Hereditary hyperekplexia

Summary

Hereditary hyperekplexia (MONDO:0021022) is a disease (an umbrella term covering 5 Mondo subtypes) with 7 cohort genes and 4 clinical trials.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Umbrella term: 5 Mondo subtypes
• Cohort genes: 7
• ClinVar variants: 470
• Phenotypes (HPO): 21
• Clinical trials: 4

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		150	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

21 HPO clinical features (Orphanet curated; top 21 by frequency):

HPO ID	Term	Frequency
HP:0001251	Ataxia	Very frequent (80-99%)
HP:0001257	Spasticity	Very frequent (80-99%)
HP:0001276	Hypertonia	Very frequent (80-99%)
HP:0001336	Myoclonus	Very frequent (80-99%)
HP:0001347	Hyperreflexia	Very frequent (80-99%)
HP:0001387	Joint stiffness	Very frequent (80-99%)
HP:0002020	Gastroesophageal reflux	Very frequent (80-99%)
HP:0002036	Hiatus hernia	Very frequent (80-99%)
HP:0002063	Rigidity	Very frequent (80-99%)
HP:0002380	Fasciculations	Very frequent (80-99%)
HP:0003552	Muscle stiffness	Very frequent (80-99%)
HP:0100022	Abnormality of movement	Very frequent (80-99%)
HP:0100633	Esophagitis	Very frequent (80-99%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001537	Umbilical hernia	Frequent (30-79%)
HP:0002360	Sleep abnormality	Frequent (30-79%)
HP:0100790	Hernia	Frequent (30-79%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001373	Joint dislocation	Occasional (5-29%)
HP:0002827	Hip dislocation	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary hyperekplexia
Mondo ID	MONDO:0021022
OMIM	149400
Orphanet	3197
DOID	DOID:0060695
ICD-11	988250063
SNOMED CT	724351008
UMLS	C4084968
MedGen	904633
GARD	0003129
Is cancer (heuristic)	no

Also known as: congenital stiff man syndrome · familial startle disease · hereditary hyperekplexia · hereditary hyperexplexia · hyperekplexia · hyperexplexia hereditary · Kok disease · Stiff baby syndrome

Data availability: 470 ClinVar variants · 5 GenCC gene-disease records.

Disease family

An umbrella term covering 5 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › movement disorder › hyperekplexia › hereditary hyperekplexia

Related subtypes (1): sporadic hyperekplexia

Subtypes (5): hyperekplexia 1, developmental and epileptic encephalopathy, 8, hyperekplexia 3, hyperekplexia 2, hyperekplexia 4

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

470 retrieved; paginated sample, class counts are floors:

