epidemiology
Prevalence records
1 prevalence record(s), Orphanet:
| Type | Class | Value | Geography | Validation |
|---|---|---|---|---|
| Cases/families | 100 | Worldwide | Validated |
Signs & symptoms
Clinical features (HPO)
22 HPO clinical features (Orphanet curated; top 22 by frequency):
| HPO ID | Term | Frequency |
|---|---|---|
| HP:0031951 | Nocturnal seizures | Very frequent (80-99%) |
| HP:0000733 | Abnormal repetitive mannerisms | Frequent (30-79%) |
| HP:0002268 | Paroxysmal dystonia | Frequent (30-79%) |
| HP:0004305 | Involuntary movements | Frequent (30-79%) |
| HP:0000020 | Urinary incontinence | Occasional (5-29%) |
| HP:0000716 | Depression | Occasional (5-29%) |
| HP:0000739 | Anxiety | Occasional (5-29%) |
| HP:0002883 | Hyperventilation | Occasional (5-29%) |
| HP:0011174 | Hyperkinetic seizures | Occasional (5-29%) |
| HP:0011182 | Interictal epileptiform activity | Occasional (5-29%) |
| HP:0011193 | EEG with focal spikes | Occasional (5-29%) |
| HP:0025236 | Somnambulism | Occasional (5-29%) |
| HP:0025237 | Confusional arousal | Occasional (5-29%) |
| HP:0031535 | Increased theta frequency activity in EEG | Occasional (5-29%) |
| HP:0031589 | Suicidal ideation | Occasional (5-29%) |
| HP:0100543 | Cognitive impairment | Occasional (5-29%) |
| HP:0000708 | Atypical behavior | Very rare (<1-4%) |
| HP:0001256 | Intellectual disability, mild | Very rare (<1-4%) |
| HP:0001345 | Psychotic mentation | Very rare (<1-4%) |
| HP:0002069 | Bilateral tonic-clonic seizure | Very rare (<1-4%) |
| HP:0007018 | Attention deficit hyperactivity disorder | Very rare (<1-4%) |
| HP:0025235 | Non-rapid eye movement parasomnia | Very rare (<1-4%) |
Identifiers
Disease identifiers
| Field | Value |
|---|---|
| Canonical name | familial sleep-related hypermotor epilepsy |
| Mondo ID | MONDO:0000030 |
| MeSH | C579932 |
| OMIM | 600513 |
| Orphanet | 98784 |
| DOID | DOID:0060681 |
| ICD-11 | 1004734747 |
| SNOMED CT | 698021005 |
| UMLS | C5577629 |
| MedGen | 1865268 |
| GARD | 0022703 |
| Is cancer (heuristic) | no |
Also known as: ADNFLE · autosomal dominant nocturnal frontal lobe epilepsy · epilepsy, nocturnal frontal lobe, familial · familial sleep-related hyperkinetic epilepsy · familial sleep-related hypermotor epilepsy · famillial SHE
Data availability: 2,279 ClinVar variants · 1 GenCC gene-disease record.
Disease family
An umbrella term covering 5 Mondo subtypes.
Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › epilepsy › focal epilepsy › familial partial epilepsy › familial sleep-related hypermotor epilepsy
Related subtypes (6): temporal lobe epilepsy, self-limited epilepsy with centrotemporal spikes, autosomal dominant epilepsy with auditory features, generalized epilepsy-paroxysmal dyskinesia syndrome, familial focal epilepsy with variable foci, mesial temporal lobe epilepsy with hippocampal sclerosis
Subtypes (5): autosomal dominant nocturnal frontal lobe epilepsy 1, autosomal dominant nocturnal frontal lobe epilepsy 2, autosomal dominant nocturnal frontal lobe epilepsy 3, autosomal dominant nocturnal frontal lobe epilepsy 4, autosomal dominant nocturnal frontal lobe epilepsy 5
Genetics & variants
GWAS landscape
No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.
