Human Gene Module / Chromosome 1 / KCND3

KCND3potassium voltage-gated channel subfamily D member 3

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
6 / 13
Rare Variants / Common Variants
6 / 0
Aliases
KCND3, BRGDA9L,  KCND3S,  KSHIVB,  KV4.3,  SCA19,  SCA22, KCND3
Associated Syndromes
-
Chromosome Band
1p13.2
Associated Disorders
ID, EP, EPS
Relevance to Autism

Two de novo missense variants that were predicted in silico to be damaging were identified in the KCND3 gene in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. TADA-Denovo analysis using a combined dataset of previously published cohorts from the Simons Simplex Collection and the Autism Sequencing Consortium, as well as a novel cohort of 262 Japanese ASD trios, in Takata et al., 2018 identified KCND3 as a gene significantly enriched in damaging de novo mutations in ASD cases (pBH < 0.05). Haplotype blocks associated with the KCND3 gene had previously been shown to associate with non-verbal communication in families from the Autism Genetics Research Exchange (AGRE) and the Autism Genome Project (AGP) (Lu et al., 2013). Inherited and de novo mutations in the KCND3 gene are also associated with a form of autosomal dominant spinocerebellar ataxia (SAC19; OMIM 607346), an ataxia syndrome in which affected individuals frequently display cognitive impairment/intellectual disability and epilepsy (Lee et al., 2012; Duarri et al., 2012; Smets et al., 2015; Kurihara et al., 2017; Huin et al., 2017). Functional analysis of the ASD-associated p.Arg86Pro missense variant, which was originally identiified in an SSC proband, in Drosophila in Marcogliese et al., 2022 demonstrated a possible loss-of-function effect (increased movement and decreased grooming behavior compared to humanized reference; failure to reduce expected viability to the extent of corresponding reference allele upon ubiquitous overexpression).

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. Four sequence-related potassium channel genes - shaker, shaw, shab, and shal - have been identified in Drosophila, and each has been shown to have human homolog(s). This gene encodes a member of the potassium channel, voltage-gated, shal-related subfamily, members of which form voltage-activated A-type potassium ion channels and are prominent in the repolarization phase of the action potential.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to KCND3 (13 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Positive Association QTL replication and targeted association highlight the nerve growth factor gene for nonverbal communication deficits in autism spectrum disorders Lu AT , et al. (2011) Yes Non-verbal communication (ADI-R)
2 Support Mutations in KCND3 cause spinocerebellar ataxia type 22 Lee YC , et al. (2013) No -
3 Support Mutations in potassium channel kcnd3 cause spinocerebellar ataxia type 19 Duarri A , et al. (2013) No -
4 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
5 Support First de novo KCND3 mutation causes severe Kv4.3 channel dysfunction leading to early onset cerebellar ataxia, intellectual disability, oral apraxia and epilepsy Smets K , et al. (2015) No ID, epilepsy/seizures
6 Support Novel De Novo KCND3 Mutation in a Japanese Patient with Intellectual Disability, Cerebellar Ataxia, Myoclonus, and Dystonia Kurihara M , et al. (2017) No ID
7 Support Expanding the phenotype of SCA19/22: Parkinsonism, cognitive impairment and epilepsy Huin V , et al. (2017) No Epilepsy/seizures, cognitive impairment
8 Recent Recommendation Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder Takata A , et al. (2018) Yes -
9 Support - Kwong AK et al. (2021) No -
10 Support - Brunet T et al. (2021) No -
11 Support - Woodbury-Smith M et al. (2022) Yes -
12 Support - Marcogliese PC et al. (2022) Yes -
13 Support - Zhou X et al. (2022) Yes -
Rare Variants   (6)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1667A>G p.His556Arg missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.254A>T p.Asp85Val missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.257G>C p.Arg86Pro missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.1418A>T p.Glu473Val missense_variant Familial - Simplex 33619735 Brunet T et al. (2021)
c.1372G>A p.Gly458Ser missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.1917C>A p.Asn639Lys missense_variant Familial Maternal - 33446253 Kwong AK et al. (2021)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Two de novo missense variants that were predicted in silico to be damaging were identified in the KCND3 gene in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. TADA-Denovo analysis using a combined dataset of previously published cohorts from the Simons Simplex Collection and the Autism Sequencing Consortium, as well as a novel cohort of 262 Japanese ASD trios, in Takata et al., 2018 identified KCND3 as a gene significantly enriched in damaging de novo mutations in ASD cases (pBH < 0.05). Haplotype blocks associated with the KCND3 gene had previously been shown to associate with non-verbal communication in families from the Autism Genetics Research Exchange (AGRE) and the Autism Genome Project (AGP) (Lu et al., 2013). Inherited and de novo mutations in the KCND3 gene are also associated with a form of autosomal dominant spinocerebellar ataxia (SAC19; OMIM 607346), an ataxia syndrome in which affected individuals frequently display cognitive impairment/intellectual disability and epilepsy (Lee et al., 2012; Duarri et al., 2012; Smets et al., 2015; Kurihara et al., 2017; Huin et al., 2017).

