Human Gene Module / Chromosome 14 / KCNH5

KCNH5potassium voltage-gated channel subfamily H member 5

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
5 / 6
Rare Variants / Common Variants
4 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
14q23.2
Associated Disorders
-
Relevance to Autism

A de novo missense variant in the KCNH5 gene (p.Arg327His) was identified in a 13-year-old male presenting with epilepsy, epileptic encephalopathy, developmental delay and regression, and autism in Veeramah et al., 2013; functional assessment of the p.Arg327His variant by voltage-clamp recordings in Yang et al., 2013 demonstrated that this variant caused a hyperpolarizing shift in the voltage dependence of activation and an acceleration of activation, findings consistent with a gain-of-function effect. Galan-Vidal et al., 2022 reported an 11-year-old male presenting with developmental delay and regression, autism and epilepsy who inherited a KCNH5 missense variant (p.Asn856His) from his healthy mother; functional assessment of the p.Asn856His variant in the same report demonstrated that this variant resulted in slower activating outward currents and slower activation kinetics, consistent with a loss-of-function effect. A rare and potentially damaging de novo missense variant in this gene has also been identified in an ASD proband from the SPARK cohort (Zhou et al., 2022).

Molecular Function

This gene encodes a member of voltage-gated potassium channels. Members of this family have diverse functions, including regulating neurotransmitter and hormone release, cardiac function, and cell volume. This protein is an outward-rectifying, noninactivating channel.

External Links
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SFARI Genomic Platforms
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Reports related to KCNH5 (6 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Exome sequencing reveals new causal mutations in children with epileptic encephalopathies Veeramah KR , et al. (2013) Yes -
2 Support - Yang Y et al. (2013) Yes -
3 Support - Zhou X et al. (2022) Yes -
4 Recent Recommendation - Galn-Vidal J et al. (2022) Yes -
5 Support - Lucie Sedlackova et al. (2024) No -
6 Support - Lele Yu et al. (2024) Yes -
Rare Variants   (4)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1111G>A p.Gly371Arg missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.998G>A p.Arg333His missense_variant De novo - - 38008000 Lucie Sedlackova et al. (2024)
c.980G>A p.Arg327His missense_variant De novo - Simplex 23647072 Veeramah KR , et al. (2013)
c.2566A>C p.Asn856His missense_variant Familial Maternal - 36068614 Galn-Vidal J et al. (2022)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

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.

4/1/2023
icon
3

Increased from to 3

Krishnan Probability Score

Score 0.49438500399921

Ranking 3691/25841 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 0.76904929239707

Ranking 4115/18225 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 0.94777767897031

Ranking 17414/18665 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 0.2958305096736

Ranking 2807/20870 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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