Human Gene Module / Chromosome X / SYN1

SYN1Synapsin 1

Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
5 / 22
Rare Variants / Common Variants
11 / 0
Aliases
SYN1, SYNI,  SYN1a,  SYN1b,  SYN1
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Functional
Chromosome Band
Xp11.3-p11.23
Associated Disorders
ID
Relevance to Autism

Rare variants in the SYN1 gene have been identified with autism (Fassio et al., 2011).

Molecular Function

Synapsin 1 is a peripheral membrane protein on synaptic vesicles that mediates vesicle binding to the cytoskeleton.

Reports related to SYN1 (22 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Synapsins as mediators of BDNF-enhanced neurotransmitter release Jovanovic JN , et al. (2000) No -
2 Highly Cited Exogenous synapsin I promotes functional maturation of developing neuromuscular synapses Lu B , et al. (1992) No -
3 Recent Recommendation Cortico-hippocampal hyperexcitability in synapsin I/II/III knockout mice: age-dependency and response to the antiepileptic drug levetiracetam Boido D , et al. (2010) No -
4 Recent Recommendation Nucleocytoplasmic shuttling of dysbindin-1, a schizophrenia-related protein, regulates synapsin I expression Fei E , et al. (2010) No -
5 Primary SYN1 loss-of-function mutations in autism and partial epilepsy cause impaired synaptic function Fassio A , et al. (2011) Yes epilepsy
6 Recent Recommendation Synapsin I is an oligomannose-carrying glycoprotein, acts as an oligomannose-binding lectin, and promotes neurite outgrowth and neuronal survival when released via glia-derived exosomes Wang S , et al. (2011) No -
7 Support Analysis of the chromosome X exome in patients with autism spectrum disorders identified novel candidate genes, including TMLHE Nava C , et al. (2012) Yes ID
8 Recent Recommendation Specificity protein 1 (Sp1)-dependent activation of the synapsin I gene (SYN1) is modulated by RE1-silencing transcription factor (REST) and 5'-cytosine-phosphoguanine (CpG) methylation Paonessa F , et al. (2012) No -
9 Recent Recommendation Autism-related behavioral abnormalities in synapsin knockout mice Greco B , et al. (2013) Yes -
10 Recent Recommendation Epileptogenic Q555X SYN1 mutant triggers imbalances in release dynamics and short-term plasticity Lignani G , et al. (2013) No -
11 Support Exome sequencing of extended families with autism reveals genes shared across neurodevelopmental and neuropsychiatric disorders Cukier HN , et al. (2014) Yes -
12 Recent Recommendation X-linked focal epilepsy with reflex bathing seizures: Characterization of a distinct epileptic syndrome Nguyen DK , et al. (2015) Yes -
13 Recent Recommendation SUMOylation of synapsin Ia maintains synaptic vesicle availability and is reduced in an autism mutation Tang LT , et al. (2015) No -
14 Support A novel SYN1 missense mutation in non-syndromic X-linked intellectual disability affects synaptic vesicle life cycle, clustering and mobility Guarnieri FC , et al. (2017) No -
15 Recent Recommendation Effects of SYN1 Q555X mutation on cortical gray matter microstructure Cabana JF , et al. (2018) No -
16 Highly Cited Synapsin I bundles F-actin in a phosphorylation-dependent manner Bhler M and Greengard P (1987) No -
17 Support Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population Monies D , et al. (2019) No -
18 Support Targeted Next-Generation Sequencing in Patients with Suggestive X-Linked Intellectual Disability Ibarluzea N , et al. (2020) No -
19 Support Phenotypic and genotypic characterization of families with complex intellectual disability identified pathogenic genetic variations in known and novel disease genes Darvish H , et al. (2020) No -
20 Support - Mojarad BA et al. (2021) No ID
21 Highly Cited Synapsin I (protein I), a nerve terminal-specific phosphoprotein. III. Its association with synaptic vesicles studied in a highly purified synaptic vesicle preparation Huttner WB , et al. (1983) No -
22 Highly Cited Synapsin I in nerve terminals: selective association with small synaptic vesicles Navone F , et al. (1984) No -
Rare Variants   (11)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.152C>G p.Ala51Gly missense_variant - - - 21441247 Fassio A , et al. (2011)
c.1648G>A p.Ala550Thr missense_variant - - - 21441247 Fassio A , et al. (2011)
c.1699A>C p.Thr567Pro missense_variant - - - 21441247 Fassio A , et al. (2011)
c.435+27G>C - intron_variant Unknown - Multiplex 23092983 Nava C , et al. (2012)
c.1648G>A p.Ala550Thr missense_variant Unknown - Unknown 33526774 Mojarad BA et al. (2021)
c.1259G>A p.Arg420Gln missense_variant Familial Maternal Multiplex 31969655 Darvish H , et al. (2020)
c.796G>A p.Val266Met missense_variant Familial Maternal Multiplex 31906484 Ibarluzea N , et al. (2020)
c.1663C>T p.Gln555Ter stop_gained Familial Maternal Multi-generational 21441247 Fassio A , et al. (2011)
c.236C>G p.Ser79Trp missense_variant Familial Maternal Multi-generational 28973667 Guarnieri FC , et al. (2017)
c.430G>A p.Glu144Lys missense_variant Familial - Extended multiplex (at least one pair of ASD affec 24410847 Cukier HN , et al. (2014)
c.1086_1087del p.Glu362AspfsTer24 frameshift_variant Familial Maternal Multiplex or multi-generational 31130284 Monies D , et al. (2019)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

