Human Gene Module / Chromosome 5 / HCN1

HCN1Hyperpolarization activated cyclic nucleotide-gated potassium channel 1

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
4 / 15
Rare Variants / Common Variants
50 / 1
Aliases
HCN1, BCNG-1,  BCNG1,  HAC-2, HCN1
Associated Syndromes
-
Chromosome Band
5p12
Associated Disorders
ADHD, ASD
Relevance to Autism

6 missense variants in the HCN1 gene, 5 of which were de novo in origin and were experimentally shown to alter channel properties, were identified in patients with epileptic encephalopathy; individuals with these variants had clinical features resembling those of Dravet syndrome with progression towards atypical absences, intellectual disability, and autistic features (Nava et al., 2014).

Molecular Function

The membrane protein encoded by this gene is a hyperpolarization-activated cation channel that contributes to the native pacemaker currents in heart and neurons. The encoded protein can homodimerize or heterodimerize with other pore-forming subunits to form a potassium channel. Detected in brain, in particular in amygdala and hippocampus.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
Rat
Entrez Gene
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to HCN1 (15 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary De novo mutations in HCN1 cause early infantile epileptic encephalopathy Nava C , et al. (2014) No Autistic features, ADHD
2 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No -
3 Recent Recommendation Autism-associated SHANK3 haploinsufficiency causes Ih channelopathy in human neurons Yi F , et al. (2016) No -
4 Support Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability Lelieveld SH et al. (2016) No -
5 Support Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes Parrini E , et al. (2016) No -
6 Positive Association Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection Pardias AF , et al. (2018) No -
7 Support A novel de novo HCN1 loss-of-function mutation in genetic generalized epilepsy causing increased neuronal excitability Bonzanni M , et al. (2018) No -
8 Recent Recommendation HCN1 mutation spectrum: from neonatal epileptic encephalopathy to benign generalized epilepsy and beyond Marini C , et al. (2018) No -
9 Support - Zou D et al. (2021) No -
10 Support - Woodbury-Smith M et al. (2022) Yes -
11 Support - Mckenzie CE et al. (2022) No -
12 Support - Zhou X et al. (2022) Yes -
13 Support - Yuan B et al. (2023) Yes -
14 Support - Sheth F et al. (2023) Yes DD, ID, epilepsy/seizures
15 Support - Hosneara Akter et al. () No -
Rare Variants   (50)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss Familial Paternal - 30351409 Marini C , et al. (2018)
c.1377+1G>A - splice_site_variant Unknown - - 30351409 Marini C , et al. (2018)
c.2507C>G p.Pro836Arg missense_variant Unknown - - 34145886 Zou D et al. (2021)
c.862A>C p.Thr288Pro missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1691T>C p.Leu564Pro missense_variant De novo - - 36881370 Yuan B et al. (2023)
c.428T>A p.Phe143Tyr missense_variant De novo - - 30351409 Marini C , et al. (2018)
c.459G>C p.Met153Ile missense_variant De novo - - 30351409 Marini C , et al. (2018)
c.459G>T p.Met153Ile missense_variant De novo - - 30351409 Marini C , et al. (2018)
c.514A>C p.Thr172Pro missense_variant De novo - - 30351409 Marini C , et al. (2018)
c.728T>G p.Met243Arg missense_variant De novo - - 30351409 Marini C , et al. (2018)
c.779C>T p.Thr260Ile missense_variant De novo - - 30351409 Marini C , et al. (2018)
c.781A>G p.Lys261Glu missense_variant Unknown - - 30351409 Marini C , et al. (2018)
c.790A>T p.Ser264Cys missense_variant De novo - - 30351409 Marini C , et al. (2018)
c.824T>C p.Ile275Thr missense_variant De novo - - 30351409 Marini C , et al. (2018)
c.913A>C p.Met305Leu missense_variant De novo - - 30351409 Marini C , et al. (2018)
c.913A>T p.Met305Leu missense_variant De novo - - 30351409 Marini C , et al. (2018)
c.1136T>G p.Met379Arg missense_variant De novo - - 30351409 Marini C , et al. (2018)
c.1171G>A p.Gly391Ser missense_variant De novo - - 30351409 Marini C , et al. (2018)
c.1171G>T p.Gly391Cys missense_variant De novo - - 30351409 Marini C , et al. (2018)
