Human Gene Module / Chromosome 2 / KCNH7

KCNH7potassium voltage-gated channel subfamily H member 7

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
7 / 11
Rare Variants / Common Variants
13 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
2q24.2
Associated Disorders
-
Relevance to Autism

In a study demonstrating that parvalbumin (PV) and somatostatin (SST) interneurons differentially contribute to the regulation of social interactions, Qi et al., 2025 found that, in a Shank3-deficient autistic mouse model, the expression of Kcnh7 was reduced in both PV and SST interneurons; furthermore, the authors observed that knocking out Kcnh7 in either interneuron subtype leads to social interaction deficits. KCNH7 was first proposed as an ASD candidate gene based on the nominal association of rare exonic and nonsynonymous variants in this gene with ASD in a gene-based rare variant association study of 2071 ASD cases and 904 controls in Griswold et al., 2015. More recently, a total of five damaging de novo missense variants in the KCNH7 gene have been reported in ASD probands from the Autism Sequencing Consortium, the SPARK cohort, and a Korean ASD cohort (De Rubeis et al., 2014; Zhou et al., 2022; Kim et al., 2024). Rare variation in KCNH7 has also been reported to associate with bipolar disorder in the Amish population (Strauss et al., 2014) and more recently with epilepsy (Wu et al., 2024). KCNH7 was also found to associate with bipolar disorder in a case-control association study in a Taiwanese population (Kuo et al., 2014). Previous mouse studies of KCNH7 in Schwarz et al., 2024 reported that global knockout of Kcnh7 in mice resulted in Purkinje cell hyperexcitability and depressive-like behavior.

Molecular Function

Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. This gene encodes a member of the potassium channel, voltage-gated, subfamily H. This member is a pore-forming (alpha) subunit.

External Links
Gene CardPubMed
Human
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Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
GPF browser
Reports related to KCNH7 (11 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Positive Association - P H Kuo et al. (2014) No -
2 Support - Kevin A Strauss et al. (2014) No Schizophrenia, MDD
3 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
4 Positive Association Targeted massively parallel sequencing of autism spectrum disorder-associated genes in a case control cohort reveals rare loss-of-function risk variants Griswold AJ , et al. (2015) Yes -
5 Support Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder Takata A , et al. (2018) Yes -
6 Support - Zhou X et al. (2022) Yes -
7 Support - Trost B et al. (2022) Yes -
8 Support - Soo-Whee Kim et al. (2024) Yes -
9 Support - Jürgen R Schwarz et al. (2024) No -
10 Support - Fan Wu et al. (2024) No -
11 Primary - Chuchu Qi et al. (2025) Yes -
Rare Variants   (13)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1324C>T p.Arg442Ter stop_gained De novo - Simplex 39634124 Fan Wu et al. (2024)
c.83A>G p.Lys28Arg missense_variant De novo - Simplex 39634124 Fan Wu et al. (2024)
c.1919A>G p.Glu640Gly missense_variant De novo - Simplex 39634124 Fan Wu et al. (2024)
c.361G>A p.Val121Met missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1206C>G p.His402Gln missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.1129G>T p.Val377Phe missense_variant De novo - - 39334436 Soo-Whee Kim et al. (2024)
c.1891G>A p.Gly631Arg missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1228T>C p.Trp410Arg missense_variant De novo - Unknown 35982159 Zhou X et al. (2022)
c.1701T>C p.Ala567= synonymous_variant De novo - Multiplex 36368308 Trost B et al. (2022)
c.2855T>G p.Ile952Arg missense_variant De novo - Simplex 29346770 Takata A , et al. (2018)
c.1181G>A p.Arg394His missense_variant Familial - Multiplex 24986916 Kevin A Strauss et al. (2014)
c.1181G>A p.Arg394His missense_variant Familial - Extended multiplex 24986916 Kevin A Strauss et al. (2014)
c.1181G>A p.Arg394His missense_variant Familial Maternal Multi-generational 24986916 Kevin A Strauss et al. (2014)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

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.

7/1/2025
3

Initial score established: 3

Krishnan Probability Score

Score 0.49941876989185

Ranking 2161/25841 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 0.98444594932785

Ranking 2001/18225 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 0.85493328558797

Ranking 3645/18665 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 -0.026110114158186

Ranking 9561/20870 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
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