214 uncertain significance, 160 likely benign, 33 pathogenic, 24 conflicting classifications of pathogenicity, 12 benign/likely benign, 10 likely pathogenic, 9 pathogenic/likely pathogenic, 8 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1070761	NM_000171.4(GLRA1):c.634_635del (p.Leu212fs)	GLRA1	Pathogenic	criteria provided, single submitter
1076337	NC_000005.9:g.(?151266262)(151266369_?)del	GLRA1	Pathogenic	criteria provided, single submitter
1076338	NC_000005.9:g.(?151239326)(151239589_?)del	GLRA1	Pathogenic	criteria provided, single submitter
1324483	NM_000171.4(GLRA1):c.736C>T (p.Arg246Trp)	GLRA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1373698	NM_000171.4(GLRA1):c.376del (p.Leu126fs)	GLRA1	Pathogenic	criteria provided, single submitter
1431352	NM_000171.4(GLRA1):c.378del (p.Phe127fs)	GLRA1	Pathogenic	criteria provided, single submitter
1436466	NM_000171.4(GLRA1):c.1101T>A (p.Tyr367Ter)	GLRA1	Pathogenic	criteria provided, single submitter
1455169	NM_000171.4(GLRA1):c.186dup (p.Pro63fs)	GLRA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1459155	NM_000171.4(GLRA1):c.895C>T (p.Arg299Ter)	GLRA1	Pathogenic	criteria provided, single submitter
16060	NM_000171.4(GLRA1):c.896G>T (p.Arg299Leu)	GLRA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16061	NM_000171.4(GLRA1):c.896G>A (p.Arg299Gln)	GLRA1	Pathogenic	criteria provided, multiple submitters, no conflicts
16063	NM_000171.4(GLRA1):c.920A>G (p.Tyr307Cys)	GLRA1	Pathogenic	criteria provided, multiple submitters, no conflicts
16067	NM_000171.4(GLRA1):c.298del (p.Arg100fs)	GLRA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16069	NM_000171.4(GLRA1):c.690C>A (p.Tyr230Ter)	GLRA1	Pathogenic	criteria provided, single submitter
16073	NM_000171.4(GLRA1):c.971C>A (p.Ser324Ter)	GLRA1	Pathogenic	criteria provided, multiple submitters, no conflicts
2014746	NM_000171.4(GLRA1):c.258_260del (p.Tyr86_Arg87delinsTer)	GLRA1	Pathogenic	criteria provided, single submitter
2045456	NM_000171.4(GLRA1):c.381dup (p.Phe128fs)	GLRA1	Pathogenic	criteria provided, single submitter
2136350	NM_000171.4(GLRA1):c.278G>T (p.Arg93Leu)	GLRA1	Pathogenic	criteria provided, single submitter
2162119	NM_000171.4(GLRA1):c.537dup (p.Cys180fs)	GLRA1	Pathogenic	criteria provided, single submitter
2196359	NM_000171.4(GLRA1):c.298C>T (p.Arg100Cys)	GLRA1	Pathogenic	criteria provided, single submitter
225379	NM_000171.4(GLRA1):c.277C>T (p.Arg93Trp)	GLRA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2422534	NC_000005.9:g.(?151230931)(151304110_?)del	GLRA1	Pathogenic	criteria provided, single submitter
2422535	NC_000005.9:g.(?151304035)(151304110_?)del	GLRA1	Pathogenic	criteria provided, single submitter
242679	NM_000171.4(GLRA1):c.839G>A (p.Arg280His)	GLRA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
242680	NM_000171.4(GLRA1):c.1259G>A (p.Arg420His)	GLRA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2756322	NM_000171.4(GLRA1):c.725del (p.Phe242fs)	GLRA1	Pathogenic	criteria provided, single submitter
2778873	NM_000171.4(GLRA1):c.99dup (p.Lys34fs)	GLRA1	Pathogenic	criteria provided, single submitter
2800421	NM_000171.4(GLRA1):c.1059+1G>A	GLRA1	Pathogenic	criteria provided, single submitter
2850498	NM_000171.4(GLRA1):c.365G>A (p.Trp122Ter)	GLRA1	Pathogenic	criteria provided, single submitter
3013590	NM_000171.4(GLRA1):c.415del (p.Ile139fs)	GLRA1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 39 · Orphanet: 7 · 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
GLRA1	Definitive	Autosomal dominant	hyperekplexia 1	7
GLRB	Definitive	Autosomal recessive	hyperekplexia 2	6
SLC6A2	Definitive	Autosomal recessive	hyperekplexia 3	9
SLC6A5	Definitive	Autosomal recessive	hyperekplexia 3	6
ATAD1	Strong	Autosomal recessive	hyperekplexia 4	4
GPHN	Supportive	Autosomal dominant	hereditary hyperekplexia	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GLRA1	Orphanet:3197	Hereditary hyperekplexia
SLC6A2	Orphanet:443236	Postural orthostatic tachycardia syndrome due to NET deficiency
SLC6A5	Orphanet:3197	Hereditary hyperekplexia
GPHN	Orphanet:308400	Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C
GPHN	Orphanet:3197	Hereditary hyperekplexia
ATAD1	Orphanet:3197	Hereditary hyperekplexia
GLRB	Orphanet:3197	Hereditary hyperekplexia

