Human Gene Module / Chromosome 1 / KCNH1

KCNH1potassium voltage-gated channel subfamily H member 1

SFARI Gene Score
3S
Suggestive Evidence, Syndromic Criteria 3.1, Syndromic
Autism Reports / Total Reports
4 / 6
Rare Variants / Common Variants
8 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
1q32.2
Associated Disorders
-
Relevance to Autism

De novo variants in the KCNH1 gene, including a de novo loss-of-function variant and several de novo missense variants, have been identified in ASD probands from multiple cohorts, including the Simons Simplex Collection, the SPARK cohort, the Autism Sequencing Consortium, and a Chinese ASD cohort (Zhou et al., 2022; Fu et al., 2022; Trost et al., 2022; Wu et al., 2024). A missense variant in this gene was recently reported in a male patient from Pakistan presenting with pharmacoresistant seizures and autistic behavior (Chand et al., 2023).

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 of a voltage-gated non-inactivating delayed rectifier potassium channel. It is activated at the onset of myoblast differentiation. The gene is highly expressed in brain and in myoblasts. Overexpression of the gene may confer a growth advantage to cancer cells and favor tumor cell proliferation. Heterozygous mutations in this gene are responsible for both Temple-Baraitser syndrome (OMIM 611816) and Zimmermann-Laband syndrome 1 (OMIM 135500).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to KCNH1 (6 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support - Zhou X et al. (2022) Yes -
2 Support - Fu JM et al. (2022) Yes -
3 Support - Trost B et al. (2022) Yes -
4 Support - Prem Chand et al. (2023) No Autistic features
5 Primary - Ruohao Wu et al. (2024) Yes -
6 Support - Axel Schmidt et al. (2024) No -
Rare Variants   (8)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1087C>T p.Arg363Ter stop_gained De novo - - 36368308 Trost B et al. (2022)
c.1053C>T p.Ser351= synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.457C>T p.Arg153Trp missense_variant De novo - - 39039281 Axel Schmidt et al. (2024)
c.1486G>A p.Gly496Arg missense_variant De novo - Simplex 35982160 Fu JM et al. (2022)
c.1537C>T p.His513Tyr missense_variant De novo - Simplex 35982160 Fu JM et al. (2022)
c.2113-7_2113-4dup - splice_region_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1070G>A p.Arg357Gln missense_variant De novo - Simplex 38764027 Ruohao Wu et al. (2024)
c.1069C>T p.Arg357Trp missense_variant Unknown - Extended multiplex 37817707 Prem Chand et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
3S

Suggestive Evidence, Syndromic

Score Delta: Score remained at 3S

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.

S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

7/1/2024
icon
3S

Increased from to 3S

Krishnan Probability Score

Score 0.49657058074401

Ranking 2565/25841 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 0.33301456027344

Ranking 6330/18225 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 0.94569192087038

Ranking 16571/18665 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 0.47704747439938

Ranking 683/20870 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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