Human Gene Module / Chromosome X / CLCN4

CLCN4chloride voltage-gated channel 4

SFARI Gene Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
3 / 13
Rare Variants / Common Variants
78 / 0
Aliases
CLCN4, CLC4,  ClC-4,  ClC-4A,  MRX15,  MRX49,  MRXSRC
Associated Syndromes
Raynaud-Claes syndrome
Chromosome Band
Xp22.2
Associated Disorders
ASD
Relevance to Autism

De novo damaging missense variants (defined by CADD score 25) in the CLCN4 gene were identified in two ASD probands from the Autism Sequencing Consortium (Kosmicki et al., 2017), while a third de novo damaging missense variant in this gene was observed in an ASD proband from the SPARK cohort (Feliciano et al., 2019). A meta-analysis of de novo variants in 4773 published ASD trios and 465 SPARK trios using TADA identified CLCN4 as an ASD candidate gene with a q-value 0.1. Mutations in the CLCN4 gene are also responsible for Raynaud-Claes syndrome (OMIM 300114), an X-linked intellectual developmental disorder characterized by borderline to severe intellectual disability and impaired language development; behavioral problems are frequently observed in individuals with this syndrome, and autistic features have been reported in a subset of affected individuals (Claes et al., 1997; Palmer et al., 2018). Palmer et al., 2022 assembled a collection of 90 rare CLCN4 missense variants in 90 families that included detailed clinical and segregation data for 43 families that included 22 males and 33 females; autism spectrum disorder (or autistic behavior) was observed in 54.5% of all males and 40% of females with de novo variants in this study, while functional assessment of the electrophysiological properties of these 59 variants in Xenopus oocytes identified variants with either loss-of-function or toxic gain-of-function effects.

