Hyperekplexia 1

Summary

Hyperekplexia 1 (MONDO:0007868) is a disease caused by GLRA1 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: GLRA1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 112

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hyperekplexia 1
Mondo ID	MONDO:0007868
OMIM	149400
DOID	DOID:0060696
UMLS	C4551954
MedGen	1647581
GARD	0024583
Is cancer (heuristic)	no

Also known as: HKPX1 · hyperekplexia 1 · hyperekplexia type 1 · hyperekplexia, hereditary 1 · hyperekplexia, hereditary type 1

Data availability: 112 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › movement disorder › hyperekplexia › hereditary hyperekplexia › hyperekplexia 1

Related subtypes (4): 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

112 retrieved; paginated sample, class counts are floors:

28 uncertain significance, 24 pathogenic, 18 conflicting classifications of pathogenicity, 13 benign/likely benign, 11 likely pathogenic, 7 pathogenic/likely pathogenic, 7 benign, 4 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
424700	NM_000171.3(GLRA1):c.[1030C>T];[288G>T]		Pathogenic	no assertion criteria provided
424701	NM_000171.3(GLRA1):c.[298delC];[523A>G]		Pathogenic	no assertion criteria provided
424702	NM_000171.3(GLRA1):c.[1259G>A];[839G>A]		Pathogenic	no assertion criteria provided
1323021	NM_000171.4(GLRA1):c.675C>A (p.Tyr225Ter)	GLRA1	Pathogenic	criteria provided, multiple submitters, no conflicts
1324483	NM_000171.4(GLRA1):c.736C>T (p.Arg246Trp)	GLRA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
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
16062	NM_000171.4(GLRA1):c.815T>A (p.Ile272Asn)	GLRA1	Pathogenic	no assertion criteria provided
16063	NM_000171.4(GLRA1):c.920A>G (p.Tyr307Cys)	GLRA1	Pathogenic	criteria provided, multiple submitters, no conflicts
16064	NM_000171.4(GLRA1):c.882G>C (p.Gln294His)	GLRA1	Pathogenic	no assertion criteria provided
16065	NM_000171.4(GLRA1):c.910A>G (p.Lys304Glu)	GLRA1	Pathogenic	criteria provided, single submitter
16066	NM_000171.4(GLRA1):c.832C>A (p.Pro278Thr)	GLRA1	Pathogenic	no assertion criteria provided
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
16071	NM_000171.4(GLRA1):c.777C>G (p.Ser259Arg)	GLRA1	Pathogenic	no assertion criteria provided
16072	NM_001146040.1(GLRA1):c.(?-287)(912+?)del	GLRA1	Pathogenic	no assertion criteria provided
16073	NM_000171.4(GLRA1):c.971C>A (p.Ser324Ter)	GLRA1	Pathogenic	criteria provided, multiple submitters, no conflicts
16074	NM_000171.4(GLRA1):c.884G>A (p.Ser295Asn)	GLRA1	Pathogenic	no assertion criteria provided
225379	NM_000171.4(GLRA1):c.277C>T (p.Arg93Trp)	GLRA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
242679	NM_000171.4(GLRA1):c.839G>A (p.Arg280His)	GLRA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
38329	NM_000171.4(GLRA1):c.737G>A (p.Arg246Gln)	GLRA1	Pathogenic	criteria provided, single submitter
38330	NM_000171.4(GLRA1):c.801G>C (p.Trp267Cys)	GLRA1	Pathogenic	no assertion criteria provided
38333	NM_000171.4(GLRA1):c.892T>A (p.Ser298Thr)	GLRA1	Pathogenic	no assertion criteria provided
38334	NM_000171.4(GLRA1):c.920A>C (p.Tyr307Ser)	GLRA1	Pathogenic	no assertion criteria provided
38335	NM_000171.4(GLRA1):c.921del (p.Ser306_Tyr307insTer)	GLRA1	Pathogenic	criteria provided, single submitter
487340	NM_000171.4(GLRA1):c.477-1G>A	GLRA1	Pathogenic	criteria provided, single submitter
522679	NM_000171.4(GLRA1):c.252+2T>C	GLRA1	Pathogenic	criteria provided, single submitter
583758	NC_000005.10:g.(?151924474)(151924569_?)del	GLRA1	Pathogenic	criteria provided, single submitter
666970	NM_000171.4(GLRA1):c.403del (p.His135fs)	GLRA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
948005	NM_000171.4(GLRA1):c.569C>T (p.Thr190Met)	GLRA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 3 · 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

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GLRA1	Orphanet:3197	Hereditary hyperekplexia
GPHN	Orphanet:308400	Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C
GPHN	Orphanet:3197	Hereditary hyperekplexia

