Human Gene Module / Chromosome 11 / DIXDC1

DIXDC1DIX domain containing 1

Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
2 / 4
Rare Variants / Common Variants
45 / 0
Aliases
DIXDC1, CCD1
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Functional
Chromosome Band
11q23.1
Associated Disorders
BPD, SCZ
Relevance to Autism

Exome sequence analysis of the DIXDC1 gene in 5977 ASD cases and 7734 controls identified a greater burden of rare sequencing-disrupting SNVs (nonsense, missense, conserved splice-site disrupting) in both DIXDC1 isoforms in cases compared to controls [isoform 1: 68/5977 cases (1.14%) vs. 64/7734 controls (0.83%), p=0.033; isoform 2: 53/5977 cases (8.9%) vs. 41/7734 controls (0.53%), p=0.006] (Martin et al., 2016). A greater burden of rare sequencing-disrupting variants in DIXDC1 was also observed for isoform 1 in bipolar disorder cases (p=0.013) and for isoform 2 in schizophrenia cases (p=0.015). Rare DIXDC1 missense variants observed in ASD cases from the discovery (AASC) cohort failed to rescue deficits in spine density and glutamatergic synapse density in DIXDC1 knockout neurons, with a subset of DIXDC1 missense variants exhibiting hyperactivity in Wnt/beta-catenin signaling activity and dominant-negative effects on spine density and glutamatergic synapse density in wild-type neurons. However, the high frequency of sequence-disrupting DIXDC1 variants in controls (0.53-0.83%, depending on the isoform), the lack of information regarding the mode of inheritance and segregation of variants in ASD cases, and the presence of functionally-relevant ASD missense variants in controls confounds the genetic evidence linking this gene to ASD. Dixdc1 knockout mice display decreased spontaneous locomotor activity, abnormal behavior in the elevated plus maze and deficits in startle reactivity (in Kivime et al., 2011) and abnormal measures of anxiety, depression, and social behavior (in Martin et al., 2016).

Molecular Function

The protein encoded by this gene is a positive regulator of the Wnt signaling pathway and is found associated with gamma tubulin at the centrosome.