Variant details and genetic-evidence tiers
ClinVar germline variants
600 retrieved; paginated sample, class counts are floors:
281 uncertain significance, 236 likely benign, 39 conflicting classifications of pathogenicity, 23 benign, 17 benign/likely benign, 2 likely pathogenic, 1 pathogenic/likely pathogenic, 1 pathogenic
| ClinVar | Variant (HGVS) | Gene | Classification | Review |
|---|---|---|---|---|
| 1453093 | NM_001242896.3(DEPDC5):c.4689_4690del (p.Gly1564_Asp1565insTer) | DEPDC5 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 1496815 | NM_178013.4(PRIMA1):c.270G>A (p.Trp90Ter) | PRIMA1 | Pathogenic | criteria provided, single submitter |
| 1202676 | NM_000744.7(CHRNA4):c.823A>T (p.Ile275Phe) | CHRNA4 | Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 1339652 | NM_198904.4(GABRG2):c.950C>A (p.Thr317Asn) | GABRG2 | Likely pathogenic | no assertion criteria provided |
| 1006054 | NM_000742.4(CHRNA2):c.1468A>G (p.Lys490Glu) | CHRNA2 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1011209 | NM_000742.4(CHRNA2):c.482C>T (p.Thr161Ile) | CHRNA2 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1018570 | NM_000742.4(CHRNA2):c.1364T>C (p.Leu455Pro) | CHRNA2 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1020204 | NM_000742.4(CHRNA2):c.116A>G (p.Asp39Gly) | CHRNA2 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1026735 | NM_000742.4(CHRNA2):c.874G>A (p.Asp292Asn) | CHRNA2 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1078883 | NM_000742.4(CHRNA2):c.1340C>T (p.Ser447Leu) | CHRNA2 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1100695 | NM_000742.4(CHRNA2):c.368A>G (p.Asn123Ser) | CHRNA2 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1216492 | NM_000742.4(CHRNA2):c.1198T>A (p.Ser400Thr) | CHRNA2 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 128736 | NM_000742.4(CHRNA2):c.1234G>A (p.Glu412Lys) | CHRNA2 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1314537 | NM_000742.4(CHRNA2):c.1385T>C (p.Leu462Pro) | CHRNA2 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 136753 | NM_000742.4(CHRNA2):c.1434C>A (p.Asp478Glu) | CHRNA2 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1467113 | NM_000742.4(CHRNA2):c.1019C>T (p.Thr340Ile) | CHRNA2 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1520721 | NM_000742.4(CHRNA2):c.323A>C (p.Asn108Thr) | CHRNA2 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1561594 | NM_000742.4(CHRNA2):c.416T>C (p.Met139Thr) | CHRNA2 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1013459 | NM_000744.7(CHRNA4):c.1217C>T (p.Pro406Leu) | CHRNA4 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1013626 | NM_000744.7(CHRNA4):c.1696C>T (p.Arg566Trp) | CHRNA4 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1025892 | NM_000744.7(CHRNA4):c.334C>T (p.Arg112Cys) | CHRNA4 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1033118 | NM_000744.7(CHRNA4):c.1741G>A (p.Glu581Lys) | CHRNA4 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1041298 | NM_000744.7(CHRNA4):c.784G>A (p.Val262Met) | CHRNA4 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1055904 | NM_000744.7(CHRNA4):c.1159G>A (p.Glu387Lys) | CHRNA4 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1060846 | NM_000744.7(CHRNA4):c.1426G>A (p.Glu476Lys) | CHRNA4 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1083771 | NM_000744.7(CHRNA4):c.1759-4G>A | CHRNA4 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1086961 | NM_000744.7(CHRNA4):c.581T>C (p.Met194Thr) | CHRNA4 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1130654 | NM_000744.7(CHRNA4):c.1582C>T (p.Pro528Ser) | CHRNA4 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1189786 | NM_000744.7(CHRNA4):c.1189G>A (p.Gly397Ser) | CHRNA4 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 128746 | NM_000744.7(CHRNA4):c.1525G>A (p.Ala509Thr) | CHRNA4 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
Genes & proteins
Mendelian disease overlap and somatic drivers
GenCC: 4 · Orphanet: 19 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0
GenCC gene–disease validity (cohort genes)
the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.
