Human Gene Module / Chromosome 12 / CUX2

CUX2cut like homeobox 2

SFARI Gene Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
7 / 15
Rare Variants / Common Variants
19 / 0
Aliases
CUX2, CDP2,  CUTL2
Associated Syndromes
-
Chromosome Band
12q24.11-q24.12
Associated Disorders
ASD
Relevance to Autism

A de novo nonsense variant in the CUX2 gene was identified in an ASD proband from the Autism Sequencing Consortium in De Rubeis et al., 2014. Chatron et al., 2018 identified nine patients with a recurrent de novo missense variant in the CUX2 gene (p.Glu590Lys) that presented with developmental and epileptic encephalopathy; in addition to recurrent phenotypes including epilepsy and intellectual disability, several individuals with this variant also presented with autistic features and/or motor stereotypies.

Molecular Function

This gene encodes a protein which contains three CUT domains and a homeodomain; both domains are DNA-binding motifs. The encoded protein may be a transcription factor involved in neural specification.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to CUX2 (15 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Dynamics of Cux2 expression suggests that an early pool of SVZ precursors is fated to become upper cortical layer neurons Zimmer C , et al. (2004) No -
2 Highly Cited Expression of Cux-1 and Cux-2 in the subventricular zone and upper layers II-IV of the cerebral cortex Nieto M , et al. (2004) No -
3 Support Cux-2 controls the proliferation of neuronal intermediate precursors of the cortical subventricular zone Cubelos B , et al. (2007) No -
4 Support Cux1 and Cux2 regulate dendritic branching, spine morphology, and synapses of the upper layer neurons of the cortex Cubelos B , et al. (2010) No -
5 Primary Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
6 Recent Recommendation The epilepsy phenotypic spectrum associated with a recurrent CUX2 variant Chatron N , et al. (2018) No Autistic features, stereotypies
7 Support A recurrent de novo CUX2 missense variant associated with intellectual disability, seizures, and autism spectrum disorder Barington M , et al. (2018) Yes -
8 Support Cux2 expression regulated by Lhx2 in the upper layer neurons of the developing cortex Yang H , et al. (2019) No -
9 Support - Woodbury-Smith M et al. (2022) Yes -
10 Support - Chuan Z et al. (2022) No -
11 Support - Suzuki T et al. (2022) No ID
12 Support - Zhou X et al. (2022) Yes -
13 Support - Chen WX et al. (2022) Yes -
14 Support - Omri Bar et al. (2024) Yes ADHD, ID, epilepsy/seizures
15 Support - Marketa Wayhelova et al. (2024) Yes -
Rare Variants   (19)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1745G>A p.Gly582Glu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2300T>C p.Phe767Ser missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.100C>T p.Arg34Trp missense_variant Unknown - - 35581205 Suzuki T et al. (2022)
c.1925C>T p.Thr642Met missense_variant Unknown - - 35571021 Chuan Z et al. (2022)
c.1897C>T p.Arg633Ter stop_gained De novo - - 25363760 De Rubeis S , et al. (2014)
c.1992G>T p.Ser664%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.2445C>T p.Tyr815%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.1768G>A p.Glu590Lys missense_variant De novo - - 29630738 Chatron N , et al. (2018)
c.1768G>A p.Glu590Lys missense_variant De novo - - 29795476 Barington M , et al. (2018)
c.3564G>A p.Gln1188= synonymous_variant De novo - Simplex 36320054 Chen WX et al. (2022)
c.1009G>A p.Asp337Asn missense_variant Unknown - Simplex 35581205 Suzuki T et al. (2022)
c.1361C>T p.Pro454Leu missense_variant Unknown - Unknown 35581205 Suzuki T et al. (2022)
c.3847G>A p.Glu1283Lys missense_variant Unknown - Simplex 35581205 Suzuki T et al. (2022)
c.3847G>A p.Glu1283Lys missense_variant Unknown - Unknown 35581205 Suzuki T et al. (2022)
c.3796G>A p.Glu1266Lys missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.3065C>A p.Ser1022Ter stop_gained Familial Maternal - 38321498 Marketa Wayhelova et al. (2024)
c.2175dup p.Ser726LeufsTer130 frameshift_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1439C>T p.Pro480Leu missense_variant Familial Paternal Simplex 38256266 Omri Bar et al. (2024)
c.2872T>C p.Trp958Arg missense_variant Unknown - Extended multiplex 35581205 Suzuki T et al. (2022)
Common Variants  

No common variants reported.

SFARI Gene score
2S

Strong Candidate, Syndromic

A de novo nonsense variant in the CUX2 gene was identified in an ASD proband from the Autism Sequencing Consortium in De Rubeis et al., 2014. Chatron et al., 2018 identified nine patients with a recurrent de novo missense variant in the CUX2 gene (p.Glu590Lys) that presented with developmental and epileptic encephalopathy; in addition to recurrent phenotypes including epilepsy and intellectual disability, several individuals with this variant also presented with autistic features and/or motor stereotypies. The recurrent de novo p.Glu590Lys missense variant was also identified in a Danish female presenting with infantile autism, intellectual disability, and seizures in Barington 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

A de novo nonsense variant in the CUX2 gene was identified in an ASD proband from the Autism Sequencing Consortium in De Rubeis et al., 2014. Chatron et al., 2018 identified nine patients with a recurrent de novo missense variant in the CUX2 gene (p.Glu590Lys) that presented with developmental and epileptic encephalopathy; in addition to recurrent phenotypes including epilepsy and intellectual disability, several individuals with this variant also presented with autistic features and/or motor stereotypies. The recurrent de novo p.Glu590Lys missense variant was also identified in a Danish female presenting with infantile autism, intellectual disability, and seizures in Barington et al., 2018.

10/1/2019
4S
icon
3S

Decreased from 4S to 3S

New Scoring Scheme
Description

A de novo nonsense variant in the CUX2 gene was identified in an ASD proband from the Autism Sequencing Consortium in De Rubeis et al., 2014. Chatron et al., 2018 identified nine patients with a recurrent de novo missense variant in the CUX2 gene (p.Glu590Lys) that presented with developmental and epileptic encephalopathy; in addition to recurrent phenotypes including epilepsy and intellectual disability, several individuals with this variant also presented with autistic features and/or motor stereotypies. The recurrent de novo p.Glu590Lys missense variant was also identified in a Danish female presenting with infantile autism, intellectual disability, and seizures in Barington et al., 2018.

Reports Added
[Cux2 expression regulated by Lhx2 in the upper layer neurons of the developing cortex.2019] [New Scoring Scheme]
7/1/2018
icon
4S

Increased from to 4S

Description

A de novo nonsense variant in the CUX2 gene was identified in an ASD proband from the Autism Sequencing Consortium in De Rubeis et al., 2014. Chatron et al., 2018 identified nine patients with a recurrent de novo missense variant in the CUX2 gene (p.Glu590Lys) that presented with developmental and epileptic encephalopathy; in addition to recurrent phenotypes including epilepsy and intellectual disability, several individuals with this variant also presented with autistic features and/or motor stereotypies. The recurrent de novo p.Glu590Lys missense variant was also identified in a Danish female presenting with infantile autism, intellectual disability, and seizures in Barington et al., 2018.

Krishnan Probability Score

Score 0.520283698179

Ranking 1698/25841 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 0.99965638459278

Ranking 864/18225 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 0.66433521936397

Ranking 961/18665 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 0.54534746236225

Ranking 260/20870 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
Submit New Gene

Report an Error