Reports related to DIXDC1 (4 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Dixdc1 is a critical regulator of DISC1 and embryonic cortical development. Singh KK , et al. (2010) No -
2 Support Abnormal behavior in mice mutant for the Disc1 binding partner, Dixdc1. Kivime S , et al. (2011) No -
3 Primary DIXDC1 contributes to psychiatric susceptibility by regulating dendritic spine and glutamatergic synapse density via GSK3 and Wnt/-catenin signaling. Martin PM , et al. (2016) Yes SCZ, BPD
4 Support DIXDC1 Phosphorylation and Control of Dendritic Morphology Are Impaired by Rare Genetic Variants. Kwan V , et al. (2016) Yes -
Rare Variants   (45)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - missense_variant Unknown - - 27752079 Martin PM , et al. (2016)
c.656+2797G>C - missense_variant Unknown - - 27752079 Martin PM , et al. (2016)
c.514C>T p.Arg172Ter stop_gained Unknown - - 27752079 Martin PM , et al. (2016)
c.1526+1G>A - splice_site_variant Unknown - - 27752079 Martin PM , et al. (2016)
c.1548C>T p.Arg517Ter stop_gained Unknown - - 27752079 Martin PM , et al. (2016)
c.37G>A p.Val13Ile missense_variant Unknown - - 27752079 Martin PM , et al. (2016)
c.50G>C p.Gly17Ala missense_variant Unknown - - 27752079 Martin PM , et al. (2016)
c.127G>A p.Val43Met missense_variant Unknown - - 27752079 Martin PM , et al. (2016)
c.461G>C p.Arg154Thr missense_variant Unknown - - 27752079 Martin PM , et al. (2016)
c.529G>A p.Val177Ile missense_variant Unknown - - 27752079 Martin PM , et al. (2016)
c.581C>T p.Pro194Leu missense_variant Unknown - - 27752079 Martin PM , et al. (2016)
c.655A>G p.Ser219Gly missense_variant Unknown - - 27752079 Martin PM , et al. (2016)
c.668C>T p.Pro223Leu missense_variant Unknown - - 27752079 Martin PM , et al. (2016)
c.700A>T p.Ile234Phe missense_variant Unknown - - 27752079 Martin PM , et al. (2016)
c.745G>A p.Ala249Thr missense_variant Unknown - - 27752079 Martin PM , et al. (2016)
c.746G>A p.Arg249Gln missense_variant Unknown - - 27752079 Martin PM , et al. (2016)
c.960A>G p.Arg321Gly missense_variant Unknown - - 27752079 Martin PM , et al. (2016)
c.1016G>T p.Arg339Leu missense_variant Unknown - - 27752079 Martin PM , et al. (2016)
c.1054A>C p.Asp352Ala missense_variant Unknown - - 27752079 Martin PM , et al. (2016)
c.1101C>T p.Gln368Ter missense_variant Unknown - - 27752079 Martin PM , et al. (2016)
c.1104G>C p.Gly369Arg missense_variant Unknown - - 27752079 Martin PM , et al. (2016)
c.1107A>T p.Ile370Leu missense_variant Unknown - - 27752079 Martin PM , et al. (2016)
c.1141A>G p.Gln381Arg missense_variant Unknown - - 27752079 Martin PM , et al. (2016)
c.1329G>A p.Ala444Thr missense_variant Unknown - - 27752079 Martin PM , et al. (2016)
c.1335C>T p.Arg446Trp missense_variant Unknown - - 27752079 Martin PM , et al. (2016)
c.1447A>C p.Tyr483Ser missense_variant Unknown - - 27752079 Martin PM , et al. (2016)
c.1485C>A p.Pro496Thr missense_variant Unknown - - 27752079 Martin PM , et al. (2016)
c.1525G>T p.Gly509Val missense_variant Unknown - - 27752079 Martin PM , et al. (2016)
c.1533G>A p.Asp512Asn missense_variant Unknown - - 27752079 Martin PM , et al. (2016)
c.1560C>T p.Arg521Cys missense_variant Unknown - - 27752079 Martin PM , et al. (2016)
c.1666C>T p.Thr556Met missense_variant Unknown - - 27752079 Martin PM , et al. (2016)
c.1834C>T p.Thr612Met missense_variant Unknown - - 27752079 Martin PM , et al. (2016)
c.1905C>T p.Arg636Trp missense_variant Unknown - - 27752079 Martin PM , et al. (2016)
c.23G>A p.Gly8Glu missense_variant Familial Paternal - 27829159 Kwan V , et al. (2016)
c.127G>A p.Val43Met missense_variant Familial Paternal - 27829159 Kwan V , et al. (2016)
c.1110A>T p.Lys371Ter missense_variant Familial Maternal - 27829159 Kwan V , et al. (2016)
c.1837C>T p.Pro613Leu missense_variant Familial Paternal - 27829159 Kwan V , et al. (2016)
NM_033425.4:c.259G>A p.Ala87Thr missense_variant Unknown - - 27752079 Martin PM , et al. (2016)
NM_033425.4:c.407T>C p.Met136Thr missense_variant Unknown - - 27752079 Martin PM , et al. (2016)
NM_033425.4:c.441C>R p.His147Gln missense_variant Unknown - - 27752079 Martin PM , et al. (2016)
NM_033425.4:c.446G>C p.Cys149Ser missense_variant Unknown - - 27752079 Martin PM , et al. (2016)
NM_033425.4:c.483T>R p.Asp161Glu missense_variant Unknown - - 27752079 Martin PM , et al. (2016)
NM_033425.4:c.564A>Y p.Lys188Asn missense_variant Unknown - - 27752079 Martin PM , et al. (2016)
NM_033425.4:c.686A>C p.Lys229Thr missense_variant Unknown - - 27752079 Martin PM , et al. (2016)
NM_033425.4:c.779A>G p.His260Arg missense_variant Unknown - - 27752079 Martin PM , et al. (2016)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

Exome sequence analysis of the DIXDC1 gene in 5977 ASD cases and 7734 controls identified a greater burden of rare sequencing-disrupting SNVs (nonsense, missense, conserved splice-site disrupting) in both DIXDC1 isoforms in cases compared to controls [isoform 1: 68/5977 cases (1.14%) vs. 64/7734 controls (0.83%), p=0.033; isoform 2: 53/5977 cases (8.9%) vs. 41/7734 controls (0.53%), p=0.006] (Martin et al., 2016). A greater burden of rare sequencing-disrupting variants in DIXDC1 was also observed for isoform 1 in bipolar disorder cases (p=0.013) and for isoform 2 in schizophrenia cases (p=0.015). Rare DIXDC1 missense variants observed in ASD cases from the discovery (AASC) cohort failed to rescue deficits in spine density and glutamatergic synapse density in DIXDC1 knockout neurons, with a subset of DIXDC1 missense variants exhibiting hyperactivity in Wnt/beta-catenin signaling activity and dominant-negative effects on spine density and glutamatergic synapse density in wild-type neurons. However, the high frequency of sequence-disrupting DIXDC1 variants in controls (0.53-0.83%, depending on the isoform), the lack of information regarding the mode of inheritance and segregation of variants in ASD cases, and the presence of functionally-relevant ASD missense variants in controls in this report confounds the genetic evidence linking this gene to ASD. Dixdc1 knockout mice display decreased spontaneous locomotor activity, abnormal behavior in the elevated plus maze and deficits in startle reactivity (in Kivime et al., 2011) and abnormal measures of anxiety, depression, and social behavior (in Martin et al., 2016). Rare missense variants in DIXDC1 were identified in whole-genome sequence data for a cohort of ASD cases in the MSSNG database; two of these variants (p.Val43Met and p.Thr612Met) were experimentally shown to impair phosphorylation of isoform 1 by MARK1 and failed to rescue dendrite branching or spine density defects in KO neurons, suggesting a loss of function (Kwan et al., 2016).

