Brugada syndrome 8

Summary

Brugada syndrome 8 (MONDO:0013148) is a disease with 3 cohort genes.

At a glance

• Cohort genes: 3
• ClinVar variants: 1,816

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Brugada syndrome 8
Mondo ID	MONDO:0013148
MeSH	C567732
OMIM	613123
DOID	DOID:0110225
UMLS	C2751083
MedGen	413928
GARD	0015622
Is cancer (heuristic)	no

Also known as: BRGDA8 · Brugada syndrome 8 · Brugada syndrome caused by mutation in HCN4 · Brugada syndrome type 8 · HCN4 Brugada syndrome

Data availability: 1,816 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › heart disorder › heart conduction disease › Brugada syndrome › Brugada syndrome 8

Related subtypes (8): Brugada syndrome 1, Brugada syndrome 2, Brugada syndrome 3, Brugada syndrome 4, Brugada syndrome 5, Brugada syndrome 6, Brugada syndrome 7, Brugada syndrome 9

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:

315 uncertain significance, 238 likely benign, 20 conflicting classifications of pathogenicity, 12 benign, 11 benign/likely benign, 3 pathogenic/likely pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1359536	NM_005477.3(HCN4):c.1061A>G (p.Tyr354Cys)	HCN4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1675066	NM_005477.3(HCN4):c.1454C>T (p.Ala485Val)	HCN4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
197253	NM_005477.3(HCN4):c.1444G>A (p.Gly482Arg)	HCN4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1504964	NM_005477.3(HCN4):c.1442A>G (p.Tyr481Cys)	HCN4	Likely pathogenic	criteria provided, single submitter
1085715	NM_005477.3(HCN4):c.2063A>G (p.Asn688Ser)	HCN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1514023	NM_005477.3(HCN4):c.1124G>A (p.Arg375His)	HCN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1594868	NM_005477.3(HCN4):c.2786T>C (p.Leu929Pro)	HCN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
167170	NM_005477.3(HCN4):c.2739G>A (p.Ala913=)	HCN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
167171	NM_005477.3(HCN4):c.1459G>A (p.Val487Met)	HCN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
167172	NM_005477.3(HCN4):c.621C>G (p.Arg207=)	HCN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1790541	NM_005477.3(HCN4):c.238C>T (p.Pro80Ser)	HCN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
180370	NM_005477.3(HCN4):c.458A>G (p.Glu153Gly)	HCN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
190772	NM_005477.3(HCN4):c.2275G>A (p.Val759Ile)	HCN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
190774	NM_005477.3(HCN4):c.2800C>T (p.Arg934Cys)	HCN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
190779	NM_005477.3(HCN4):c.1132C>T (p.Arg378Cys)	HCN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
190784	NM_005477.3(HCN4):c.2804C>T (p.Ser935Phe)	HCN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
190786	NM_005477.3(HCN4):c.418G>A (p.Gly140Ser)	HCN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
190788	NM_005477.3(HCN4):c.584C>T (p.Ala195Val)	HCN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
191449	NM_005477.3(HCN4):c.3577G>C (p.Glu1193Gln)	HCN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
191450	NM_005477.3(HCN4):c.3461G>A (p.Arg1154Gln)	HCN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
198183	NM_005477.3(HCN4):c.1915G>A (p.Val639Met)	HCN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
198822	NM_005477.3(HCN4):c.2523G>A (p.Ser841=)	HCN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
198823	NM_005477.3(HCN4):c.2553A>G (p.Thr851=)	HCN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
198828	NM_005477.3(HCN4):c.2273G>A (p.Arg758His)	HCN4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1001210	NM_005477.3(HCN4):c.515C>G (p.Pro172Arg)	HCN4	Uncertain significance	criteria provided, single submitter
1003330	NM_005477.3(HCN4):c.2917G>T (p.Gly973Trp)	HCN4	Uncertain significance	criteria provided, single submitter
1003826	NM_005477.3(HCN4):c.1357A>G (p.Ile453Val)	HCN4	Uncertain significance	criteria provided, single submitter
1004050	NM_005477.3(HCN4):c.2941G>T (p.Glu981Ter)	HCN4	Uncertain significance	criteria provided, single submitter
1004807	NM_005477.3(HCN4):c.2437G>A (p.Gly813Arg)	HCN4	Uncertain significance	criteria provided, multiple submitters, no conflicts
1005511	NM_005477.3(HCN4):c.2398C>A (p.Arg800Ser)	HCN4	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 4 · 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
HCN4	Moderate	Autosomal dominant	Brugada syndrome 8	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HCN4	Orphanet:130	Brugada syndrome
HCN4	Orphanet:166282	Hereditary sick sinus syndrome
HCN1	Orphanet:36387	Genetic epilepsy with febrile seizure plus
HCN1	Orphanet:442835	Non-specific early-onset epileptic encephalopathy