Molecular Function

Proton-coupled chloride transporter. Functions as antiport system and exchanges chloride ions against protons.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to CLCN4 (13 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support De novo and inherited mutations in the X-linked gene CLCN4 are associated with syndromic intellectual disability and behavior and seizure disorders in males and females Palmer EE , et al. (2016) No Autistic features
2 Support Refining the role of de novo protein-truncating variants in neurodevelopmental disorders by using population reference samples Kosmicki JA , et al. (2017) Yes -
3 Primary Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
4 Support - Xu X et al. (2021) No Autistic features
5 Support - Pode-Shakked B et al. (2021) No -
6 Support - Álvarez-Mora MI et al. (2022) No -
7 Support - Zhou X et al. (2022) Yes -
8 Recent Recommendation - Palmer EE et al. (2022) No ASD, ADHD
9 Support - Rossi J et al. (2023) No Autistic features, stereotypy
10 Support - Hailan He et al. () No Autistic features, epilepsy/seizures
11 Support - Axel Schmidt et al. (2024) No -
12 Support X-linked mental retardation with neonatal hypotonia in a French family (MRX15): gene assignment to Xp11.22-Xp21.1 Raynaud M , et al. (1996) No -
13 Support Regional localization of two genes for nonspecific X-linked mental retardation to Xp22.3-p22.2 (MRX49) and Xp11.3-p11.21 (MRX50) Claes S , et al. (1998) No Autistic features
Rare Variants   (78)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.964G>T p.Glu322Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.608C>T p.Thr203Ile missense_variant De novo - - 38758281 Hailan He et al. ()
c.823G>A p.Val275Met missense_variant De novo - - 38758281 Hailan He et al. ()
c.274G>A p.Val92Met missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1348G>A p.Gly450Arg missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1630G>A p.Gly544Arg missense_variant De novo - - 37271660 Rossi J et al. (2023)
c.43G>A p.Asp15Asn missense_variant De novo - - 27550844 Palmer EE , et al. (2016)
c.1294+5G>A - splice_site_variant Familial Maternal - 38758281 Hailan He et al. ()
- - copy_number_loss Familial Maternal Multiplex 27550844 Palmer EE , et al. (2016)
c.1106C>T p.Pro369Leu missense_variant De novo - - 36385166 Palmer EE et al. (2022)
c.1465C>A p.Gln489Lys missense_variant De novo - - 36385166 Palmer EE et al. (2022)
c.1648G>C p.Val550Leu missense_variant De novo - - 36385166 Palmer EE et al. (2022)
c.662T>C p.Leu221Pro missense_variant De novo - - 27550844 Palmer EE , et al. (2016)
c.823G>A p.Val275Met missense_variant De novo - - 27550844 Palmer EE , et al. (2016)
c.1601C>T p.Ser534Leu missense_variant De novo - - 27550844 Palmer EE , et al. (2016)
c.1630G>C p.Gly544Arg missense_variant De novo - - 27550844 Palmer EE , et al. (2016)
c.1664C>T p.Ala555Val missense_variant De novo - - 27550844 Palmer EE , et al. (2016)
c.2152C>T p.Arg718Trp missense_variant De novo - - 27550844 Palmer EE , et al. (2016)
c.2025C>G p.Tyr675Ter stop_gained De novo - Simplex 36385166 Palmer EE et al. (2022)
c.1885C>T p.Arg629Trp missense_variant De novo - - 31452935 Feliciano P et al. (2019)
c.121C>T p.Arg41Trp missense_variant Familial Maternal - 38758281 Hailan He et al. ()
c.1807C>T p.Arg603Trp missense_variant De novo - Simplex 38758281 Hailan He et al. ()
c.823G>A p.Val275Met missense_variant Familial Maternal - 38758281 Hailan He et al. ()
c.1042C>G p.Leu348Val missense_variant Familial Maternal - 38758281 Hailan He et al. ()
c.1438G>C p.Gly480Arg missense_variant Familial Maternal - 38758281 Hailan He et al. ()
c.265G>A p.Asp89Asn missense_variant De novo - Simplex 36385166 Palmer EE et al. (2022)
c.1348G>A p.Gly450Arg missense_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.677C>T p.Pro226Leu missense_variant De novo - Simplex 36385166 Palmer EE et al. (2022)
c.804T>G p.Phe268Leu missense_variant De novo - Simplex 36385166 Palmer EE et al. (2022)
c.806G>A p.Gly269Asp missense_variant De novo - Simplex 36385166 Palmer EE et al. (2022)
c.835C>G p.Leu279Val missense_variant De novo - Simplex 36385166 Palmer EE et al. (2022)
c.840A>T p.Glu280Asp missense_variant De novo - Simplex 36385166 Palmer EE et al. (2022)
c.848G>A p.Ser283Asn missense_variant De novo - Simplex 36385166 Palmer EE et al. (2022)
c.928C>T p.Pro310Ser missense_variant De novo - Simplex 36385166 Palmer EE et al. (2022)