Score Delta: Score remained at 4

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.

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Exome sequence analysis of the DIXDC1 gene in 5977 ASD cases and 7734 controls identified a greater burden of rare sequencing-disrupting SNVs (nonsense, missense, conserved splice-site disrupting) in both DIXDC1 isoforms in cases compared to controls [isoform 1: 68/5977 cases (1.14%) vs. 64/7734 controls (0.83%), p=0.033; isoform 2: 53/5977 cases (8.9%) vs. 41/7734 controls (0.53%), p=0.006] (Martin et al., 2016). A greater burden of rare sequencing-disrupting variants in DIXDC1 was also observed for isoform 1 in bipolar disorder cases (p=0.013) and for isoform 2 in schizophrenia cases (p=0.015). Rare DIXDC1 missense variants observed in ASD cases from the discovery (AASC) cohort failed to rescue deficits in spine density and glutamatergic synapse density in DIXDC1 knockout neurons, with a subset of DIXDC1 missense variants exhibiting hyperactivity in Wnt/beta-catenin signaling activity and dominant-negative effects on spine density and glutamatergic synapse density in wild-type neurons. However, the high frequency of sequence-disrupting DIXDC1 variants in controls (0.53-0.83%, depending on the isoform), the lack of information regarding the mode of inheritance and segregation of variants in ASD cases, and the presence of functionally-relevant ASD missense variants in controls in this report confounds the genetic evidence linking this gene to ASD. Dixdc1 knockout mice display decreased spontaneous locomotor activity, abnormal behavior in the elevated plus maze and deficits in startle reactivity (in Kivime et al., 2011) and abnormal measures of anxiety, depression, and social behavior (in Martin et al., 2016). Rare missense variants in DIXDC1 were identified in whole-genome sequence data for a cohort of ASD cases in the MSSNG database; two of these variants (p.Val43Met and p.Thr612Met) were experimentally shown to impair phosphorylation of isoform 1 by MARK1 and failed to rescue dendrite branching or spine density defects in KO neurons, suggesting a loss of function (Kwan et al., 2016).

Reports Added
[New Scoring Scheme]
10/1/2016
icon
4

Increased from to 4

Description

Exome sequence analysis of the DIXDC1 gene in 5977 ASD cases and 7734 controls identified a greater burden of rare sequencing-disrupting SNVs (nonsense, missense, conserved splice-site disrupting) in both DIXDC1 isoforms in cases compared to controls [isoform 1: 68/5977 cases (1.14%) vs. 64/7734 controls (0.83%), p=0.033; isoform 2: 53/5977 cases (8.9%) vs. 41/7734 controls (0.53%), p=0.006] (Martin et al., 2016). A greater burden of rare sequencing-disrupting variants in DIXDC1 was also observed for isoform 1 in bipolar disorder cases (p=0.013) and for isoform 2 in schizophrenia cases (p=0.015). Rare DIXDC1 missense variants observed in ASD cases from the discovery (AASC) cohort failed to rescue deficits in spine density and glutamatergic synapse density in DIXDC1 knockout neurons, with a subset of DIXDC1 missense variants exhibiting hyperactivity in Wnt/beta-catenin signaling activity and dominant-negative effects on spine density and glutamatergic synapse density in wild-type neurons. However, the high frequency of sequence-disrupting DIXDC1 variants in controls (0.53-0.83%, depending on the isoform), the lack of information regarding the mode of inheritance and segregation of variants in ASD cases, and the presence of functionally-relevant ASD missense variants in controls in this report confounds the genetic evidence linking this gene to ASD. Dixdc1 knockout mice display decreased spontaneous locomotor activity, abnormal behavior in the elevated plus maze and deficits in startle reactivity (in Kivimäe et al., 2011) and abnormal measures of anxiety, depression, and social behavior (in Martin et al., 2016). Rare missense variants in DIXDC1 were identified in whole-genome sequence data for a cohort of ASD cases in the MSSNG database; two of these variants (p.Val43Met and p.Thr612Met) were experimentally shown to impair phosphorylation of isoform 1 by MARK1 and failed to rescue dendrite branching or spine density defects in KO neurons, suggesting a loss of function (Kwan et al., 2016).

Krishnan Probability Score

Score 0.49261413430547

Ranking 4469/25841 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 4.2687131476292E-6

Ranking 14540/18225 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 0.94796397803257

Ranking 17490/18665 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 0.42138605698378

Ranking 1218/20870 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.
Submit New Gene

Report an Error

SFARI Gene Update

We are pleased to announce some changes to the ongoing curation of the data in SFARI Gene. In the context of a continued effort to develop the human gene module and its manually curated list of autism risk genes, we are modifying other aspects of the site to focus on the information that is of greatest interest to the research community. The version of SFARI Gene that has been developed until now will be frozen and will remain available as “SFARI Gene Archive”. Please see the announcement for more details.
Close