| Gene | Classification | Inheritance | Disease | Records |
|---|---|---|---|---|
| CHRNA4 | Definitive | Autosomal dominant | familial sleep-related hypermotor epilepsy | 4 |
Orphanet rare-disease linkage (cohort genes)
| Gene | Orphanet ID | Rare disease |
|---|---|---|
| CHRNA4 | Orphanet:98784 | Sleep-related hypermotor epilepsy |
| DNAJC5 | Orphanet:228343 | CLN4 disease |
| DEPDC5 | Orphanet:442835 | Non-specific early-onset epileptic encephalopathy |
| DEPDC5 | Orphanet:98784 | Sleep-related hypermotor epilepsy |
| DEPDC5 | Orphanet:98820 | Familial focal epilepsy with variable foci |
| CHRNA2 | Orphanet:98784 | Sleep-related hypermotor epilepsy |
| CHRNB2 | Orphanet:98784 | Sleep-related hypermotor epilepsy |
| ADAR | Orphanet:225154 | Familial infantile bilateral striatal necrosis |
| ADAR | Orphanet:41 | Dyschromatosis symmetrica hereditaria |
| ADAR | Orphanet:51 | Aicardi-Goutières syndrome |
| ADAR | Orphanet:694356 | ADAR-related hereditary spastic paraplegia |
| CRH | Orphanet:98784 | Sleep-related hypermotor epilepsy |
| EXTL3 | Orphanet:508533 | Skeletal dysplasia-T-cell immunodeficiency-developmental delay syndrome |
| GABRG2 | Orphanet:1945 | Self-limited epilepsy with centrotemporal spikes |
| GABRG2 | Orphanet:33069 | Dravet syndrome |
| GABRG2 | Orphanet:36387 | Genetic epilepsy with febrile seizure plus |
| GABRG2 | Orphanet:442835 | Non-specific early-onset epileptic encephalopathy |
| GABRG2 | Orphanet:64280 | Childhood absence epilepsy |
| OPLAH | Orphanet:33572 | 5-oxoprolinase deficiency |
Cohort genes → proteins
14 cohort genes, 13 distinct canonical proteins.
Evidence partition
| Subset | Genes |
|---|---|
| multi_evidence | 14 |
Cohort genes (full)
| Symbol | HGNC | Ensembl | UniProt | Name | Evidence |
|---|---|---|---|---|---|
| CHRNA4 | HGNC:1958 | ENSG00000101204 | P43681 | Neuronal acetylcholine receptor subunit alpha-4 | gencc,clinvar |
| ABHD16B | HGNC:16128 | ENSG00000183260 | Q9H3Z7 | ABHD16B | clinvar |
| PPDPF | HGNC:16142 | ENSG00000125534 | Q9H3Y8 | Pancreatic progenitor cell differentiation and proliferation factor | clinvar |
| DNAJC5 | HGNC:16235 | ENSG00000101152 | Q9H3Z4 | DnaJ homolog subfamily C member 5 | clinvar |
| PRIMA1 | HGNC:18319 | ENSG00000175785 | Q86XR5 | Proline-rich membrane anchor 1 | clinvar |
| DEPDC5 | HGNC:18423 | ENSG00000100150 | O75140 | GATOR1 complex protein DEPDC5 | clinvar |
| CHRNA2 | HGNC:1956 | ENSG00000120903 | Q15822 | Neuronal acetylcholine receptor subunit alpha-2 | clinvar |
| CHRNB2 | HGNC:1962 | ENSG00000160716 | P17787 | Neuronal acetylcholine receptor subunit beta-2 | clinvar |
| ADAR | HGNC:225 | ENSG00000160710 | P55265 | Double-stranded RNA-specific adenosine deaminase | clinvar |
| CRH | HGNC:2355 | ENSG00000147571 | P06850 | Corticoliberin | clinvar |
| HAR1A | HGNC:33117 | ENSG00000225978 | highly accelerated region 1A | clinvar | |
| EXTL3 | HGNC:3518 | ENSG00000012232 | O43909 | Exostosin-like 3 | clinvar |
| GABRG2 | HGNC:4087 | ENSG00000113327 | P18507 | Gamma-aminobutyric acid receptor subunit gamma-2 | clinvar |
| OPLAH | HGNC:8149 | ENSG00000178814 | O14841 | 5-oxoprolinase | clinvar |
Cohort function summary
Lead sentence per gene, UniProt-curated.