Cohort genes → proteins

7 cohort genes, 7 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	7

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GLRA1	HGNC:4326	ENSG00000145888	P23415	Glycine receptor subunit alpha-1	gencc,clinvar
SLC6A2	HGNC:11048	ENSG00000103546	P23975	Sodium-dependent noradrenaline transporter	gencc
SLC6A5	HGNC:11051	ENSG00000165970	Q9Y345	Sodium- and chloride-dependent glycine transporter 2	gencc
GPHN	HGNC:15465	ENSG00000171723	Q9NQX3	Gephyrin	gencc
ATAD1	HGNC:25903	ENSG00000138138	Q8NBU5	Outer mitochondrial transmembrane helix translocase	gencc
GLRB	HGNC:4329	ENSG00000109738	P48167	Glycine receptor subunit beta	gencc
ATOX1	HGNC:798	ENSG00000177556	O00244	Copper transport protein ATOX1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GLRA1	Glycine receptor subunit alpha-1	Subunit of heteromeric glycine-gated chloride channels.
SLC6A2	Sodium-dependent noradrenaline transporter	Mediates sodium- and chloride-dependent transport of norepinephrine (also known as noradrenaline), the primary signaling neurotransmitter in the autonomic sympathetic nervous system.
SLC6A5	Sodium- and chloride-dependent glycine transporter 2	Sodium- and chloride-dependent glycine transporter.
GPHN	Gephyrin	Microtubule-associated protein involved in membrane protein-cytoskeleton interactions.
ATAD1	Outer mitochondrial transmembrane helix translocase	Outer mitochondrial translocase required to remove mislocalized tail-anchored transmembrane proteins on mitochondria.
GLRB	Glycine receptor subunit beta	Subunit of heteromeric glycine-gated chloride channels.
ATOX1	Copper transport protein ATOX1	Binds and deliver cytosolic copper to the copper ATPase proteins.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 7 · Druggable fraction: 0.0

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
Other/Unknown	7	1.8×	0.017

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GLRA1	Other/Unknown	no		GABAA/Glycine_rcpt, Neurotrans-gated_channel_TM, Neur_channel
SLC6A2	Other/Unknown	no		Na/ntran_symport, Na/ntran_symport_noradrenaline, SNS_sf
SLC6A5	Other/Unknown	no		Na/ntran_symport, SNS_sf
GPHN	Other/Unknown	no		MoaB/Mog_dom, MoeA_linker/N, MoeA_C_domain_IV
ATAD1	Other/Unknown	no		AAA+_ATPase, ATPase_AAA_core, ATPase_AAA_CS
GLRB	Other/Unknown	no		Neurotrans-gated_channel_TM, Neur_channel, Neur_chan_lig-bd
ATOX1	Other/Unknown	no		HMA_dom, Heavy-metal-associated_CS, HMA_dom_sf

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)	7
unknown	0

Top tissues across cohort

Tissue	Cohort genes
islet of Langerhans	2
male germ line stem cell (sensu Vertebrata) in testis	2
pancreatic ductal cell	1
buccal mucosa cell	1
decidua	1
placenta	1
oocyte	1
secondary oocyte	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
left testis	1
right testis	1
Brodmann (1909) area 10	1
frontal pole	1
middle frontal gyrus	1
C1 segment of cervical spinal cord	1
right adrenal gland	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GLRA1	39	tissue_specific	marker	islet of Langerhans, male germ line stem cell (sensu Vertebrata) in testis, pancreatic ductal cell
SLC6A2	121	ubiquitous	marker	placenta, buccal mucosa cell, decidua
SLC6A5	36	ubiquitous	marker	secondary oocyte, male germ line stem cell (sensu Vertebrata) in testis, oocyte
GPHN	270	ubiquitous	marker	cerebellar cortex, cerebellar hemisphere, right hemisphere of cerebellum
ATAD1	252	ubiquitous	marker	right testis, left testis, islet of Langerhans
GLRB	236	ubiquitous	marker	frontal pole, Brodmann (1909) area 10, middle frontal gyrus
ATOX1	286	ubiquitous	marker	C1 segment of cervical spinal cord, right lobe of liver, right adrenal gland

Protein interactions among cohort

Intra-cohort edges: 7.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATAD1	3,099
GPHN	2,500
ATOX1	2,122
GLRB	1,382
SLC6A5	1,314
SLC6A2	1,213
GLRA1	897

Intra-cohort edges

A	B	Sources
GLRA1	GLRB	intact
GLRA1	GPHN	string_interaction
GLRA1	SLC6A5	string_interaction
GLRB	GPHN	biogrid_interaction, string_interaction
GLRB	SLC6A2	string_interaction
GLRB	SLC6A5	string_interaction
GPHN	SLC6A5	string_interaction

Structural data

PDB: 7 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC6A2	P23975	36
ATOX1	O00244	17
GLRB	P48167	12
GLRA1	P23415	9
SLC6A5	Q9Y345	4
ATAD1	Q8NBU5	2
GPHN	Q9NQX3	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 21. Enrichment computed across 7 evidence-associated genes (7 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 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
SLC-mediated transport of neurotransmitters	2	116.5×	0.003	SLC6A2, SLC6A5
SLC transporter disorders	2	58.3×	0.004	SLC6A2, SLC6A5
R-HSA-425366	2	51.8×	0.004	SLC6A2, SLC6A5
Defective SLC6A5 causes hyperekplexia 3 (HKPX3)	1	815.7×	0.005	SLC6A5
Disorders of transmembrane transporters	2	39.8×	0.005	SLC6A2, SLC6A5
Defective SLC6A2 causes orthostatic intolerance (OI)	1	407.9×	0.006	SLC6A2
Ion influx/efflux at host-pathogen interface	1	407.9×	0.006	ATOX1
Neurotransmitter receptors and postsynaptic signal transmission	2	28.6×	0.006	GLRA1, GLRB
Molybdenum cofactor biosynthesis	1	233.1×	0.010	GPHN
SLC-mediated transmembrane transport	2	16.9×	0.012	SLC6A2, SLC6A5
Class I peroxisomal membrane protein import	1	74.2×	0.026	ATAD1
Detoxification of Reactive Oxygen Species	1	42.9×	0.040	ATOX1
Antimicrobial peptides	1	32.0×	0.046	ATOX1
Transport of small molecules	2	7.2×	0.046	SLC6A2, SLC6A5
Protein localization	1	27.2×	0.051	ATAD1
Cellular response to chemical stress	1	20.4×	0.063	ATOX1
Disease	2	3.7×	0.117	SLC6A2, SLC6A5
Cellular responses to stress	1	5.3×	0.204	ATOX1
Cellular responses to stimuli	1	4.5×	0.224	ATOX1
Innate Immune System	1	3.6×	0.257	ATOX1
Immune System	1	1.9×	0.430	ATOX1

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
synaptic transmission, glycinergic	3	1805.6×	9e-09	GLRA1, SLC6A5, GLRB
gamma-aminobutyric acid receptor clustering	2	963.0×	4e-05	GPHN, GLRB
righting reflex	2	535.0×	1e-04	GLRA1, GLRB
startle response	2	321.0×	2e-04	GLRA1, GLRB
acrosome reaction	2	253.4×	3e-04	GLRA1, GLRB
adult walking behavior	2	141.6×	6e-04	GLRA1, GLRB
chemical synaptic transmission	3	33.1×	6e-04	SLC6A2, SLC6A5, GLRB
neurotransmitter transport	2	120.4×	8e-04	SLC6A2, SLC6A5
glycine receptor clustering	1	2407.4×	0.002	GPHN
extraction of mislocalized protein from mitochondrial outer membrane	1	2407.4×	0.002	ATAD1
chloride transmembrane transport	2	67.8×	0.002	GLRA1, GLRB
sodium ion transmembrane transport	2	58.0×	0.002	SLC6A2, SLC6A5
neuropeptide signaling pathway	2	49.1×	0.003	GLRA1, GLRB
establishment of synaptic specificity at neuromuscular junction	1	1203.7×	0.003	GPHN
monoatomic ion transport	2	44.6×	0.003	GLRA1, GLRB
copper ion export	1	802.5×	0.004	ATOX1
Mo-molybdopterin cofactor biosynthetic process	1	343.9×	0.008	GPHN
negative regulation of transmission of nerve impulse	1	343.9×	0.008	GLRA1
glycine import across plasma membrane	1	343.9×	0.008	SLC6A5
obsolete norepinephrine transport	1	267.5×	0.008	SLC6A2
dopamine uptake involved in synaptic transmission	1	267.5×	0.008	SLC6A2
norepinephrine uptake	1	267.5×	0.008	SLC6A2
copper ion transport	1	240.7×	0.008	ATOX1
negative regulation of synaptic transmission, glutamatergic	1	240.7×	0.008	ATAD1
inhibitory postsynaptic potential	1	240.7×	0.008	GLRA1
response to metal ion	1	218.9×	0.008	GPHN
response to alcohol	1	218.9×	0.008	GLRA1
positive regulation of acrosome reaction	1	218.9×	0.008	GLRA1
visual perception	2	22.7×	0.008	GLRA1, GLRB
regulation of respiratory gaseous exchange by nervous system process	1	185.2×	0.010	GLRA1