c.1172G>A p.Gly391Asp missense_variant De novo - - 30351409 Marini C , et al. (2018)
c.1189A>C p.Ile397Leu missense_variant De novo - - 30351409 Marini C , et al. (2018)
c.1195T>C p.Ser399Pro missense_variant De novo - - 30351409 Marini C , et al. (2018)
c.1769G>A p.Arg590Gln missense_variant De novo - - 30351409 Marini C , et al. (2018)
c.459G>C p.Met153Ile missense_variant De novo - - 27864847 Parrini E , et al. (2016)
c.414del p.Tyr138Ter frameshift_variant De novo - - 30351409 Marini C , et al. (2018)
c.1172G>A p.Gly391Asp missense_variant De novo - - 27864847 Parrini E , et al. (2016)
c.2068C>A p.Pro690Thr missense_variant Unknown - - 39342494 Hosneara Akter et al. ()
c.737A>C p.Glu246Ala missense_variant De novo - - 35359652 Mckenzie CE et al. (2022)
c.457A>G p.Met153Val missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.140G>T p.Gly47Val missense_variant Unknown - Simplex 24747641 Nava C , et al. (2014)
c.1145G>C p.Gly382Ala missense_variant De novo - - 27479843 Lelieveld SH et al. (2016)
c.2236A>C p.Thr746Pro missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.2238T>A p.Thr746= synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.299C>T p.Ser100Phe missense_variant De novo - Simplex 24747641 Nava C , et al. (2014)
c.814T>C p.Ser272Pro missense_variant De novo - Simplex 24747641 Nava C , et al. (2014)
c.835C>T p.His279Tyr missense_variant De novo - Simplex 24747641 Nava C , et al. (2014)
c.890G>C p.Arg297Thr missense_variant De novo - Simplex 24747641 Nava C , et al. (2014)
c.1201G>C p.Asp401His missense_variant De novo - Simplex 24747641 Nava C , et al. (2014)
c.905T>C p.Ile302Thr missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.254A>C p.Glu85Ala missense_variant Familial Maternal - 30351409 Marini C , et al. (2018)
c.1232A>G p.Tyr411Cys missense_variant Familial Paternal - 30351409 Marini C , et al. (2018)
c.2143C>G p.Arg715Gly missense_variant Familial Paternal - 30351409 Marini C , et al. (2018)
c.469C>G p.Leu157Val missense_variant De novo - Multiplex 29936235 Bonzanni M , et al. (2018)
- p.Asn338_Lys410del copy_number_loss Familial Paternal Simplex 24747641 Nava C , et al. (2014)
c.1460T>C p.Met487Thr missense_variant Familial Maternal Simplex 37543562 Sheth F et al. (2023)
c.986G>C p.Cys329Ser missense_variant Familial - Multi-generational 30351409 Marini C , et al. (2018)
c.1240G>A p.Val414Met missense_variant Familial - Multi-generational 30351409 Marini C , et al. (2018)
c.2039C>A p.Ser680Tyr missense_variant Familial - Multi-generational 30351409 Marini C , et al. (2018)
c.512C>G p.Thr171Arg missense_variant Familial Paternal Multi-generational 30351409 Marini C , et al. (2018)
c.913A>C p.Met305Leu missense_variant De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants   (1)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.1618+17949T>C - intron_variant - - - 29483656 Pardias AF , et al. (2018)
SFARI Gene score
3

Suggestive Evidence

6 missense variants in the HCN1 gene, 5 of which were de novo in origin and were experimentally shown to alter channel properties, were identified in patients with epileptic encephalopathy; individuals with these variants had clinical features resembling those of Dravet syndrome with progression towards atypical absences, intellectual disability, and autistic features (Nava et al., 2014). In the same report, a deletion spanning exon 4 of the HCN1 gene was identifed in a female patient with sporadic intellectual disability and ASD, but no epilepsy; this deletion was inherited from an asymptomatic father. The protein encoded by the high confidence ASD gene SHANK3 was found to interact with hyperpolarization-activated cyclic nucleotide-gated channel proteins (HCN proteins) including HCN1, suggesting that SHANK3 functions in part to organize HCN channels (Yi et al., 2016). Marini et al., 2018 described a cohort of 33 previously unpublished epilepsy patients with pathogenic or likely pathogenic HCN1 variants, including 19 probands with de novo missense variants; three of the 19 probands with de novo HCN1 missense variants in this report were reported to present with autism or autistic features.