| Symbol | Protein name | Function (lead sentence) |
|---|---|---|
| CHRNA4 | Neuronal acetylcholine receptor subunit alpha-4 | Component of neuronal acetylcholine receptors (nAChRs) that function as pentameric, ligand-gated cation channels with high calcium permeability among other activities. nAChRs are excitatory neurotrasnmitter receptors formed by a collection… |
| ABHD16B | ABHD16B | Hydrolyzes the sn-1 position of glycerophospholipids with high specificity towards phosphatidylserine (PS), PS-PLA1 enzyme. |
| PPDPF | Pancreatic progenitor cell differentiation and proliferation factor | Probable regulator of exocrine pancreas development. |
| DNAJC5 | DnaJ homolog subfamily C member 5 | Acts as a general chaperone in regulated exocytosis. |
| PRIMA1 | Proline-rich membrane anchor 1 | Required to anchor acetylcholinesterase (ACHE) to the basal lamina of the neuromuscular junction and to the membrane of neuronal synapses in brain. |
| DEPDC5 | GATOR1 complex protein DEPDC5 | As a component of the GATOR1 complex functions as an inhibitor of the amino acid-sensing branch of the mTORC1 pathway. |
| CHRNA2 | Neuronal acetylcholine receptor subunit alpha-2 | Component of neuronal acetylcholine receptors (nAChRs) that function as pentameric, ligand-gated cation channels with high calcium permeability among other activities. nAChRs are excitatory neurotrasnmitter receptors formed by a collection… |
| CHRNB2 | Neuronal acetylcholine receptor subunit beta-2 | Component of neuronal acetylcholine receptors (nAChRs) that function as pentameric, ligand-gated cation channels with high calcium permeability among other activities. nAChRs are excitatory neurotrasnmitter receptors formed by a collection… |
| ADAR | Double-stranded RNA-specific adenosine deaminase | Catalyzes the hydrolytic deamination of adenosine to inosine in double-stranded RNA (dsRNA) referred to as A-to-I RNA editing. |
| CRH | Corticoliberin | Hormone regulating the release of corticotropin from pituitary gland. |
| EXTL3 | Exostosin-like 3 | Glycosyltransferase which regulates the biosynthesis of heparan sulfate (HS). |
| GABRG2 | Gamma-aminobutyric acid receptor subunit gamma-2 | Gamma subunit of the heteropentameric ligand-gated chloride channel gated by gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain. |
| OPLAH | 5-oxoprolinase | Catalyzes the cleavage of 5-oxo-L-proline to form L-glutamate coupled to the hydrolysis of ATP to ADP and inorganic phosphate. |
Protein-family classification
Druggable: 3 · Difficult: 0 · Unknown: 11 · Druggable fraction: 0.21
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) | 3 | 2.6× | 0.105 |
| Other/Unknown | 11 | 1.4× | 0.105 |
Per-gene assignment
| Symbol | Family | Druggable? | EC | InterPro (top 3) |
|---|---|---|---|---|
| CHRNA4 | Other/Unknown | no | Nicotinic_acetylcholine_rcpt, Neurotrans-gated_channel_TM, Neur_channel | |
| ABHD16B | Other/Unknown | no | AB_hydrolase_1, AB_hydrolase_fold | |
| PPDPF | Other/Unknown | no | PPDPF | |
| DNAJC5 | Other/Unknown | no | DnaJ_domain, DnaJ_domain_CS, J_dom_sf | |
| PRIMA1 | Other/Unknown | no | PRIMA1 | |
| DEPDC5 | Other/Unknown | no | DEP_dom, IML1, WH-like_DNA-bd_sf | |
| CHRNA2 | Other/Unknown | no | Nicotinic_acetylcholine_rcpt, Neurotrans-gated_channel_TM, Neur_channel | |
| CHRNB2 | Other/Unknown | no | Nicotinic_acetylcholine_rcpt, Neurotrans-gated_channel_TM, Neur_channel | |
| ADAR | Enzyme (other) | yes | 3.5.4.37 | A_deamin, dsRBD_dom, WH-like_DNA-bd_sf |
| CRH | Other/Unknown | no | CRF, Urocortin_CRF, Corticotropin-releasing_fac_CS | |
| HAR1A | Other/Unknown | no | ||
| EXTL3 | Enzyme (other) | yes | 2.4.1.223 | Exostosin, GT64_dom, Nucleotide-diphossugar_trans |
| GABRG2 | Other/Unknown | no | GABRG-1/4, GABBAg2_rcpt, GABAA/Glycine_rcpt | |
| OPLAH | Enzyme (other) | yes | 3.5.2.9 | Hydantoinase_A, Hydantoinase_B, Hydant_A_N |
Expression context
Cohort genes with no expression data: 0.