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HCN4	HGNC:16882	ENSG00000138622	Q9Y3Q4	Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4	gencc,clinvar
ADPGK	HGNC:25250	ENSG00000159322	Q9BRR6	ADP-dependent glucokinase	clinvar
HCN1	HGNC:4845	ENSG00000164588	O60741	Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HCN4	Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4	Hyperpolarization-activated ion channel that are permeable to Na(+) and K(+) ions with very slow activation and inactivation.
ADPGK	ADP-dependent glucokinase	Catalyzes the phosphorylation of D-glucose to D-glucose 6-phosphate using ADP as the phosphate donor.
HCN1	Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1	Hyperpolarization-activated ion channel that are permeable to sodium and potassium ions.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Ion channel	2	74.3×	5e-04
Kinase	1	9.2×	0.104

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HCN4	Ion channel	yes		cNMP-bd_dom, K_chnl_volt-dep_EAG/ELK/ERG, Ion_trans_dom
ADPGK	Kinase	yes	2.7.1.147	ADP_PFK/GK, Ribokinase-like
HCN1	Ion channel	yes		cNMP-bd_dom, K_chnl_volt-dep_EAG/ELK/ERG, Ion_trans_dom

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cardiac atrium	1
right atrium auricular region	1
tibialis anterior	1
monocyte	1
mononuclear cell	1
oocyte	1
Brodmann (1909) area 23	1
endothelial cell	1
primary visual cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HCN4	86	tissue_specific	yes	tibialis anterior, right atrium auricular region, cardiac atrium
ADPGK	263	ubiquitous	marker	oocyte, monocyte, mononuclear cell
HCN1	147	broad	marker	endothelial cell, Brodmann (1909) area 23, primary visual cortex

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HCN4	1,279
ADPGK	1,205
HCN1	726

Intra-cohort edges

A	B	Sources
HCN1	HCN4	biogrid_interaction, intact

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HCN1	O60741	17
HCN4	Q9Y3Q4	8

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ADPGK	Q9BRR6	91.36

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
HCN channels	2	1903.3×	1e-06	HCN4, HCN1
Glucose metabolism	1	292.8×	0.009	ADPGK
Glycolysis	1	95.2×	0.017	ADPGK
Metabolism of carbohydrates and carbohydrate derivatives	1	40.1×	0.031	ADPGK
Metabolism	1	3.9×	0.237	ADPGK

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 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 SA node cell action potential	2	1872.4×	1e-05	HCN4, HCN1
regulation of membrane depolarization	2	1248.3×	1e-05	HCN4, HCN1
sodium ion import across plasma membrane	2	416.1×	8e-05	HCN4, HCN1
regulation of heart rate by cardiac conduction	2	249.7×	1e-04	HCN4, HCN1
potassium ion import across plasma membrane	2	244.2×	1e-04	HCN4, HCN1
cellular response to cAMP	2	193.7×	2e-04	HCN4, HCN1
regulation of membrane potential	2	153.9×	3e-04	HCN4, HCN1
sodium ion transmembrane transport	2	135.4×	3e-04	HCN4, HCN1
glycolytic process through glucose-6-phosphate	1	5617.3×	6e-04	ADPGK
positive regulation of membrane hyperpolarization	1	5617.3×	6e-04	HCN1
potassium ion transmembrane transport	2	90.6×	6e-04	HCN4, HCN1
negative regulation of action potential	1	1404.3×	0.002	HCN1
general adaptation syndrome, behavioral process	1	1123.5×	0.002	HCN1
membrane depolarization during SA node cell action potential	1	1123.5×	0.002	HCN4
SA node cell action potential	1	936.2×	0.002	HCN4
sinoatrial node development	1	702.2×	0.003	HCN4
cellular response to cGMP	1	702.2×	0.003	HCN4
regulation of cardiac muscle cell action potential involved in regulation of contraction	1	624.1×	0.003	HCN4
negative regulation of synaptic transmission, glutamatergic	1	561.7×	0.003	HCN1
response to L-glutamate	1	561.7×	0.003	HCN1
retinal cone cell development	1	468.1×	0.003	HCN1
membrane depolarization during cardiac muscle cell action potential	1	468.1×	0.003	HCN4
maternal behavior	1	374.5×	0.004	HCN1
apical protein localization	1	330.4×	0.004	HCN1
regulation of cardiac muscle contraction	1	295.6×	0.005	HCN4
monoatomic cation transport	1	255.3×	0.005	HCN4
cellular response to interferon-beta	1	175.5×	0.007	HCN1
blood circulation	1	170.2×	0.007	HCN4
neuronal action potential	1	160.5×	0.007	HCN1
regulation of heart rate	1	156.0×	0.007	HCN4

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) 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
HCN4	IVABRADINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HCN4	2	4
ADPGK	0	0
HCN1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
IVABRADINE	4	HCN4
ZATEBRADINE	2	HCN4

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
HCN4	30	Binding:20, ADMET:5, Functional:4, Toxicity:1
HCN1	21	Binding:12, Functional:8, ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ADPGK	2.7.1.147	ADP-specific glucose/glucosamine kinase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

2 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)
IVABRADINE	4	HCN4
ZATEBRADINE	2	HCN4

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	HCN4
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	HCN1
D	Druggable family + AlphaFold only, no drug	1	ADPGK
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ADPGK	0	—
HCN1	21	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.