Human Gene Module / Chromosome 15 / ST8SIA2

ST8SIA2ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 2

Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
4 / 9
Rare Variants / Common Variants
5 / 6
Aliases
ST8SIA2, UNQ3057,  HsT19690,  SIAT8B,  ST8SIA-II,  STX
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Genetic Association
Chromosome Band
15q26.1
Associated Disorders
EP, EPS, SCZ
Relevance to Autism

To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. Exploratory analyses examining specific sub-groups of the AGP discovery cohort and a smaller replication cohort from AGRE identified two SNPs within the ST8SIA2 gene with strong association signals for the verbal sub-group (Anney et al., 2010).

Molecular Function

The protein encoded by this gene is a type II membrane protein that is thought to catalyze the transfer of sialic acid from CMP-sialic acid to N-linked oligosaccharides and glycoproteins. The encoded protein may be found in the Golgi apparatus and may be involved in the production of polysialic acid, a modulator of the adhesive properties of neural cell adhesion molecule (NCAM1). This protein is a member of glycosyltransferase family 29.

Reports related to ST8SIA2 (9 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Association between polymorphisms in the promoter region of the sialyltransferase 8B (SIAT8B) gene and schizophrenia. Arai M , et al. (2005) No -
2 Support Positive association between SIAT8B and schizophrenia in the Chinese Han population. Tao R , et al. (2006) No -
3 Primary A genome-wide scan for common alleles affecting risk for autism. Anney R , et al. (2010) Yes -
4 Support Identification of sialyltransferase 8B as a generalized susceptibility gene for psychotic and mood disorders on chromosome 15q25-26. McAuley EZ , et al. (2012) No SCZ
5 Support Characterization of a 520 kb deletion on chromosome 15q26.1 including ST8SIA2 in a patient with behavioral disturbance, autism spectrum disorder, a... Kamien B , et al. (2013) Yes Epilepsy
6 Support Effects of intronic single nucleotide polymorphisms (iSNPs) of a polysialyltransferase, ST8SIA2 gene found in psychiatric disorders on its gene pro... Hane M , et al. (2016) No -
7 Support Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior. Doan RN , et al. (2016) Yes -
8 Recent Recommendation Differential effect of disease-associated ST8SIA2 haplotype on cerebral white matter diffusion properties in schizophrenia and healthy controls. Fullerton JM , et al. (2018) No -
9 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks. Ruzzo EK , et al. (2019) Yes -
Rare Variants   (5)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
A>G - intergenic_variant - - Unknown 27667684 Doan RN , et al. (2016)
T>C - intergenic_variant - - Unknown 27667684 Doan RN , et al. (2016)
delT - intergenic_variant - - Unknown 27667684 Doan RN , et al. (2016)
c.99-1G>T - splice_site_variant Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
- - copy_number_loss Unknown Not maternal Multi-generational 24357335 Kamien B , et al. (2013)
Common Variants   (6)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
- G/A upstream_gene_variant - - - 22693595 McAuley EZ , et al. (2012)
c.161+1988A>C;c.99-2148A>C C/A intron_variant - - - 22693595 McAuley EZ , et al. (2012)
c.99-6453T>G;c.99-10651T>G C/A intron_variant - - - 22693595 McAuley EZ , et al. (2012)
c.548+1882A>G;c.485+1882A>G G/A intron_variant - - - 22693595 McAuley EZ , et al. (2012)
c.549-738A>G;c.486-738A>G Minor allele G intron_variant - - - 20663923 Anney R , et al. (2010)
c.842+1488C>T;c.779+1488C>T Minor allele A intron_variant - - - 20663923 Anney R , et al. (2010)
SFARI Gene score
2

Strong Candidate

To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. Exploratory analyses examining specific sub-groups of the AGP discovery cohort and a smaller replication cohort from AGRE identified two SNPs within the ST8SIA2 gene with strong association signals for the verbal sub-group (Anney et al., 2010). ST8SIA2 has also been shown to associate with schizophrenia and bipolar disorder (Arai et al., 2006; Tao et al., 2007; McAuley et al., 2012). SNPs that associated with bipolar disorder and autism were found to affect the expression of pre-mRNA and mRNA of ST8SIA2, as well as alter the cellular levels of ST8SIA2 and polySia (Hane et al., 2016), whereas specific ST8SIA2 haplotypes have been demonstrated to have differential effects on cerebral white matter diffusion properties in schizophrenia cases and healthy controls (Fullerton et al., 2018). A 520 kb deletion at 15q26.1 encompassing ST8SIA2 and two other genes was detected in a male patient with autism spectrum disorder, epilepsy, and severe behavioral disturbances; this patient was part of a pedigree containing multiple affected individuals, although segregation of the 15q26.1 deletion with disease could not be determined (Kamien et al., 2014).

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.

10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. Exploratory analyses examining specific sub-groups of the AGP discovery cohort and a smaller replication cohort from AGRE identified two SNPs within the ST8SIA2 gene with strong association signals for the verbal sub-group (Anney et al., 2010). ST8SIA2 has also been shown to associate with schizophrenia and bipolar disorder (Arai et al., 2006; Tao et al., 2007; McAuley et al., 2012). SNPs that associated with bipolar disorder and autism were found to affect the expression of pre-mRNA and mRNA of ST8SIA2, as well as alter the cellular levels of ST8SIA2 and polySia (Hane et al., 2016), whereas specific ST8SIA2 haplotypes have been demonstrated to have differential effects on cerebral white matter diffusion properties in schizophrenia cases and healthy controls (Fullerton et al., 2018). A 520 kb deletion at 15q26.1 encompassing ST8SIA2 and two other genes was detected in a male patient with autism spectrum disorder, epilepsy, and severe behavioral disturbances; this patient was part of a pedigree containing multiple affected individuals, although segregation of the 15q26.1 deletion with disease could not be determined (Kamien et al., 2014).

Reports Added
[New Scoring Scheme]
7/1/2019
3
icon
3

Decreased from 3 to 3

Description

To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. Exploratory analyses examining specific sub-groups of the AGP discovery cohort and a smaller replication cohort from AGRE identified two SNPs within the ST8SIA2 gene with strong association signals for the verbal sub-group (Anney et al., 2010). ST8SIA2 has also been shown to associate with schizophrenia and bipolar disorder (Arai et al., 2006; Tao et al., 2007; McAuley et al., 2012). SNPs that associated with bipolar disorder and autism were found to affect the expression of pre-mRNA and mRNA of ST8SIA2, as well as alter the cellular levels of ST8SIA2 and polySia (Hane et al., 2016), whereas specific ST8SIA2 haplotypes have been demonstrated to have differential effects on cerebral white matter diffusion properties in schizophrenia cases and healthy controls (Fullerton et al., 2018). A 520 kb deletion at 15q26.1 encompassing ST8SIA2 and two other genes was detected in a male patient with autism spectrum disorder, epilepsy, and severe behavioral disturbances; this patient was part of a pedigree containing multiple affected individuals, although segregation of the 15q26.1 deletion with disease could not be determined (Kamien et al., 2014).

7/1/2018
icon
3

Increased from to 3

Description

To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. Exploratory analyses examining specific sub-groups of the AGP discovery cohort and a smaller replication cohort from AGRE identified two SNPs within the ST8SIA2 gene with strong association signals for the verbal sub-group (Anney et al., 2010). ST8SIA2 has also been shown to associate with schizophrenia and bipolar disorder (Arai et al., 2006; Tao et al., 2007; McAuley et al., 2012). SNPs that associated with bipolar disorder and autism were found to affect the expression of pre-mRNA and mRNA of ST8SIA2, as well as alter the cellular levels of ST8SIA2 and polySia (Hane et al., 2016), whereas specific ST8SIA2 haplotypes have been demonstrated to have differential effects on cerebral white matter diffusion properties in schizophrenia cases and healthy controls (Fullerton et al., 2018). A 520 kb deletion at 15q26.1 encompassing ST8SIA2 and two other genes was detected in a male patient with autism spectrum disorder, epilepsy, and severe behavioral disturbances; this patient was part of a pedigree containing multiple affected individuals, although segregation of the 15q26.1 deletion with disease could not be determined (Kamien et al., 2014).

Krishnan Probability Score

Score 0.56834751430252

Ranking 1119/25841 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 0.51275689440507

Ranking 5388/18225 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 0.92553783247211

Ranking 10231/18665 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 6

Ranking 271/461 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 0.043607537793319

Ranking 7410/20870 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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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.
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