Human Gene Module / Chromosome X / CLCN4

CLCN4chloride voltage-gated channel 4

Score
3S
Suggestive Evidence, Syndromic Criteria 3.1, Syndromic
Autism Reports / Total Reports
2 / 5
Rare Variants / Common Variants
19 / 0
Aliases
CLCN4, CLC4,  ClC-4,  ClC-4A,  MRX15,  MRX49,  MRXSRC
Associated Syndromes
Raynaud-Claes syndrome
Genetic Category
Rare Single Gene Mutation, Syndromic
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).

Molecular Function

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

Reports related to CLCN4 (5 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 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 -
5 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   (19)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss Familial Maternal Multiplex 27550844 Palmer EE , et al. (2016)
c.43G>A p.Asp15Asn missense_variant De novo NA - 27550844 Palmer EE , et al. (2016)
c.662T>C p.Leu221Pro missense_variant De novo NA - 27550844 Palmer EE , et al. (2016)
c.823G>A p.Val275Met missense_variant De novo NA - 27550844 Palmer EE , et al. (2016)
c.1601C>T p.Ser534Leu missense_variant De novo NA - 27550844 Palmer EE , et al. (2016)
c.1630G>C p.Gly544Arg missense_variant De novo NA - 27550844 Palmer EE , et al. (2016)
c.1664C>T p.Ala555Val missense_variant De novo NA - 27550844 Palmer EE , et al. (2016)
c.2152C>T p.Arg718Trp missense_variant De novo NA - 27550844 Palmer EE , et al. (2016)
c.1885C>T p.Arg629Trp missense_variant De novo NA - 31452935 Feliciano P et al. (2019)
c.1107+5G>A - splice_site_variant Familial Maternal Simplex 27550844 Palmer EE , et al. (2016)
c.1621G>C p.Glu541Gln missense_variant De novo NA Simplex 28191890 Kosmicki JA , et al. (2017)
c.2152C>T p.Arg718Trp missense_variant De novo NA Simplex 28191890 Kosmicki JA , et al. (2017)
c.232G>A p.Gly78Ser missense_variant Familial Maternal Simplex 27550844 Palmer EE , et al. (2016)
c.635T>G p.Val212Gly missense_variant Familial Maternal Multiplex 27550844 Palmer EE , et al. (2016)
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)
Common Variants  

No common variants reported.

SFARI Gene score
3S

Suggestive Evidence, 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 4S

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.

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."

1/1/2020
4S
icon
4S

Score remained at 4S

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).

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.
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
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).
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.
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