9 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) | 14 |
| unknown | 0 |
Top tissues across cohort
| Tissue | Cohort genes |
|---|---|
| cortical plate | 2 |
| left testis | 2 |
| right testis | 2 |
| Brodmann (1909) area 9 | 2 |
| right frontal lobe | 2 |
| cervix squamous epithelium | 2 |
| middle temporal gyrus | 2 |
| cingulate cortex | 1 |
| right lobe of liver | 1 |
| testis | 1 |
| lower esophagus mucosa | 1 |
| mucosa of transverse colon | 1 |
| right coronary artery | 1 |
| cardiac muscle of right atrium | 1 |
| C1 segment of cervical spinal cord | 1 |
| sural nerve | 1 |
| tibial nerve | 1 |
| frontal pole | 1 |
| middle frontal gyrus | 1 |
| paraflocculus | 1 |
Per-gene tissue summary (top 30)
| Symbol | Bgee breadth | FANTOM5 breadth | SCXA | Top tissues |
|---|---|---|---|---|
| CHRNA4 | 138 | tissue_specific | yes | right lobe of liver, cortical plate, cingulate cortex |
| ABHD16B | 106 | yes | right testis, left testis, testis | |
| PPDPF | 262 | ubiquitous | marker | lower esophagus mucosa, right coronary artery, mucosa of transverse colon |
| DNAJC5 | 254 | ubiquitous | marker | cardiac muscle of right atrium, right frontal lobe, Brodmann (1909) area 9 |
| PRIMA1 | 127 | broad | marker | tibial nerve, sural nerve, C1 segment of cervical spinal cord |
| DEPDC5 | 236 | ubiquitous | marker | paraflocculus, frontal pole, middle frontal gyrus |
| CHRNA2 | 143 | tissue_specific | yes | cervix squamous epithelium, primordial germ cell in gonad, gingival epithelium |
| CHRNB2 | 208 | broad | yes | tongue squamous epithelium, cervix squamous epithelium, type B pancreatic cell |
| ADAR | 295 | ubiquitous | marker | endothelial cell, middle temporal gyrus, visceral pleura |
| CRH | 97 | tissue_specific | marker | lateral nuclear group of thalamus, placenta, buccal mucosa cell |
| HAR1A | 166 | yes | male germ line stem cell (sensu Vertebrata) in testis, right frontal lobe, Brodmann (1909) area 9 | |
| EXTL3 | 210 | ubiquitous | marker | stromal cell of endometrium, ventricular zone, cortical plate |
| GABRG2 | 174 | tissue_specific | marker | middle temporal gyrus, Brodmann (1909) area 23, superior frontal gyrus |
| OPLAH | 217 | ubiquitous | marker | apex of heart, right testis, left testis |
Protein interactions among cohort
Intra-cohort edges: 3.
Hub genes (top 10 by interactor count)
| Symbol | Interactor count |
|---|---|
| DNAJC5 | 3,802 |
| ADAR | 3,166 |
| GABRG2 | 2,392 |
| CRH | 2,247 |
| CHRNA4 | 1,989 |
| CHRNB2 | 1,547 |
| DEPDC5 | 1,273 |
| OPLAH | 1,204 |
| EXTL3 | 1,202 |
| CHRNA2 | 982 |
Intra-cohort edges
| A | B | Sources |
|---|---|---|
| CHRNA2 | DEPDC5 | string_interaction |
| CHRNA4 | CHRNB2 | biogrid_interaction, intact, string_interaction |
| CHRNB2 | DEPDC5 | string_interaction |
Structural data
PDB: 9 · AlphaFold-only: 4 · No structure: 1
Cohort genes with PDB structures (top 30)
| Symbol | UniProt | PDB entries |
|---|---|---|
| GABRG2 | P18507 | 75 |
| ADAR | P55265 | 24 |
| CHRNB2 | P17787 | 15 |
| CHRNA4 | P43681 | 12 |
| DEPDC5 | O75140 | 11 |
| CRH | P06850 | 5 |
| EXTL3 | O43909 | 4 |
| DNAJC5 | Q9H3Z4 | 2 |
| CHRNA2 | Q15822 | 1 |
AlphaFold-only cohort genes (top 30 by pLDDT)
| Symbol | UniProt | pLDDT |
|---|---|---|
| OPLAH | O14841 | 88.08 |
| ABHD16B | Q9H3Z7 | 86.64 |
| PRIMA1 | Q86XR5 | 63.74 |
| PPDPF | Q9H3Y8 | 60.64 |
Function
Pathway analysis
Distinct Reactome pathways touched by cohort: 26. Enrichment computed across 14 evidence-associated genes (10 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 10 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.