Score Delta: Score remained at 3

criteria met
See SFARI Gene'scoring criteria
3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

1/1/2023
S
icon
3

Increased from S to 3

Description

6 missense variants in the HCN1 gene, 5 of which were de novo in origin and were experimentally shown to alter channel properties, were identified in patients with epileptic encephalopathy; individuals with these variants had clinical features resembling those of Dravet syndrome with progression towards atypical absences, intellectual disability, and autistic features (Nava et al., 2014). In the same report, a deletion spanning exon 4 of the HCN1 gene was identifed in a female patient with sporadic intellectual disability and ASD, but no epilepsy; this deletion was inherited from an asymptomatic father. The protein encoded by the high confidence ASD gene SHANK3 was found to interact with hyperpolarization-activated cyclic nucleotide-gated channel proteins (HCN proteins) including HCN1, suggesting that SHANK3 functions in part to organize HCN channels (Yi et al., 2016). Marini et al., 2018 described a cohort of 33 previously unpublished epilepsy patients with pathogenic or likely pathogenic HCN1 variants, including 19 probands with de novo missense variants; three of the 19 probands with de novo HCN1 missense variants in this report were reported to present with autism or autistic features.

10/1/2019
S
icon
S

Increased from S to S

New Scoring Scheme
Description

6 missense variants in the HCN1 gene, 5 of which were de novo in origin and were experimentally shown to alter channel properties, were identified in patients with epileptic encephalopathy; individuals with these variants had clinical features resembling those of Dravet syndrome with progression towards atypical absences, intellectual disability, and autistic features (Nava et al., 2014). In the same report, a deletion spanning exon 4 of the HCN1 gene was identifed in a female patient with sporadic intellectual disability and ASD, but no epilepsy; this deletion was inherited from an asymptomatic father. The protein encoded by the high confidence ASD gene SHANK3 was found to interact with hyperpolarization-activated cyclic nucleotide-gated channel proteins (HCN proteins) including HCN1, suggesting that SHANK3 functions in part to organize HCN channels (Yi et al., 2016). Marini et al., 2018 described a cohort of 33 previously unpublished epilepsy patients with pathogenic or likely pathogenic HCN1 variants, including 19 probands with de novo missense variants; three of the 19 probands with de novo HCN1 missense variants in this report were reported to present with autism or autistic features.

Reports Added
[New Scoring Scheme]
10/1/2018
S
icon
S

Increased from S to S

Description

6 missense variants in the HCN1 gene, 5 of which were de novo in origin and were experimentally shown to alter channel properties, were identified in patients with epileptic encephalopathy; individuals with these variants had clinical features resembling those of Dravet syndrome with progression towards atypical absences, intellectual disability, and autistic features (Nava et al., 2014). In the same report, a deletion spanning exon 4 of the HCN1 gene was identifed in a female patient with sporadic intellectual disability and ASD, but no epilepsy; this deletion was inherited from an asymptomatic father. The protein encoded by the high confidence ASD gene SHANK3 was found to interact with hyperpolarization-activated cyclic nucleotide-gated channel proteins (HCN proteins) including HCN1, suggesting that SHANK3 functions in part to organize HCN channels (Yi et al., 2016). Marini et al., 2018 described a cohort of 33 previously unpublished epilepsy patients with pathogenic or likely pathogenic HCN1 variants, including 19 probands with de novo missense variants; three of the 19 probands with de novo HCN1 missense variants in this report were reported to present with autism or autistic features.