c.944G>A p.Arg315His missense_variant De novo - Simplex 36385166 Palmer EE et al. (2022)
c.949G>A p.Val317Ile missense_variant De novo - Simplex 36385166 Palmer EE et al. (2022)
c.1185C>G p.Ser395Arg missense_variant De novo - Simplex 36385166 Palmer EE et al. (2022)
c.1646T>A p.Ile549Asn missense_variant De novo - Simplex 36385166 Palmer EE et al. (2022)
c.1664C>T p.Ala555Val missense_variant De novo - Simplex 36385166 Palmer EE et al. (2022)
c.2152C>T p.Arg718Trp missense_variant De novo - Simplex 36385166 Palmer EE et al. (2022)
c.875G>A p.Trp292Ter stop_gained Familial Maternal - 34580403 Pode-Shakked B et al. (2021)
c.832del p.Ser278ValfsTer2 frameshift_variant Unknown - - 39039281 Axel Schmidt et al. (2024)
c.1621G>C p.Glu541Gln missense_variant De novo - Simplex 28191890 Kosmicki JA , et al. (2017)
c.2152C>T p.Arg718Trp missense_variant De novo - Simplex 28191890 Kosmicki JA , et al. (2017)
c.1343C>T p.Ala448Val missense_variant Familial Maternal Simplex 34479510 Xu X et al. (2021)
c.2066_2067del p.His689ProfsTer71 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.1107+5G>A - splice_site_variant Familial Maternal Simplex 27550844 Palmer EE , et al. (2016)
c.1664C>T p.Ala555Val missense_variant Familial Maternal Multiplex 38758281 Hailan He et al. ()
c.206C>T p.Ser69Leu missense_variant Familial Maternal Simplex 36385166 Palmer EE et al. (2022)
c.608C>T p.Thr203Ile missense_variant Familial Maternal Simplex 36385166 Palmer EE et al. (2022)
c.823G>C p.Val275Leu missense_variant Familial Maternal Simplex 36385166 Palmer EE et al. (2022)
c.826C>T p.Leu276Phe missense_variant Familial Maternal Simplex 36385166 Palmer EE et al. (2022)
c.949G>A p.Val317Ile missense_variant Familial Maternal Simplex 36385166 Palmer EE et al. (2022)
c.87C>G p.Asp29Glu missense_variant Familial Maternal Multiplex 36385166 Palmer EE et al. (2022)
c.232G>A p.Gly78Ser missense_variant Familial Maternal Simplex 27550844 Palmer EE , et al. (2016)
c.1025G>A p.Gly342Glu missense_variant Familial Maternal Simplex 36385166 Palmer EE et al. (2022)
c.1078C>A p.Arg360Ser missense_variant Familial Maternal Simplex 36385166 Palmer EE et al. (2022)
c.1597G>A p.Val533Met missense_variant Familial Maternal Simplex 36385166 Palmer EE et al. (2022)
c.1886C>T p.Thr629Ile missense_variant Familial Maternal Simplex 36385166 Palmer EE et al. (2022)
c.1906G>A p.Val636Met missense_variant Familial Maternal Simplex 36385166 Palmer EE et al. (2022)
c.2192G>T p.Gly731Val missense_variant Familial Maternal Simplex 36385166 Palmer EE et al. (2022)
c.100G>A p.Asp34Asn missense_variant Familial Maternal Multiplex 36385166 Palmer EE et al. (2022)
c.185A>G p.Lys62Arg missense_variant Familial Maternal Multiplex 36385166 Palmer EE et al. (2022)
c.926A>G p.Asn309Ser missense_variant Familial Maternal Multiplex 36385166 Palmer EE et al. (2022)
c.956T>C p.Phe319Ser missense_variant Familial Maternal Multiplex 36385166 Palmer EE et al. (2022)
c.1090A>G p.Arg364Gly missense_variant Unknown - Extended multiplex 36385166 Palmer EE et al. (2022)
c.635T>G p.Val212Gly missense_variant Familial Maternal Multiplex 27550844 Palmer EE , et al. (2016)
c.274G>A p.Val92Met missense_variant Familial Paternal Extended multiplex 36385166 Palmer EE et al. (2022)
c.758G>A p.Arg253Gln missense_variant Familial Maternal Multiplex 35183220 Álvarez-Mora MI et al. (2022)
c.1576G>A p.Gly526Ser missense_variant Familial Maternal Extended multiplex 36385166 Palmer EE et al. (2022)
c.1904C>G p.Pro635Arg missense_variant Familial Maternal Extended multiplex 36385166 Palmer EE et al. (2022)
c.661C>G p.Leu221Val missense_variant Familial Maternal Multi-generational 27550844 Palmer EE , et al. (2016)
- p.Asp15SerfsTer18 frameshift_variant Familial Maternal Multi-generational 27550844 Palmer EE , et al. (2016)
c.1606G>A p.Val536Met missense_variant Familial Maternal Multi-generational 27550844 Palmer EE , et al. (2016)
c.2191G>C p.Gly731Arg missense_variant Familial Maternal Multi-generational 27550844 Palmer EE , et al. (2016)
c.1876dup p.Ile626AsnfsTer135 frameshift_variant Familial Maternal Multiplex 27550844 Palmer EE , et al. (2016)
c.925_928del p.Asn309ProfsTer67 frameshift_variant Familial Maternal Extended multiplex 36385166 Palmer EE et al. (2022)
c.1987_1990del p.Gln663GlyfsTer6 frameshift_variant Familial Maternal Extended multiplex 36385166 Palmer EE et al. (2022)
Common Variants  