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 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.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

Two de novo missense variants that were predicted in silico to be damaging were identified in the KCND3 gene in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. TADA-Denovo analysis using a combined dataset of previously published cohorts from the Simons Simplex Collection and the Autism Sequencing Consortium, as well as a novel cohort of 262 Japanese ASD trios, in Takata et al., 2018 identified KCND3 as a gene significantly enriched in damaging de novo mutations in ASD cases (pBH < 0.05). Haplotype blocks associated with the KCND3 gene had previously been shown to associate with non-verbal communication in families from the Autism Genetics Research Exchange (AGRE) and the Autism Genome Project (AGP) (Lu et al., 2013). Inherited and de novo mutations in the KCND3 gene are also associated with a form of autosomal dominant spinocerebellar ataxia (SAC19; OMIM 607346), an ataxia syndrome in which affected individuals frequently display cognitive impairment/intellectual disability and epilepsy (Lee et al., 2012; Duarri et al., 2012; Smets et al., 2015; Kurihara et al., 2017; Huin et al., 2017).

4/1/2021
3
icon
3

Decreased from 3 to 3

Description

Two de novo missense variants that were predicted in silico to be damaging were identified in the KCND3 gene in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. TADA-Denovo analysis using a combined dataset of previously published cohorts from the Simons Simplex Collection and the Autism Sequencing Consortium, as well as a novel cohort of 262 Japanese ASD trios, in Takata et al., 2018 identified KCND3 as a gene significantly enriched in damaging de novo mutations in ASD cases (pBH < 0.05). Haplotype blocks associated with the KCND3 gene had previously been shown to associate with non-verbal communication in families from the Autism Genetics Research Exchange (AGRE) and the Autism Genome Project (AGP) (Lu et al., 2013). Inherited and de novo mutations in the KCND3 gene are also associated with a form of autosomal dominant spinocerebellar ataxia (SAC19; OMIM 607346), an ataxia syndrome in which affected individuals frequently display cognitive impairment/intellectual disability and epilepsy (Lee et al., 2012; Duarri et al., 2012; Smets et al., 2015; Kurihara et al., 2017; Huin et al., 2017).

Reports Added
[Exome sequencing in paediatric patients with movement disorders2021]
1/1/2021
3
icon
3

Decreased from 3 to 3

Description

Two de novo missense variants that were predicted in silico to be damaging were identified in the KCND3 gene in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. TADA-Denovo analysis using a combined dataset of previously published cohorts from the Simons Simplex Collection and the Autism Sequencing Consortium, as well as a novel cohort of 262 Japanese ASD trios, in Takata et al., 2018 identified KCND3 as a gene significantly enriched in damaging de novo mutations in ASD cases (pBH < 0.05). Haplotype blocks associated with the KCND3 gene had previously been shown to associate with non-verbal communication in families from the Autism Genetics Research Exchange (AGRE) and the Autism Genome Project (AGP) (Lu et al., 2013). Inherited and de novo mutations in the KCND3 gene are also associated with a form of autosomal dominant spinocerebellar ataxia (SAC19; OMIM 607346), an ataxia syndrome in which affected individuals frequently display cognitive impairment/intellectual disability and epilepsy (Lee et al., 2012; Duarri et al., 2012; Smets et al., 2015; Kurihara et al., 2017; Huin et al., 2017).

Reports Added
[De novo variants in neurodevelopmental disorders-experiences from a tertiary care center2021]
10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Two de novo missense variants that were predicted in silico to be damaging were identified in the KCND3 gene in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. TADA-Denovo analysis using a combined dataset of previously published cohorts from the Simons Simplex Collection and the Autism Sequencing Consortium, as well as a novel cohort of 262 Japanese ASD trios, in Takata et al., 2018 identified KCND3 as a gene significantly enriched in damaging de novo mutations in ASD cases (pBH < 0.05). Haplotype blocks associated with the KCND3 gene had previously been shown to associate with non-verbal communication in families from the Autism Genetics Research Exchange (AGRE) and the Autism Genome Project (AGP) (Lu et al., 2013). Inherited and de novo mutations in the KCND3 gene are also associated with a form of autosomal dominant spinocerebellar ataxia (SAC19; OMIM 607346), an ataxia syndrome in which affected individuals frequently display cognitive impairment/intellectual disability and epilepsy (Lee et al., 2012; Duarri et al., 2012; Smets et al., 2015; Kurihara et al., 2017; Huin et al., 2017).

Reports Added
[New Scoring Scheme]
7/1/2018
icon
4

Increased from to 4

Description

Two de novo missense variants that were predicted in silico to be damaging were identified in the KCND3 gene in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. TADA-Denovo analysis using a combined dataset of previously published cohorts from the Simons Simplex Collection and the Autism Sequencing Consortium, as well as a novel cohort of 262 Japanese ASD trios, in Takata et al., 2018 identified KCND3 as a gene significantly enriched in damaging de novo mutations in ASD cases (pBH < 0.05). Haplotype blocks associated with the KCND3 gene had previously been shown to associate with non-verbal communication in families from the Autism Genetics Research Exchange (AGRE) and the Autism Genome Project (AGP) (Lu et al., 2013). Inherited and de novo mutations in the KCND3 gene are also associated with a form of autosomal dominant spinocerebellar ataxia (SAC19; OMIM 607346), an ataxia syndrome in which affected individuals frequently display cognitive impairment/intellectual disability and epilepsy (Lee et al., 2012; Duarri et al., 2012; Smets et al., 2015; Kurihara et al., 2017; Huin et al., 2017).

Krishnan Probability Score

Score 0.56907862229936

Ranking 1062/25841 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 0.8037525954068

Ranking 3915/18225 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 0.85777285975508

Ranking 3757/18665 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 0.41958088899047

Ranking 1241/20870 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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