Human Gene Module / Chromosome 8 / KCNQ3

KCNQ3potassium voltage-gated channel subfamily Q member 3

SFARI Gene Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
13 / 22
Rare Variants / Common Variants
46 / 1
EAGLE Score
11.1
Strong Learn More
Aliases
KCNQ3, BFNC2,  EBN2,  KV7.3
Associated Syndromes
-
Chromosome Band
8q24.22
Associated Disorders
DD/NDD, ADHD, ID, ASD
Genetic Category
Rare Single Gene Mutation, Genetic Association, Functional
Relevance to Autism

A de novo balanced translocation t(3;8)(q21;q24) with a breakpoint lying within intron 1 of the KCNQ3 gene was identified in a Danish boy diagnosed with childhood autism. Furthermore, the same KCNQ3 missense variant (c.1720C>T; p.P574S) was identified in three unrelated individuals with childhood autism and no history of convulsions; this variant resulted in significant reduction of potassium current amplitude when co-expressed with KV7.5 in Xenopus oocytes (Gilling et al., 2013).

Molecular Function

This gene encodes a protein that functions in the regulation of neuronal excitability. The encoded protein forms an M-channel by associating with the products of the related KCNQ2 or KCNQ5 genes, which both encode integral membrane proteins. M-channel currents are inhibited by M1 muscarinic acetylcholine receptors and are activated by retigabine, a novel anti-convulsant drug. Defects in this gene are a cause of benign familial neonatal convulsions type 2 (BFNC2), also known as epilepsy, benign neonatal type 2 (EBN2).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to KCNQ3 (22 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Positive Association Family-based association analysis to finemap bipolar linkage peak on chromosome 8q24 using 2,500 genotyped SNPs and 15,000 imputed SNPs Zhang P , et al. (2010) No -
2 Primary Dysfunction of the Heteromeric KV7.3/KV7.5 Potassium Channel is Associated with Autism Spectrum Disorders Gilling M , et al. (2013) Yes -
3 Positive Association De novo mutations in epileptic encephalopathies Epi4K Consortium , et al. (2013) No IS, LGS, DD, ID, ASD, ADHD
4 Support Exome sequencing in multiplex autism families suggests a major role for heterozygous truncating mutations Toma C , et al. (2013) Yes -
5 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
6 Support Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains Geisheker MR , et al. (2017) Yes -
7 Support Variant recurrence in neurodevelopmental disorders: the use of publicly available genomic data identifies clinically relevant pathogenic missense variants Lecoquierre F , et al. (2019) No -
8 Recent Recommendation Autism and developmental disability caused by KCNQ3 gain-of-function variants Sands TT , et al. (2019) Yes Abnormal EEG, absent speech
9 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
10 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes ID
11 Support - Valentino F et al. (2021) Yes -
12 Support - Pode-Shakked B et al. (2021) No -
13 Support - Aguilera C et al. (2021) No -
14 Support - Gamal El-Din TM et al. (2021) Yes -
15 Support - Woodbury-Smith M et al. (2022) Yes -
16 Support - Arredondo K et al. (2022) No ASD, ADHD, ID
17 Support - Chuan Z et al. (2022) No -
18 Support - Zhou X et al. (2022) Yes -
19 Support - Varghese N et al. (2023) Yes -
20 Recent Recommendation - Bianca Graziano et al. (2024) Yes -
21 Support - Mario Nappi et al. (2024) No -
22 Highly Cited A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family Charlier C , et al. (1998) No -
Rare Variants   (46)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - translocation De novo - Simplex 23596459 Gilling M , et al. (2013)
c.276G>T p.Pro92= synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.569G>A p.Arg190Gln missense_variant De novo - - 33004838 Wang T et al. (2020)
c.656G>A p.Gly219Asp missense_variant De novo - - 33004838 Wang T et al. (2020)
c.680G>A p.Arg227Gln missense_variant De novo - - 33004838 Wang T et al. (2020)
c.688C>T p.Arg230Cys missense_variant De novo - - 33004838 Wang T et al. (2020)
c.689G>A p.Arg230His missense_variant De novo - - 33004838 Wang T et al. (2020)
c.716G>C p.Arg239Pro missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1090C>T p.Arg364Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1123G>A p.Ala375Thr missense_variant De novo - - 33004838 Wang T et al. (2020)
c.1411C>T p.Arg471Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1850G>C p.Ser617Thr missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1918G>A p.Val640Met missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2561C>T p.Ser854Leu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2270G>A p.Arg757Gln missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1403A>G p.Asn468Ser missense_variant Unknown - - 35571021 Chuan Z et al. (2022)
c.328C>T p.Arg110Cys missense_variant De novo - - 31177578 Sands TT , et al. (2019)
c.329G>A p.Arg110His missense_variant De novo - - 31177578 Sands TT , et al. (2019)
c.680G>A p.Arg227Gln missense_variant De novo - - 31177578 Sands TT , et al. (2019)
c.688C>A p.Arg230Ser missense_variant De novo - - 31177578 Sands TT , et al. (2019)
c.688C>T p.Arg230Cys missense_variant De novo - - 31177578 Sands TT , et al. (2019)
c.689G>A p.Arg230His missense_variant De novo - - 31177578 Sands TT , et al. (2019)
c.927G>A p.Trp309Ter stop_gained Familial Maternal - 33004838 Wang T et al. (2020)
c.688C>T p.Arg230Cys missense_variant De novo - - 34653234 Aguilera C et al. (2021)
c.688C>T p.Arg230Cys missense_variant De novo - - 34356170 Valentino F et al. (2021)
c.1066C>T p.Ala356Thr missense_variant De novo - - 39602259 Mario Nappi et al. (2024)
c.706C>T p.Arg236Cys missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.296G>A p.Gly99Asp missense_variant De novo - - 28628100 Geisheker MR , et al. (2017)
c.320G>A p.Arg107Gln missense_variant Unknown - - 28628100 Geisheker MR , et al. (2017)
c.328C>T p.Arg110Cys missense_variant Unknown - - 28628100 Geisheker MR , et al. (2017)
c.688C>T p.Arg230Cys missense_variant De novo - - 31036916 Lecoquierre F , et al. (2019)
c.707G>A p.Arg236His missense_variant Familial Paternal - 33004838 Wang T et al. (2020)
c.788C>T p.Thr263Met missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.688C>T p.Arg230Cys missense_variant De novo - - 23934111 Epi4K Consortium , et al. (2013)
c.689G>A p.Arg230His missense_variant Familial Maternal - 31177578 Sands TT , et al. (2019)
c.1582C>T p.Arg528Cys missense_variant Unknown Not maternal - 33004838 Wang T et al. (2020)
c.328C>T p.Arg110Cys missense_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.329G>A p.Arg110His missense_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.329G>T p.Arg110Leu missense_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.688C>T p.Arg230Cys missense_variant De novo - Simplex 34580403 Pode-Shakked B et al. (2021)
c.439G>A p.Glu147Lys missense_variant Familial Paternal Multiplex 33004838 Wang T et al. (2020)
c.1964C>T p.Thr655Met missense_variant Familial Maternal Multiplex 23999528 Toma C , et al. (2013)
c.1720C>T p.Pro574Ser missense_variant Familial Paternal Unknown 23596459 Gilling M , et al. (2013)
c.929G>T p.Gly310Val missense_variant Familial - Multi-generational 9425900 Charlier C , et al. (1998)
c.1091G>A p.Arg364His missense_variant Familial Maternal Multiplex 35384780 Arredondo K et al. (2022)
c.1720C>T p.Pro574Ser missense_variant Familial Maternal Multi-generational 23596459 Gilling M , et al. (2013)
Common Variants   (1)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
- C/T upstream_gene_variant - - - 21176025 Zhang P , et al. (2010)
SFARI Gene score
1

