HCN4
protein-codinghyperpolarization activated cyclic nucleotide gated potassium channel 4, the group of Cyclic nucleotide gated channels
Gene summary
This gene encodes a member of the hyperpolarization-activated cyclic nucleotide-gated potassium channels. The encoded protein shows slow kinetics of activation and inactivation, and is necessary for the cardiac pacemaking process. This channel may also mediate responses to sour stimuli. Mutations in this gene have been linked to sick sinus syndrome 2, also known as atrial fibrillation with bradyarrhythmia or familial sinus bradycardia. Two pseudogenes have been identified on chromosome 15. [provided by RefSeq, Oct 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~49.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0008102
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0015263
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0008102
Submitter: ClinGen
HCN4-sinus node dysfunction with or without hypertrabeculation phenotype-autosomal dominant HCN4 encodes hyperpolarization-activated cyclic nucleotide channel 4 subunits, which form an ion channel that plays a key role in cardiac rhythmicity as a major constituent of the hyperpolarisation-activated “funny” current (If) in the sinoatrial node, also known as the spontaneous cardiac pacemaker. Genetic variation in HCN4 was first described by Schulze-Bahr (PMID 12750403) in 2003 in a patient with sinus node dysfunction (SND). In 2014 Schweizer et al. (PMID 25145518) and Milano et al (PMID 25145517) separately reported families in which genetic variation within HCN4 segregated with the combined SND and ventricular hypertrabeculation phenotype. At least 25 unique variants have been reported to cause SND, primarily sinus bradycardia (PMIDs 12750403, 25145518, 25145517, 16407510, 35257104, 26688388, 23178648, 34088380, 31731876, 32600061, 28104484, 20662977, 16407510, 26206080, 32577394, 17646576, 35328031, 30471092, 33082984, 29440115, 15123648, 36244448). Fifteen publications report variants as the likely aetiology of both SND and ventricular hypertrabeculation (PMIDs 25145518, 25145517, 33008772, 35257104, 26688388, 34088380, 31731876, 32600061, 28104484, 26206080, 32577394, 35328031, 30471092, 33082984, 29440115). The phenotypes of SND and ventricular hypertrabeculation were lumped as per criteria outlined by the ClinGen Lumping and Splitting Working Group (no differences in molecular mechanism, or inheritance pattern were identified). The mechanism of pathogenicity appears to be primarily one of loss of function (PMID 25145518). Segregation data support an autosomal dominant inheritance pattern (PMID 16407510). Genetic variants resulting in SND, and ventricular hypertrabeculation are predominately non-truncating, and reside within the transmembrane region (residues 267-517). The significance of genetic variation located outside of the transmembrane region remains unclear (PMID 33500567). Genetic hotspots exist within the conserved pore-forming region (amino acid residues 465-486). The association between HCN4 and SND with or without ventricular hypertrabeculation, is supported by both genetic and experimental evidence. The maximum score for genetic evidence (12 points) has been reached through review of case-level data, extensive family segregation and case-control data (variant burden analysis PMID 33500567; GWAS highlighting HCN4 as a modulator of heart rate PMID 23583979; case level and segregation data listed in publications above). Experimental evidence supporting the disease-gene association includes functional alteration data (PMIDs 33008772, 28104484, 25145517, 17646576, 25145517, 25145518, 12750403, 15123648, 23178648, 24607718, 16407510, 36244448), pharmacological targets (ivabradine-induced bradycardia), protein interaction data (STRING database) and multiple animal models demonstrating sinus node dysfunction with HCN4 knockout (PMID 17914461; PMID 18219271). Studies of individuals with specific variants located within the HCN4 pore-forming domain (p.Tyr481His, p.Gly482Arg, and p.Arg483_Val487del) support an association between HCN4 and thoracic aortic aneurysms (PMIDs 27173043, 31731876, 33185997, 35257104, 32577394). Additionally, genetic variation in HCN4 has also been associated with early onset atrial fibrillation (PMID 24607718s, 23178648, 28104484, 12750403), left atrial dilatation (PMID 33008772), mitral valve prolapse (PMIDs 26206080, 27173043, 25145518), atrioventricular block (PMID 36381173), ventricular tachycardia (PMID 36244448), ventricular fibrillation (PMIDs 36381173, 29440115), and tachycardia-induced cardiomyopathy (PMID 29987112). Further data is required to assess the strength of these gene-disease-gene associations. In summary, HCN4 is definitively associated with autosomal dominant sinus node dysfunction with or without ventricular hypertrabeculation. This classification was approved by the ClinGen Hereditary Cardiovascular Disease GCEP on 22/10/24 (SOP version 11).