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 5

Druggability breadth: 4 of 7 evidence-associated genes (57%) 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
GLRA1	TELMISARTAN
SLC6A2	CETIRIZINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SLC6A2	471	4
GLRA1	15	4
SLC6A5	0	0
GPHN	0	0
ATAD1	0	0
GLRB	0	0
ATOX1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
TELMISARTAN	4	GLRA1
CHOLECALCIFEROL	4	GLRA1
DUTASTERIDE	4	GLRA1
CINACALCET	4	GLRA1, SLC6A2
ADAPALENE	4	GLRA1
PIMOZIDE	4	GLRA1, SLC6A2
SULINDAC	4	GLRA1
REGORAFENIB	4	GLRA1, SLC6A2
ASTEMIZOLE	4	GLRA1, SLC6A2
MEFLOQUINE	4	GLRA1, SLC6A2
DRONABINOL	4	GLRA1
FLUSPIRILENE	4	GLRA1, SLC6A2
GLYCINE	4	GLRA1
RISPERIDONE	4	GLRA1, SLC6A2
CETIRIZINE	4	SLC6A2
BEPRIDIL	4	SLC6A2
CANDESARTAN CILEXETIL	4	SLC6A2
BEXAROTENE	4	SLC6A2
CLOTRIMAZOLE	4	SLC6A2
AMINOCAPROIC ACID	4	SLC6A2
SIMVASTATIN	4	SLC6A2
NABUMETONE	4	SLC6A2
METAXALONE	4	SLC6A2
ACETOPHENAZINE	4	SLC6A2
MESORIDAZINE	4	SLC6A2
PHENELZINE	4	SLC6A2
NIRAPARIB	4	SLC6A2
INDACATEROL	4	SLC6A2
IMIPRAMINE	4	SLC6A2
EPINASTINE	4	SLC6A2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SLC6A2	929	Binding:885, ADMET:25, Functional:15, Toxicity:3, Unclassified:1
GLRA1	59	Binding:51, Functional:7, Toxicity:1
SLC6A5	54	Binding:50, Functional:4
GLRB	30	Binding:29, Toxicity:1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SLC6A2	929

Pharmacogenomics

Cohort genes with a PharmGKB record: 7; 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)
TELMISARTAN	4	GLRA1
CHOLECALCIFEROL	4	GLRA1
DUTASTERIDE	4	GLRA1
CINACALCET	4	GLRA1, SLC6A2
ADAPALENE	4	GLRA1
PIMOZIDE	4	GLRA1, SLC6A2
SULINDAC	4	GLRA1
REGORAFENIB	4	GLRA1, SLC6A2
ASTEMIZOLE	4	GLRA1, SLC6A2
MEFLOQUINE	4	GLRA1, SLC6A2
DRONABINOL	4	GLRA1
FLUSPIRILENE	4	GLRA1, SLC6A2
GLYCINE	4	GLRA1
RISPERIDONE	4	GLRA1, SLC6A2
CETIRIZINE	4	SLC6A2
BEPRIDIL	4	SLC6A2
CANDESARTAN CILEXETIL	4	SLC6A2
BEXAROTENE	4	SLC6A2
CLOTRIMAZOLE	4	SLC6A2
AMINOCAPROIC ACID	4	SLC6A2
SIMVASTATIN	4	SLC6A2
NABUMETONE	4	SLC6A2
METAXALONE	4	SLC6A2
ACETOPHENAZINE	4	SLC6A2
MESORIDAZINE	4	SLC6A2
PHENELZINE	4	SLC6A2
NIRAPARIB	4	SLC6A2
INDACATEROL	4	SLC6A2
IMIPRAMINE	4	SLC6A2
EPINASTINE	4	SLC6A2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	GLRA1, SLC6A2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	5	SLC6A5, GPHN, ATAD1, GLRB, ATOX1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SLC6A5	54	GLRA1
GPHN	0	—
ATAD1	0	—
GLRB	30	—
ATOX1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 4.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	4

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05652101	Not specified	RECRUITING	Hyperekplexia : Adaptative Skills and Neurodevelopmental Trajectory
NCT01476514	Not specified	TERMINATED	Effects of Mutations of the Glycine Gene Associated With Hyperekplexia on Central Pain Processing
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