| Pathway | Cohort genes | Fold | FDR | Sample cohort genes |
|---|---|---|---|---|
| Highly calcium permeable nicotinic acetylcholine receptors | 3 | 380.7× | 9e-07 | CHRNA4, CHRNA2, CHRNB2 |
| Highly calcium permeable postsynaptic nicotinic acetylcholine receptors | 3 | 311.4× | 9e-07 | CHRNA4, CHRNA2, CHRNB2 |
| Presynaptic nicotinic acetylcholine receptors | 3 | 285.5× | 9e-07 | CHRNA4, CHRNA2, CHRNB2 |
| Acetylcholine binding and downstream events | 3 | 244.7× | 9e-07 | CHRNA4, CHRNA2, CHRNB2 |
| Postsynaptic nicotinic acetylcholine receptors | 3 | 244.7× | 9e-07 | CHRNA4, CHRNA2, CHRNB2 |
| Highly sodium permeable postsynaptic acetylcholine nicotinic receptors | 2 | 326.3× | 6e-05 | CHRNA4, CHRNB2 |
| Neurotransmitter receptors and postsynaptic signal transmission | 3 | 30.1× | 4e-04 | CHRNA4, CHRNA2, CHRNB2 |
| Transmission across Chemical Synapses | 3 | 22.8× | 8e-04 | CHRNA4, CHRNA2, CHRNB2 |
| Defective OPLAH causes OPLAHD | 1 | 1142.0× | 0.003 | OPLAH |
| Neuronal System | 3 | 13.3× | 0.003 | CHRNA4, CHRNA2, CHRNB2 |
| C6 deamination of adenosine | 1 | 571.0× | 0.004 | ADAR |
| Formation of editosomes by ADAR proteins | 1 | 571.0× | 0.004 | ADAR |
| MECP2 regulates transcription of neuronal ligands | 1 | 142.8× | 0.014 | CRH |
| Glutathione synthesis and recycling | 1 | 95.2× | 0.019 | OPLAH |
| GABA synthesis, release, reuptake and degradation | 1 | 63.4× | 0.027 | DNAJC5 |
| HS-GAG biosynthesis | 1 | 34.6× | 0.046 | EXTL3 |
| GABA receptor activation | 1 | 31.7× | 0.048 | GABRG2 |
| Signaling by ERBB4 | 1 | 27.2× | 0.052 | GABRG2 |
| XBP1(S) activates chaperone genes | 1 | 21.6× | 0.062 | EXTL3 |
| Amino acids regulate mTORC1 | 1 | 20.0× | 0.063 | DEPDC5 |
| Class B/2 (Secretin family receptors) | 1 | 19.0× | 0.064 | CRH |
| Sensory processing of sound by inner hair cells of the cochlea | 1 | 16.3× | 0.071 | DNAJC5 |
| Interferon alpha/beta signaling | 1 | 15.2× | 0.072 | ADAR |
| PKR-mediated signaling | 1 | 14.1× | 0.074 | ADAR |
| G alpha (s) signalling events | 1 | 7.3× | 0.134 | CRH |
| Neutrophil degranulation | 1 | 2.3× | 0.358 | DNAJC5 |
GO biological processes by enrichment
Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 12 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.
| GO term | Cohort genes | Fold | FDR | Sample cohort genes |
|---|---|---|---|---|
| synaptic transmission, cholinergic | 3 | 200.6× | 6e-05 | CHRNA4, CHRNA2, CHRNB2 |
| acetylcholine receptor signaling pathway | 3 | 156.0× | 6e-05 | CHRNA4, CHRNA2, CHRNB2 |
| membrane depolarization | 3 | 127.7× | 8e-05 | CHRNA4, CHRNA2, CHRNB2 |
| response to nicotine | 3 | 105.3× | 1e-04 | CHRNA4, CHRNA2, CHRNB2 |
| behavioral response to nicotine | 2 | 312.1× | 5e-04 | CHRNA4, CHRNB2 |
| monoatomic ion transmembrane transport | 3 | 52.0× | 6e-04 | CHRNA4, CHRNA2, CHRNB2 |
| regulation of dopamine secretion | 2 | 200.6× | 8e-04 | CHRNA4, CHRNB2 |
| nervous system process | 2 | 200.6× | 8e-04 | CHRNA4, CHRNB2 |
| monoatomic ion transport | 3 | 39.0× | 9e-04 | CHRNA4, CHRNA2, CHRNB2 |
| neuromuscular synaptic transmission | 2 | 100.3× | 0.003 | CHRNA4, CHRNA2 |
| associative learning | 2 | 80.2× | 0.004 | CHRNB2, CRH |