Inheritance Pattern: AD
Disease ID:MONDO:0013148
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0013148
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0008102
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0012061
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0013148
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0011001
Submitter: ClinGen
Inheritance Pattern: AD
Disease ID:MONDO:0008102
Submitter: Genomics England PanelApp
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular
Intervention: Cardiovascular; Neurologic
Rationale: Variants may result in several cardiac conditions involving arrhythmia, and, depending on the condition, surveillance with approximately yearly EKG and medical interventions, including daily quinidine for prevention (though treatment of asymptomatic individuals is controversial), ICD placement in individuals with previous cardiac arrest/syncope, and isoproterenol for electrical storms, may be beneficial; Certain agents should be avoided, including medications such as certain anesthetics, antidepressants, and antipsychotics, and care should be taken in the instance of high fever
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to HCN4 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_005477.3. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 5 | 748 | 12 | 765 | ||
| missense | 5 | 17 | 1127 | 76 | 5 | 1230 |
| nonsense | 12 | 12 | ||||
| start loss | 1 | 1 | 2 | |||
| frameshift | 2 | 1 | 48 | 51 | ||
| splice donor/acceptor (+/-2bp) | 2 | 8 | 10 | |||
| Total | 7 | 20 | 1201 | 825 | 17 | 2070 |
Highest pathogenic variant AF is 0.000009293335
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_005468.1 | 8 | MANE Select | |
| Ensembl | ENSP00000261917.3 | 8 | MANE Select | |
| RefSeq | XP_011519450.1 | 6 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| hcn4 | Danio rerio | Structure: heart contraction Quality: decreased rate abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- cAMP signaling pathway - Homo sapiens (human)
- Taste transduction - Homo sapiens (human)
- Antiarrhythmic Pathway, Pharmacodynamics
- Disopyramide Action Pathway
- Procainamide (Antiarrhythmic) Action Pathway
Biological Process
- regulation of heart rate
- regulation of membrane depolarization
- cation transport
- muscle contraction
- blood circulation
Molecular Function
- intracellular cAMP-activated cation channel activity
- voltage-gated sodium channel activity
- voltage-gated potassium channel activity
- cAMP binding
- identical protein binding
Cellular Component
- plasma membrane
- intrinsic component of plasma membrane
- perinuclear region of cytoplasm
- HCN channel complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000261917
- Coding exons
- 8
- Length
- 49406
- Individuals with no LoFs
- 125705
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 42
- Defined
- 125747
- p
- 0.000167
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.75 | 478 | 679 | 0.703 | 0.0000452 | 7601 |
| Missense (PolyPhen) | 55 | 54.848 | 1.0028 | 620 | ||
| Synonymous | 0.629 | 296 | 310 | 0.955 | 0.0000217 | 2652 |
| Loss of Function | 4.79 | 3 | 32.5 | 0.0924 | 0.00000162 | 362 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00021 | 0.00018 | rare |
| Latino/Admixed American | 0.00021 | 0.00020 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00017 | 0.00016 | rare |
| Finnish | 0.000092 | 0.000092 | rare |
| European (Non-Finnish) | 0.00020 | 0.00018 | rare |
| South Asian | 0.00013 | 0.00013 | rare |
| Other | 0.00034 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Hyperpolarization-activated ion channel with very slow activation and inactivation exhibiting weak selectivity for potassium over sodium ions. Contributes to the native pacemaker currents in heart (If) that regulate the rhythm of heart beat. May contribute to the native pacemaker currents in neurons (Ih). May mediate responses to sour stimuli. {ECO:0000269|PubMed:10228147, ECO:0000269|PubMed:10430953, ECO:0000269|PubMed:16407510, ECO:0000269|PubMed:19165230, ECO:0000269|PubMed:20829353}.;
- Disease
- DISEASE: Sick sinus syndrome 2 (SSS2) [MIM:163800]: The term 'sick sinus syndrome' encompasses a variety of conditions caused by sinus node dysfunction. The most common clinical manifestations are syncope, presyncope, dizziness, and fatigue. Electrocardiogram typically shows sinus bradycardia, sinus arrest, and/or sinoatrial block. Episodes of atrial tachycardias coexisting with sinus bradycardia ('tachycardia-bradycardia syndrome') are also common in this disorder. SSS occurs most often in the elderly associated with underlying heart disease or previous cardiac surgery, but can also occur in the fetus, infant, or child without heart disease or other contributing factors. SSS2 onset is in utero or at birth. {ECO:0000269|PubMed:15123648, ECO:0000269|PubMed:16407510, ECO:0000269|PubMed:20662977, ECO:0000269|PubMed:23103389}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Brugada syndrome 8 (BRGDA8) [MIM:613123]: A tachyarrhythmia characterized by right bundle branch block and ST segment elevation on an electrocardiogram (ECG). It can cause the ventricles to beat so fast that the blood is prevented from circulating efficiently in the body. When this situation occurs, the individual will faint and may die in a few minutes if the heart is not reset. {ECO:0000269|PubMed:19165230}. Note=The gene represented in this entry may be involved in disease pathogenesis.;
Recessive Scores
- pRec
- 0.140
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.836
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |