Human Gene Module / Chromosome 9 / ASTN2

ASTN2astrotactin 2

Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
5 / 13
Rare Variants / Common Variants
23 / 3
Aliases
ASTN2, RP11-45A16.2,  KIAA0634,  bA67K19.1
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Genetic Association
Chromosome Band
9q33.1
Associated Disorders
DD/NDD, EPS, ADHD, ASD, ID
Relevance to Autism

Association has been found between the ASTN2 gene and autism. Glessner et al. (2009) identified a rare ASTN2 deletion in an autism case. Another study found a link between rare ASTN2 CNVs and schizophrenia.

Molecular Function

This gene encodes a protein that is expressed in the brain and may function in neuronal migration, based on functional studies of the related astrotactin 1 gene in human and mouse. A deletion at this locus has been associated with schizophrenia.

Reports related to ASTN2 (13 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Recent Recommendation Molecular genetics of adult ADHD: converging evidence from genome-wide association and extended pedigree linkage studies. Lesch KP , et al. (2008) No -
2 Recent Recommendation Recurrent CNVs disrupt three candidate genes in schizophrenia patients. Vrijenhoek T , et al. (2008) No -
3 Primary Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Glessner JT , et al. (2009) Yes -
4 Recent Recommendation Astn2, a novel member of the astrotactin gene family, regulates the trafficking of ASTN1 during glial-guided neuronal migration. Wilson PM , et al. (2010) No -
5 Recent Recommendation Genome-wide association analysis identifies susceptibility loci for migraine without aura. Freilinger T , et al. (2012) No -
6 Support A discovery resource of rare copy number variations in individuals with autism spectrum disorder. Prasad A , et al. (2013) Yes -
7 Support Identification of candidate intergenic risk loci in autism spectrum disorder. Walker S and Scherer SW (2013) Yes -
8 Recent Recommendation Disruption of the ASTN2/TRIM32 locus at 9q33.1 is a risk factor in males for autism spectrum disorders, ADHD and other neurodevelopmental phenotypes. Lionel AC , et al. (2014) Yes ADHD, DD, ID, epilepsy, OCD
9 Positive Association Novel genetic loci associated with hippocampal volume. Hibar DP , et al. (2017) No -
10 Positive Association Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with ... Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium (2017) Yes -
11 Support Expanding the genetic heterogeneity of intellectual disability. Anazi S , et al. (2017) No Dysmorphic features
12 Recent recommendation ASTN2 modulates synaptic strength by trafficking and degradation of surface proteins. Behesti H , et al. (2018) No ASD, ID, epilepsy/seizures
13 Highly Cited Astrotactin: a novel neuronal cell surface antigen that mediates neuron-astroglial interactions in cerebellar microcultures. Edmondson JC , et al. (1988) No -
Rare Variants   (23)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss - - - 19404257 Glessner JT , et al. (2009)
- - copy_number_gain - - - 18940311 Vrijenhoek T , et al. (2008)
- - copy_number_loss - - - 18940311 Vrijenhoek T , et al. (2008)
- - copy_number_loss Unknown - Unknown 23275889 Prasad A , et al. (2013)
- - copy_number_loss De novo - Unknown 24381304 Lionel AC , et al. (2014)
- - copy_number_loss Unknown - Unknown 24381304 Lionel AC , et al. (2014)
- - copy_number_loss Unknown - Simplex 23879678 Walker S and Scherer SW (2013)
- - copy_number_gain Familial Maternal Unknown 24381304 Lionel AC , et al. (2014)
- - copy_number_loss Familial Maternal Unknown 24381304 Lionel AC , et al. (2014)
- - copy_number_loss Familial Paternal Unknown 24381304 Lionel AC , et al. (2014)
- - copy_number_loss Unknown Not maternal Unknown 24381304 Lionel AC , et al. (2014)
- - copy_number_loss Unknown Not paternal Unknown 24381304 Lionel AC , et al. (2014)
- - copy_number_loss Familial Maternal Simplex 23879678 Walker S and Scherer SW (2013)
- - copy_number_gain Familial Maternal Multi-generational 24381304 Lionel AC , et al. (2014)
- - copy_number_gain Familial Paternal Multi-generational 24381304 Lionel AC , et al. (2014)
- - copy_number_loss Familial Maternal Multi-generational 24381304 Lionel AC , et al. (2014)
- - copy_number_gain Familial Paternal Multi-generational 30242134 Behesti H , et al. (2018)
c.870T>A p.Ser257Thr missense_variant Familial Paternal Unknown 24381304 Lionel AC , et al. (2014)
c.1150C>T p.Ser350Leu missense_variant Familial Paternal Unknown 24381304 Lionel AC , et al. (2014)
c.1476G>T p.Val459Leu missense_variant Familial Maternal Unknown 24381304 Lionel AC , et al. (2014)
c.1638A>T p.Thr513Ser missense_variant Familial Maternal Unknown 24381304 Lionel AC , et al. (2014)
c.3522C>A p.Leu1141Met missense_variant Familial Maternal Unknown 24381304 Lionel AC , et al. (2014)
c.[892G>C];[892G>C] p.[Asp298His];[Asp298His] missense_variant;missense_variant - - Multi-generational 28940097 Anazi S , et al. (2017)
Common Variants   (3)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.653+1664C>G;c.3344+1664C>G;c.800+1664C>G;c.3497+1664C>G - intron_variant - - - 28098162 Hibar DP , et al. (2017)
- - intergenic_variant - - - 28540026 Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium (2017)
c.512-46957C>A;c.3203-46957C>A;c.659-46957C>A;c.3356-46957C>A - intron_variant - - - 28540026 Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium (2017)
SFARI Gene score
2

Strong Candidate

The report from Glessner et al. indicates that 6/~2000 cases and 1/~2500 controls have deletions that overlap with the ASTN2 locus, inheritance unknown. Multiple case events are exonic while the only control event is within an intron. Of the 6 variants, 2 were confirmed by Affymetrix arrays but the status of the remainder is unknown. Statistical support is lacking (the p value of 9.5 x 10-3 is for all genes within the GO term ?neuron development?, not ASTN2 alone. ASTN2 CNVs in 2/800 cases versus 0/700 controls were reported in Vrijenhoek T et al., A GWAS provides support for ASTN2 (paper unavailable electronically but nominal support presumed) (Lesch KP et al.).

Score Delta: Score remained at 3

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.

10/1/2018
3
icon
3

Score remained at 3

Description

The report from Glessner et al. indicates that 6/~2000 cases and 1/~2500 controls have deletions that overlap with the ASTN2 locus, inheritance unknown. Multiple case events are exonic while the only control event is within an intron. Of the 6 variants, 2 were confirmed by Affymetrix arrays but the status of the remainder is unknown. Statistical support is lacking (the p value of 9.5 x 10-3 is for all genes within the GO term ?neuron development?, not ASTN2 alone. ASTN2 CNVs in 2/800 cases versus 0/700 controls were reported in Vrijenhoek T et al., A GWAS provides support for ASTN2 (paper unavailable electronically but nominal support presumed) (Lesch KP et al.).

7/1/2018
4.4 + acc1
icon
3

Decreased from 4.4 + acc1 to 3

Description

The report from Glessner et al. indicates that 6/~2000 cases and 1/~2500 controls have deletions that overlap with the ASTN2 locus, inheritance unknown. Multiple case events are exonic while the only control event is within an intron. Of the 6 variants, 2 were confirmed by Affymetrix arrays but the status of the remainder is unknown. Statistical support is lacking (the p value of 9.5 x 10-3 is for all genes within the GO term ?neuron development?, not ASTN2 alone. ASTN2 CNVs in 2/800 cases versus 0/700 controls were reported in Vrijenhoek T et al., A GWAS provides support for ASTN2 (paper unavailable electronically but nominal support presumed) (Lesch KP et al.).

4/1/2018
3
icon
4.4 + acc1

Increased from 3 to 4.4 + acc1

Description

3

10/1/2017
3
icon
3

Increased from 3 to 3

Description

The report from Glessner et al. indicates that 6/~2000 cases and 1/~2500 controls have deletions that overlap with the ASTN2 locus, inheritance unknown. Multiple case events are exonic while the only control event is within an intron. Of the 6 variants, 2 were confirmed by Affymetrix arrays but the status of the remainder is unknown. Statistical support is lacking (the p value of 9.5 x 10-3 is for all genes within the GO term ?neuron development?, not ASTN2 alone. ASTN2 CNVs in 2/800 cases versus 0/700 controls were reported in Vrijenhoek T et al., A GWAS provides support for ASTN2 (paper unavailable electronically but nominal support presumed) (Lesch KP et al.).

4/1/2017
3
icon
3

Increased from 3 to 3

Description

The report from Glessner et al. indicates that 6/~2000 cases and 1/~2500 controls have deletions that overlap with the ASTN2 locus, inheritance unknown. Multiple case events are exonic while the only control event is within an intron. Of the 6 variants, 2 were confirmed by Affymetrix arrays but the status of the remainder is unknown. Statistical support is lacking (the p value of 9.5 x 10-3 is for all genes within the GO term ?neuron development?, not ASTN2 alone. ASTN2 CNVs in 2/800 cases versus 0/700 controls were reported in Vrijenhoek T et al., A GWAS provides support for ASTN2 (paper unavailable electronically but nominal support presumed) (Lesch KP et al.).

1/1/2017
3
icon
3

Increased from 3 to 3

Description

The report from Glessner et al. indicates that 6/~2000 cases and 1/~2500 controls have deletions that overlap with the ASTN2 locus, inheritance unknown. Multiple case events are exonic while the only control event is within an intron. Of the 6 variants, 2 were confirmed by Affymetrix arrays but the status of the remainder is unknown. Statistical support is lacking (the p value of 9.5 x 10-3 is for all genes within the GO term ?neuron development?, not ASTN2 alone. ASTN2 CNVs in 2/800 cases versus 0/700 controls were reported in Vrijenhoek T et al., A GWAS provides support for ASTN2 (paper unavailable electronically but nominal support presumed) (Lesch KP et al.).

7/1/2014
No data
icon
3

Increased from No data to 3

Description

The report from Glessner et al. indicates that 6/~2000 cases and 1/~2500 controls have deletions that overlap with the ASTN2 locus, inheritance unknown. Multiple case events are exonic while the only control event is within an intron. Of the 6 variants, 2 were confirmed by Affymetrix arrays but the status of the remainder is unknown. Statistical support is lacking (the p value of 9.5 x 10-3 is for all genes within the GO term ?neuron development?, not ASTN2 alone. ASTN2 CNVs in 2/800 cases versus 0/700 controls were reported in Vrijenhoek T et al., A GWAS provides support for ASTN2 (paper unavailable electronically but nominal support presumed) (Lesch KP et al.).

4/1/2014
No data
icon
3

Increased from No data to 3

Description

The report from Glessner et al. indicates that 6/~2000 cases and 1/~2500 controls have deletions that overlap with the ASTN2 locus, inheritance unknown. Multiple case events are exonic while the only control event is within an intron. Of the 6 variants, 2 were confirmed by Affymetrix arrays but the status of the remainder is unknown. Statistical support is lacking (the p value of 9.5 x 10-3 is for all genes within the GO term ?neuron development?, not ASTN2 alone. ASTN2 CNVs in 2/800 cases versus 0/700 controls were reported in Vrijenhoek T et al., A GWAS provides support for ASTN2 (paper unavailable electronically but nominal support presumed) (Lesch KP et al.).

Krishnan Probability Score

Score 0.56772529750509

Ranking 1161/25841 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 0.98917228378034

Ranking 1831/18225 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 0.94907007384497

Ranking 17941/18665 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).
Larsen Cumulative Evidence Score

Score 21

Ranking 96/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Zhang D Score

Score 0.23040140503017

Ranking 3770/20870 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.
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
Astn1 astrotactin 1 Mouse Protein Binding 11899 Q61137
Auts2 autism susceptibility candidate 2 Mouse DNA Binding 319974 Q6PED7
CCT4 chaperonin containing TCP1, subunit 4 (delta) Human Protein Binding 10575 P50991
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