| B cell activation | 2 | 75.9× | 0.004 | CHRNA4, CHRNB2 |
| presynaptic modulation of chemical synaptic transmission | 2 | 75.9× | 0.004 | CHRNA4, CHRNA2 |
| sensory perception of pain | 2 | 62.4× | 0.005 | CHRNA4, CHRNB2 |
| chemical synaptic transmission | 3 | 19.3× | 0.005 | CHRNA4, CHRNB2, CRH |
| somatic diversification of immune receptors via somatic mutation | 1 | 1404.3× | 0.005 | ADAR |
| lateral geniculate nucleus development | 1 | 1404.3× | 0.005 | CHRNB2 |
| positive regulation of digestive system process | 1 | 1404.3× | 0.005 | CRH |
| modulation of inhibitory postsynaptic potential | 1 | 1404.3× | 0.005 | CHRNA2 |
| negative regulation of post-transcriptional gene silencing by regulatory ncRNA | 1 | 1404.3× | 0.005 | ADAR |
| cognition | 2 | 47.6× | 0.006 | CHRNA4, CHRNB2 |
| regulation of serotonin secretion | 1 | 702.2× | 0.008 | CRH |
| diterpenoid metabolic process | 1 | 702.2× | 0.008 | CRH |
| regulation of circadian sleep/wake cycle, REM sleep | 1 | 702.2× | 0.008 | CHRNB2 |
| negative regulation of circadian sleep/wake cycle, REM sleep | 1 | 702.2× | 0.008 | CRH |
| positive regulation of corticosterone secretion | 1 | 702.2× | 0.008 | CRH |
| positive regulation of detection of glucose | 1 | 702.2× | 0.008 | EXTL3 |
| positive regulation of circadian sleep/wake cycle, wakefulness | 1 | 468.1× | 0.010 | CRH |
| vestibulocochlear nerve development | 1 | 468.1× | 0.010 | CHRNB2 |
| negative regulation of luteinizing hormone secretion | 1 | 468.1× | 0.010 | CRH |
Therapeutics
Drug target analysis
Approved (phase 4): 4 · Phase ≥3: 4 · Phased (≥1): 4 · Undrugged: 10
Druggability breadth: 7 of 14 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 |
|---|---|
| CHRNA4 | VARENICLINE |
| CHRNA2 | VARENICLINE |
| CHRNB2 | VARENICLINE |
| GABRG2 | ENZALUTAMIDE |
Top cohort targets by molecule count
| Symbol | Molecules | Max phase |
|---|---|---|
| CHRNA4 | 64 | 4 |
| GABRG2 | 55 | 4 |
| CHRNB2 | 26 | 4 |
| CHRNA2 | 4 | 4 |
| ABHD16B | 0 | 0 |
| PPDPF | 0 | 0 |
| DNAJC5 | 0 | 0 |
| PRIMA1 | 0 | 0 |
| DEPDC5 | 0 | 0 |
| ADAR | 0 | 0 |
Drugs targeting cohort genes (top 30)
| Molecule | Max phase | Targets in cohort |
|---|---|---|
| VARENICLINE | 4 | CHRNA2, CHRNA4, CHRNB2 |
| PONATINIB | 4 | CHRNA4 |
| CHLOROPROCAINE | 4 | CHRNA4 |
| ANISOTROPINE | 4 | CHRNA4 |
| PALONOSETRON | 4 | CHRNA4 |
| CHLORPHENTERMINE | 4 | CHRNA4 |
| PYRVINIUM | 4 | CHRNA4 |
| DIPHEMANIL | 4 | CHRNA4 |
| SERTINDOLE | 4 | CHRNA4 |
| ATRACURIUM | 4 | CHRNA4 |
| NITAZOXANIDE | 4 | CHRNA4 |
| ILOPERIDONE | 4 | CHRNA4 |
| MOXISYLYTE | 4 | CHRNA4 |
| RIFAXIMIN | 4 | CHRNA4 |
| DAUNORUBICIN | 4 | CHRNA4 |
| PALBOCICLIB | 4 | CHRNA4 |
| OXYPERTINE | 4 | CHRNA4 |
| VANDETANIB | 4 | CHRNA4 |
| MEDAZEPAM | 4 | CHRNA4 |
| RIFAMPIN | 4 | CHRNA4 |
| ZIMELDINE | 4 | CHRNA4 |
| THIORIDAZINE | 4 | CHRNA4 |
| SUNITINIB | 4 | CHRNA4 |
| EPALRESTAT | 4 | CHRNA4 |
| NIMESULIDE | 4 | CHRNA4 |
| TROPISETRON | 4 | CHRNA4, CHRNB2 |
| FENTANYL | 4 | CHRNA4 |
| CRIZOTINIB | 4 | CHRNA4, GABRG2 |
| AZELASTINE | 4 | CHRNA4, GABRG2 |
| ACETYLCHOLINE | 4 | CHRNA4, CHRNB2 |
Bioactivity and enzyme data
Enzyme cohort genes (≥1 EC): 3.