High Confidence

Score Delta: Score remained at 1

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

10/1/2020
1
icon
1

Score remained at 1

Description

A de novo balanced translocation t(3;8)(q21;q24) with a breakpoint lying within intron 1 of the KCNQ3 gene was identified in a Danish male diagnosed with childhood autism. Furthermore, the same KCNQ3 missense variant (c.1720C>T; p.P574S) was identified in three unrelated individuals with childhood autism and no history of convulsions; this variant resulted in significant reduction of potassium current amplitude when co-expressed with KV7.5 in Xenopus oocytes (Gilling et al., 2013). Mutations in this gene are also associated with benign familial neonatal seizures-2 (BFNS2; OMIM 121201). Sands et al., 2019 reported eleven individuals with KCNQ3 missense variants that were experimentally demonstrated to confer gain-of-function effects; all eleven individuals exhibited global developmental delay and autistic features, with five individuals (45%) receiving a diagnosis of ASD.

Reports Added
[Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders2020]
1/1/2020
1
icon
1

Score remained at 1

Description

A de novo balanced translocation t(3;8)(q21;q24) with a breakpoint lying within intron 1 of the KCNQ3 gene was identified in a Danish male diagnosed with childhood autism. Furthermore, the same KCNQ3 missense variant (c.1720C>T; p.P574S) was identified in three unrelated individuals with childhood autism and no history of convulsions; this variant resulted in significant reduction of potassium current amplitude when co-expressed with KV7.5 in Xenopus oocytes (Gilling et al., 2013). Mutations in this gene are also associated with benign familial neonatal seizures-2 (BFNS2; OMIM 121201). Sands et al., 2019 reported eleven individuals with KCNQ3 missense variants that were experimentally demonstrated to confer gain-of-function effects; all eleven individuals exhibited global developmental delay and autistic features, with five individuals (45%) receiving a diagnosis of ASD.

