Human Gene Module / Chromosome X / SYN1

SYN1Synapsin 1

SFARI Gene Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
5 / 23
Rare Variants / Common Variants
13 / 0
EAGLE Score
2.35
Limited Learn More
Aliases
SYN1, SYNI,  SYN1a,  SYN1b,  SYN1
Associated Syndromes
-
Chromosome Band
Xp11.3-p11.23
Associated Disorders
ID
Genetic Category
Rare Single Gene Mutation, Functional
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.

SFARI Genomic Platforms
Reports related to SYN1 (23 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 Support - Xiong J et al. (2021) No -
22 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 -
23 Highly Cited Synapsin I in nerve terminals: selective association with small synaptic vesicles Navone F , et al. (1984) No -
Rare Variants   (13)
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.1444C>T p.Gln482Ter stop_gained Familial Maternal Simplex 34243774 Xiong J et al. (2021)
c.1076C>A p.Thr359Lys missense_variant Familial Maternal Simplex 34243774 Xiong J 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

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.

4/1/2022
1

Initial score established: 1

10/1/2021
3

Initial score established: 3

Description

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

7/1/2021
3

Initial score established: 3

Description

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

4/1/2021
3

Initial score established: 3

Description

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

1/1/2021
3

Initial score established: 3

Description

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

10/1/2020
3

Initial score established: 3

Description

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

7/1/2020
3

Initial score established: 3

Description

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

4/1/2020
3

Initial score established: 3

Description

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

10/1/2019
3

Initial score established: 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
3

Initial score established: 3

Description

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

4/1/2019
3

Initial score established: 3

Description

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

1/1/2019
3

Initial score established: 3

Description

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

10/1/2018
3

Initial score established: 3

Description

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

7/1/2018
4

Initial score established: 4

Description

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

4/1/2018
4.4

Initial score established: 4.4

Description

4

1/1/2018
4

Initial score established: 4

Description

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

10/1/2017
3

Initial score established: 3

Description

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

7/1/2017
4

Initial score established: 4

Description

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

4/1/2017
4

Initial score established: 4

Description

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

1/1/2017
4

Initial score established: 4

Description

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

10/1/2016
3

Initial score established: 3

Description

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

7/1/2016
4

Initial score established: 4

Description

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

4/1/2016
4

Initial score established: 4

Description

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

1/1/2016
4

Initial score established: 4

Description

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

10/1/2015
3

Initial score established: 3

Description

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

7/1/2015
4

Initial score established: 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]
4/1/2015
4

Initial score established: 4

Description

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

1/1/2015
4

Initial score established: 4

Description

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

10/1/2014
3

Initial score established: 3

Description

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

7/1/2014
4

Initial score established: 4

Description

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

4/1/2014
4

Initial score established: 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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