No common variants reported.

SFARI Gene score
2S

Strong Candidate, Syndromic

De novo damaging missense variants (defined by CADD score 25) in the CLCN4 gene were identified in two ASD probands from previously published studies, while a third de novo damaging missense variant in this gene was observed in an ASD proband from the SPARK cohort (Feliciano et al., 2019). A meta-analysis of de novo variants in 4773 published ASD trios and 465 SPARK trios using TADA identified CLCN4 as an ASD candidate gene with a q-value 0.1. Mutations in the CLCN4 gene are also responsible for Raynaud-Claes syndrome (OMIM 300114), an X-linked intellectual developmental disorder characterized by borderline to severe intellectual disability and impaired language development; behavioral problems are frequently observed in individuals with this syndrome, and autistic features have been reported in a subset of affected individuals (Claes et al., 1997; Palmer et al., 2018).

Score Delta: Score remained at 2S

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.

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."

4/1/2022
3S
icon
2S

Decreased from 3S to 2S

Description

De novo damaging missense variants (defined by CADD score 25) in the CLCN4 gene were identified in two ASD probands from previously published studies, while a third de novo damaging missense variant in this gene was observed in an ASD proband from the SPARK cohort (Feliciano et al., 2019). A meta-analysis of de novo variants in 4773 published ASD trios and 465 SPARK trios using TADA identified CLCN4 as an ASD candidate gene with a q-value 0.1. Mutations in the CLCN4 gene are also responsible for Raynaud-Claes syndrome (OMIM 300114), an X-linked intellectual developmental disorder characterized by borderline to severe intellectual disability and impaired language development; behavioral problems are frequently observed in individuals with this syndrome, and autistic features have been reported in a subset of affected individuals (Claes et al., 1997; Palmer et al., 2018).

1/1/2020
3S
icon
3S

Decreased from 3S to 3S

Description

De novo damaging missense variants (defined by CADD score 25) in the CLCN4 gene were identified in two ASD probands from previously published studies, while a third de novo damaging missense variant in this gene was observed in an ASD proband from the SPARK cohort (Feliciano et al., 2019). A meta-analysis of de novo variants in 4773 published ASD trios and 465 SPARK trios using TADA identified CLCN4 as an ASD candidate gene with a q-value 0.1. Mutations in the CLCN4 gene are also responsible for Raynaud-Claes syndrome (OMIM 300114), an X-linked intellectual developmental disorder characterized by borderline to severe intellectual disability and impaired language development; behavioral problems are frequently observed in individuals with this syndrome, and autistic features have been reported in a subset of affected individuals (Claes et al., 1997; Palmer et al., 2018).

Reports Added
[Refining the role of de novo protein-truncating variants in neurodevelopmental disorders by using population reference samples.2017]
10/1/2019
icon
3S

Increased from to 3S

New Scoring Scheme
Description

De novo damaging missense variants (defined by CADD score 25) in the CLCN4 gene were identified in two ASD probands from previously published studies, while a third de novo damaging missense variant in this gene was observed in an ASD proband from the SPARK cohort (Feliciano et al., 2019). A meta-analysis of de novo variants in 4773 published ASD trios and 465 SPARK trios using TADA identified CLCN4 as an ASD candidate gene with a q-value 0.1. Mutations in the CLCN4 gene are also responsible for Raynaud-Claes syndrome (OMIM 300114), an X-linked intellectual developmental disorder characterized by borderline to severe intellectual disability and impaired language development; behavioral problems are frequently observed in individuals with this syndrome, and autistic features have been reported in a subset of affected individuals (Claes et al., 1997; Palmer et al., 2018).

Reports Added
[New Scoring Scheme]
Krishnan Probability Score

Score 0.5672449701645

Ranking 1187/25841 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 0.98878792045761

Ranking 1852/18225 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 0.941436244009

Ranking 14932/18665 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 0.24153535080494

Ranking 3601/20870 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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