Rare variants in the SYN1 gene have been identified with autism (PMID 21441247).

Score Delta: Score remained at 4

1

High Confidence

See all Category 1 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.

1/1/2021
4
icon
4

Score remained at 4

Description

Rare variants in the SYN1 gene have been identified with autism (PMID 21441247).

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Rare variants in the SYN1 gene have been identified with autism (PMID 21441247).

Reports Added
[New Scoring Scheme]
7/1/2019
4
icon
4

Decreased from 4 to 4

Description

Rare variants in the SYN1 gene have been identified with autism (PMID 21441247).

4/1/2018
4
icon
4.4

Decreased from 4 to 4.4

Description

4

10/1/2017
4
icon
4

Decreased from 4 to 4

Description

Rare variants in the SYN1 gene have been identified with autism (PMID 21441247).

7/1/2015
4
icon
4

Decreased from 4 to 4

Description

Rare variants in the SYN1 gene have been identified with autism (PMID 21441247).

Reports Added
[SYN1 loss-of-function mutations in autism and partial epilepsy cause impaired synaptic function.2011] [Analysis of the chromosome X exome in patients with autism spectrum disorders identified novel candidate genes, including TMLHE.2012] [Autism-related behavioral abnormalities in synapsin knockout mice.2013] [Exome sequencing of extended families with autism reveals genes shared across neurodevelopmental and neuropsychiatric disorders.2014] [Exogenous synapsin I promotes functional maturation of developing neuromuscular synapses.1992] [Synapsin I bundles F-actin in a phosphorylation-dependent manner.1987] [Synapsin I (protein I), a nerve terminal-specific phosphoprotein. III. Its association with synaptic vesicles studied in a highly purified synaptic...1983] [Synapsin I in nerve terminals: selective association with small synaptic vesicles.1984] [Synapsins as mediators of BDNF-enhanced neurotransmitter release.2000] [Cortico-hippocampal hyperexcitability in synapsin I/II/III knockout mice: age-dependency and response to the antiepileptic drug levetiracetam.2010] [Nucleocytoplasmic shuttling of dysbindin-1, a schizophrenia-related protein, regulates synapsin I expression.2010] [Synapsin I is an oligomannose-carrying glycoprotein, acts as an oligomannose-binding lectin, and promotes neurite outgrowth and neuronal survival w...2011] [Specificity protein 1 (Sp1)-dependent activation of the synapsin I gene (SYN1) is modulated by RE1-silencing transcription factor (REST) and 5'-cyt...2012] [Epileptogenic Q555X SYN1 mutant triggers imbalances in release dynamics and short-term plasticity.2013] [X-linked focal epilepsy with reflex bathing seizures: Characterization of a distinct epileptic syndrome.2015] [SUMOylation of synapsin Ia maintains synaptic vesicle availability and is reduced in an autism mutation.2015]
7/1/2014
No data
icon
4

Increased from No data to 4

Description

Rare variants in the SYN1 gene have been identified with autism (PMID 21441247).

4/1/2014
No data
icon
4

Increased from No data to 4

Description

Rare variants in the SYN1 gene have been identified with autism (PMID 21441247).

Krishnan Probability Score

Score 0.57357879943415

Ranking 684/25841 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 0.87952975333251

Ranking 3385/18225 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 0.93208906824304

Ranking 11881/18665 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 16

Ranking 124/461 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 0.42212494341879

Ranking 1208/20870 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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