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GLRA1	HGNC:4326	ENSG00000145888	P23415	Glycine receptor subunit alpha-1	gencc,clinvar
GPHN	HGNC:15465	ENSG00000171723	Q9NQX3	Gephyrin	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.
GPHN	Gephyrin	Microtubule-associated protein involved in membrane protein-cytoskeleton interactions.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GLRA1	Other/Unknown	no		GABAA/Glycine_rcpt, Neurotrans-gated_channel_TM, Neur_channel
GPHN	Other/Unknown	no		MoaB/Mog_dom, MoeA_linker/N, MoeA_C_domain_IV

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
islet of Langerhans	1
male germ line stem cell (sensu Vertebrata) in testis	1
pancreatic ductal cell	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	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
GPHN	270	ubiquitous	marker	cerebellar cortex, cerebellar hemisphere, right hemisphere of cerebellum

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GPHN	2,500
GLRA1	897

Intra-cohort edges

A	B	Sources
GLRA1	GPHN	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GLRA1	P23415	9
GPHN	Q9NQX3	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Molybdenum cofactor biosynthesis	1	815.7×	0.002	GPHN
Neurotransmitter receptors and postsynaptic signal transmission	1	50.1×	0.020	GLRA1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
glycine receptor clustering	1	8426.0×	0.004	GPHN
establishment of synaptic specificity at neuromuscular junction	1	4213.0×	0.004	GPHN
synaptic transmission, glycinergic	1	2106.5×	0.004	GLRA1
gamma-aminobutyric acid receptor clustering	1	1685.2×	0.004	GPHN
Mo-molybdopterin cofactor biosynthetic process	1	1203.7×	0.004	GPHN
negative regulation of transmission of nerve impulse	1	1203.7×	0.004	GLRA1
righting reflex	1	936.2×	0.004	GLRA1
inhibitory postsynaptic potential	1	842.6×	0.004	GLRA1
response to metal ion	1	766.0×	0.004	GPHN
response to alcohol	1	766.0×	0.004	GLRA1
positive regulation of acrosome reaction	1	766.0×	0.004	GLRA1
regulation of respiratory gaseous exchange by nervous system process	1	648.1×	0.004	GLRA1
startle response	1	561.7×	0.004	GLRA1
neuromuscular process controlling posture	1	526.6×	0.004	GLRA1
cellular response to ethanol	1	526.6×	0.004	GLRA1
acrosome reaction	1	443.5×	0.004	GLRA1
neurotransmitter receptor localization to postsynaptic specialization membrane	1	401.2×	0.004	GPHN
cellular response to zinc ion	1	337.0×	0.005	GLRA1
adult walking behavior	1	247.8×	0.006	GLRA1
neuronal action potential	1	240.7×	0.006	GLRA1
chloride transport	1	227.7×	0.006	GLRA1
establishment of protein localization	1	216.1×	0.006	GPHN
cellular response to amino acid stimulus	1	153.2×	0.009	GLRA1
chloride transmembrane transport	1	118.7×	0.010	GLRA1
synapse assembly	1	115.4×	0.010	GPHN
regulation of membrane potential	1	115.4×	0.010	GLRA1
muscle contraction	1	104.0×	0.011	GLRA1
neuropeptide signaling pathway	1	86.0×	0.012	GLRA1
monoatomic ion transport	1	78.0×	0.013	GLRA1
visual perception	1	39.8×	0.025	GLRA1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 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
GLRA1	TELMISARTAN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GLRA1	15	4
GPHN	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
ADAPALENE	4	GLRA1
PIMOZIDE	4	GLRA1
SULINDAC	4	GLRA1
REGORAFENIB	4	GLRA1
ASTEMIZOLE	4	GLRA1
MEFLOQUINE	4	GLRA1
DRONABINOL	4	GLRA1
FLUSPIRILENE	4	GLRA1
GLYCINE	4	GLRA1
RISPERIDONE	4	GLRA1
FRUCTOSE	2	GLRA1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
GLRA1	59	Binding:51, Functional:7, Toxicity:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

15 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
ADAPALENE	4	GLRA1
PIMOZIDE	4	GLRA1
SULINDAC	4	GLRA1
REGORAFENIB	4	GLRA1
ASTEMIZOLE	4	GLRA1
MEFLOQUINE	4	GLRA1
DRONABINOL	4	GLRA1
FLUSPIRILENE	4	GLRA1
GLYCINE	4	GLRA1
RISPERIDONE	4	GLRA1
FRUCTOSE	2	GLRA1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	GLRA1
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	1	GPHN

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
GPHN	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.