Reports Added
[HCN1 mutation spectrum: from neonatal epileptic encephalopathy to benign generalized epilepsy and beyond.2018]
7/1/2018
S
icon
S

Increased from S to S

Description

6 missense variants in the HCN1 gene, 5 of which were de novo in origin and were experimentally shown to alter channel properties, were identified in patients with epileptic encephalopathy; individuals with these variants had clinical features resembling those of Dravet syndrome with progression towards atypical absences, intellectual disability, and autistic features (Nava et al., 2014). In the same report, a deletion spanning exon 4 of the HCN1 gene was identifed in a female patient with sporadic intellectual disability and ASD, but no epilepsy; this deletion was inherited from an asymptomatic father. The protein encoded by the high confidence ASD gene SHANK3 was found to interact with hyperpolarization-activated cyclic nucleotide-gated channel proteins (HCN proteins) including HCN1, suggesting that SHANK3 functions in part to organize HCN channels (Yi et al., 2016).

Reports Added
[A novel de novo HCN1 loss-of-function mutation in genetic generalized epilepsy causing increased neuronal excitability.2018]
1/1/2017
S
icon
S

Increased from S to S

Description

6 missense variants in the HCN1 gene, 5 of which were de novo in origin and were experimentally shown to alter channel properties, were identified in patients with epileptic encephalopathy; individuals with these variants had clinical features resembling those of Dravet syndrome with progression towards atypical absences, intellectual disability, and autistic features (Nava et al., 2014). In the same report, a deletion spanning exon 4 of the HCN1 gene was identifed in a female patient with sporadic intellectual disability and ASD, but no epilepsy; this deletion was inherited from an asymptomatic father. The protein encoded by the high confidence ASD gene SHANK3 was found to interact with hyperpolarization-activated cyclic nucleotide-gated channel proteins (HCN proteins) including HCN1, suggesting that SHANK3 functions in part to organize HCN channels (Yi et al., 2016).

Reports Added
[Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes.2016]
7/1/2016
S
icon
S

Increased from S to S

Description

6 missense variants in the HCN1 gene, 5 of which were de novo in origin and were experimentally shown to alter channel properties, were identified in patients with epileptic encephalopathy; individuals with these variants had clinical features resembling those of Dravet syndrome with progression towards atypical absences, intellectual disability, and autistic features (Nava et al., 2014). In the same report, a deletion spanning exon 4 of the HCN1 gene was identifed in a female patient with sporadic intellectual disability and ASD, but no epilepsy; this deletion was inherited from an asymptomatic father. The protein encoded by the high confidence ASD gene SHANK3 was found to interact with hyperpolarization-activated cyclic nucleotide-gated channel proteins (HCN proteins) including HCN1, suggesting that SHANK3 functions in part to organize HCN channels (Yi et al., 2016).

Reports Added
[Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016]
4/1/2016
icon
S

Increased from to S

Description

6 missense variants in the HCN1 gene, 5 of which were de novo in origin and were experimentally shown to alter channel properties, were identified in patients with epileptic encephalopathy; individuals with these variants had clinical features resembling those of Dravet syndrome with progression towards atypical absences, intellectual disability, and autistic features (Nava et al., 2014). In the same report, a deletion spanning exon 4 of the HCN1 gene was identifed in a female patient with sporadic intellectual disability and ASD, but no epilepsy; this deletion was inherited from an asymptomatic father. The protein encoded by the high confidence ASD gene SHANK3 was found to interact with hyperpolarization-activated cyclic nucleotide-gated channel proteins (HCN proteins) including HCN1, suggesting that SHANK3 functions in part to organize HCN channels (Yi et al., 2016).

Reports Added
[De novo mutations in HCN1 cause early infantile epileptic encephalopathy.2014] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Autism-associated SHANK3 haploinsufficiency causes Ih channelopathy in human neurons.2016]
Krishnan Probability Score

Score 0.48453418728871

Ranking 7521/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.95313850283212

Ranking 2629/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.94461790828262

Ranking 16146/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score 0.14191739496333

Ranking 5320/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
HCN1 hyperpolarization-activated, cyclic nucleotide-gated K+ 1 Mouse Protein Binding 15165 O88704
HCN3 hyperpolarization-activated, cyclic nucleotide-gated K+ 3 Mouse Protein Binding 15168 O88705
HCN4 hyperpolarization activated cyclic nucleotide-gated potassium channel 4 Human Protein Binding 10021 Q9Y3Q4
Pex5l peroxisomal biogenesis factor 5-like Mouse Protein Binding 58869 Q8C437
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