Cohort genes with ChEMBL bioactivity (full, sorted by assay count)
| Symbol | Assays | Type breakdown |
|---|---|---|
| GABRG2 | 1,155 | Binding:940, Functional:201, ADMET:10, Toxicity:4 |
| CHRNB2 | 696 | Binding:567, Functional:127, Toxicity:1, ADMET:1 |
| CHRNA4 | 624 | Binding:497, Functional:125, Toxicity:1, ADMET:1 |
| CHRNA2 | 40 | Binding:37, Functional:2, ADMET:1 |
| ADAR | 2 | Binding:2 |
| DNAJC5 | 1 | Binding:1 |
| CRH | 1 | Binding:1 |
Cohort enzymes (BRENDA EC)
| Symbol | EC numbers | Names |
|---|---|---|
| ADAR | 3.5.4.37 | double-stranded RNA adenine deaminase |
| EXTL3 | 2.4.1.223 | glucuronosyl-galactosyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase |
| OPLAH | 3.5.2.9 | 5-oxoprolinase (ATP-hydrolysing) |
Cohort genes with high screening signal
≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.
| Symbol | ChEMBL assays |
|---|---|
| CHRNA4 | 624 |
| CHRNB2 | 696 |
| GABRG2 | 1,155 |
Pharmacogenomics
Cohort genes with a PharmGKB record: 14; 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) |
|---|---|---|
| VARENICLINE | 4 | CHRNA2, CHRNA4, CHRNB2 |
| PONATINIB | 4 | CHRNA4 |
| CHLOROPROCAINE | 4 | CHRNA4 |
| ANISOTROPINE | 4 | CHRNA4 |
| PALONOSETRON | 4 | CHRNA4 |
| CHLORPHENTERMINE | 4 | CHRNA4 |
| PYRVINIUM | 4 | CHRNA4 |
| DIPHEMANIL | 4 | CHRNA4 |
| SERTINDOLE | 4 | CHRNA4 |
| ATRACURIUM | 4 | CHRNA4 |
| NITAZOXANIDE | 4 | CHRNA4 |
| ILOPERIDONE | 4 | CHRNA4 |
| MOXISYLYTE | 4 | CHRNA4 |
| RIFAXIMIN | 4 | CHRNA4 |
| DAUNORUBICIN | 4 | CHRNA4 |
| PALBOCICLIB | 4 | CHRNA4 |
| OXYPERTINE | 4 | CHRNA4 |
| VANDETANIB | 4 | CHRNA4 |
| MEDAZEPAM | 4 | CHRNA4 |
| RIFAMPIN | 4 | CHRNA4 |
| ZIMELDINE | 4 | CHRNA4 |
| THIORIDAZINE | 4 | CHRNA4 |
| SUNITINIB | 4 | CHRNA4 |
| EPALRESTAT | 4 | CHRNA4 |
| NIMESULIDE | 4 | CHRNA4 |
| TROPISETRON | 4 | CHRNA4, CHRNB2 |
| FENTANYL | 4 | CHRNA4 |
| CRIZOTINIB | 4 | CHRNA4, GABRG2 |
| AZELASTINE | 4 | CHRNA4, GABRG2 |
| ACETYLCHOLINE | 4 | CHRNA4, CHRNB2 |
Druggability pyramid
Cohort genes binned by druggability tier (high → low):
| Tier | Definition | Genes | Symbols |
|---|---|---|---|
| A | Approved (phase 4 drug) | 4 | CHRNA4, CHRNA2, CHRNB2, GABRG2 |
| B | Phased (≥1) drug, not yet approved | 0 | |
| C | Druggable family + PDB, no drug | 2 | ADAR, EXTL3 |
| D | Druggable family + AlphaFold only, no drug | 1 | OPLAH |
| E | Difficult family or no structure, no drug | 7 | ABHD16B, PPDPF, DNAJC5, PRIMA1, DEPDC5, CRH, HAR1A |
Undrugged target profiles
10 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).
| Symbol | ChEMBL assays | Drugged partners (top 3) |
|---|---|---|
| ABHD16B | 0 | — |
| PPDPF | 0 | — |
| DNAJC5 | 1 | — |
| PRIMA1 | 0 | — |
| DEPDC5 | 0 | — |
| ADAR | 2 | — |
| CRH | 1 | — |
| HAR1A | 0 | — |
| EXTL3 | 0 | — |
| OPLAH | 0 | — |
Clinical trials & evidence
Clinical trials
Clinical trials: 0.