Reports Added
[Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism2020]
10/1/2019
2
icon
1

Decreased from 2 to 1

New Scoring Scheme
Description

A de novo balanced translocation t(3;8)(q21;q24) with a breakpoint lying within intron 1 of the KCNQ3 gene was identified in a Danish male diagnosed with childhood autism. Furthermore, the same KCNQ3 missense variant (c.1720C>T; p.P574S) was identified in three unrelated individuals with childhood autism and no history of convulsions; this variant resulted in significant reduction of potassium current amplitude when co-expressed with KV7.5 in Xenopus oocytes (Gilling et al., 2013). Mutations in this gene are also associated with benign familial neonatal seizures-2 (BFNS2; OMIM 121201). Sands et al., 2019 reported eleven individuals with KCNQ3 missense variants that were experimentally demonstrated to confer gain-of-function effects; all eleven individuals exhibited global developmental delay and autistic features, with five individuals (45%) receiving a diagnosis of ASD.

Reports Added
[New Scoring Scheme]
7/1/2019
3
icon
2

Decreased from 3 to 2

Description

A de novo balanced translocation t(3;8)(q21;q24) with a breakpoint lying within intron 1 of the KCNQ3 gene was identified in a Danish male diagnosed with childhood autism. Furthermore, the same KCNQ3 missense variant (c.1720C>T; p.P574S) was identified in three unrelated individuals with childhood autism and no history of convulsions; this variant resulted in significant reduction of potassium current amplitude when co-expressed with KV7.5 in Xenopus oocytes (Gilling et al., 2013). Mutations in this gene are also associated with benign familial neonatal seizures-2 (BFNS2; OMIM 121201). Sands et al., 2019 reported eleven individuals with KCNQ3 missense variants that were experimentally demonstrated to confer gain-of-function effects; all eleven individuals exhibited global developmental delay and autistic features, with five individuals (45%) receiving a diagnosis of ASD.

Reports Added
[Variantrecurrence in neurodevelopmental disorders: the use of publicly available genomic data identifies clinically relevant pathogenic missense v...2019] [Autism and developmental disability caused by KCNQ3 gain-of-function variants.2019]
7/1/2017
3
icon
3

Decreased from 3 to 3

Description

A de novo balanced translocation t(3;8)(q21;q24) with a breakpoint lying within intron 1 of the KCNQ3 gene was identified in a Danish male diagnosed with childhood autism. Furthermore, the same KCNQ3 missense variant (c.1720C>T; p.P574S) was identified in three unrelated individuals with childhood autism and no history of convulsions; this variant resulted in significant reduction of potassium current amplitude when co-expressed with KV7.5 in Xenopus oocytes (Gilling et al., 2013). Mutations in this gene are also associated with benign familial neonatal seizures-2 (BFNS2; OMIM 121201).

Reports Added
[Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains.2017]
1/1/2016
3
icon
3

Decreased from 3 to 3

Description

A de novo balanced translocation t(3;8)(q21;q24) with a breakpoint lying within intron 1 of the KCNQ3 gene was identified in a Danish male diagnosed with childhood autism. Furthermore, the same KCNQ3 missense variant (c.1720C>T; p.P574S) was identified in three unrelated individuals with childhood autism and no history of convulsions; this variant resulted in significant reduction of potassium current amplitude when co-expressed with KV7.5 in Xenopus oocytes (Gilling et al., 2013). Mutations in this gene are also associated with benign familial neonatal seizures-2 (BFNS2; OMIM 121201).

Reports Added
[Dysfunction of the Heteromeric KV7.3/KV7.5 Potassium Channel is Associated with Autism Spectrum Disorders.2013] [Exome sequencing in multiplex autism families suggests a major role for heterozygous truncating mutations.2013] [Family-based association analysis to finemap bipolar linkage peak on chromosome 8q24 using 2,500 genotyped SNPs and 15,000 imputed SNPs.2010] [A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family.1998] [De novo mutations in epileptic encephalopathies.2013] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014]
7/1/2015
icon
3

Increased from to 3

Description

A de novo balanced translocation t(3;8)(q21;q24) with a breakpoint lying within intron 1 of the KCNQ3 gene was identified in a Danish male diagnosed with childhood autism. Furthermore, the same KCNQ3 missense variant (c.1720C>T; p.P574S) was identified in three unrelated individuals with childhood autism and no history of convulsions; this variant resulted in significant reduction of potassium current amplitude when co-expressed with KV7.5 in Xenopus oocytes (Gilling et al., 2013). Mutations in this gene are also associated with benign familial neonatal seizures-2 (BFNS2; OMIM 121201).

Krishnan Probability Score

Score 0.57200873874368

Ranking 729/25841 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 0.98560429367235

Ranking 1967/18225 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 0.68415932139871

Ranking 1063/18665 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
Larsen Cumulative Evidence Score

Score 19

Ranking 108/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Original Source
Zhang D Score

Score 0.2521903694078

Ranking 3457/20870 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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