SYN1Synapsin 1
Autism Reports / Total Reports
7 / 28Rare Variants / Common Variants
38 / 0Chromosome Band
Xp11.3-p11.23Associated Disorders
IDGenetic Category
Rare Single Gene Mutation, FunctionalRelevance 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.
External Links
SFARI Genomic Platforms
Reports related to SYN1 (28 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 | Support | - | Zhou X et al. (2022) | Yes | - |
| 23 | Recent Recommendation | - | Parenti I et al. (2022) | No | ASD, ADHD |
| 24 | Support | - | Bnger I et al. (2023) | No | Behavioral problems |
| 25 | Support | - | Miyake N et al. (2023) | Yes | - |
| 26 | Support | - | Karthika Ajit Valaparambil et al. () | No | - |
| 27 | 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 | - |
| 28 | Highly Cited | Synapsin I in nerve terminals: selective association with small synaptic vesicles | Navone F , et al. (1984) | No | - |
Rare Variants (38)
| 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.586G>T | p.Gly196Ter | stop_gained | De novo | - | Simplex | 36973392 | Miyake N et al. (2023) | |
| c.505C>T | p.Arg169Trp | missense_variant | De novo | - | Simplex | 35982159 | Zhou X et al. (2022) | |
| c.954G>T | p.Lys318Asn | missense_variant | De novo | - | Simplex | 36568968 | Parenti I et al. (2022) | |
| c.986C>T | p.Thr329Met | missense_variant | De novo | - | Simplex | 36568968 | Parenti I et al. (2022) | |
| 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.745C>T | p.Gln249Ter | stop_gained | Familial | Maternal | Simplex | 36568968 | Parenti I et al. (2022) | |
| c.980+43_981del | - | frameshift_variant | Familial | Paternal | Simplex | 36568968 | Parenti I et al. (2022) | |
| c.1447C>T | p.Gln483Ter | stop_gained | Familial | Maternal | Multiplex | 36568968 | Parenti I et al. (2022) | |
| c.1790C>T | p.Pro597Leu | missense_variant | Unknown | - | - | 37943464 | Karthika Ajit Valaparambil et al. () | |
| c.1076C>A | p.Thr359Lys | missense_variant | Familial | Maternal | Simplex | 34243774 | Xiong J et al. (2021) | |
| c.340A>G | p.Arg114Gly | missense_variant | Familial | Maternal | Simplex | 36568968 | Parenti I et al. (2022) | |
| c.614T>A | p.Leu205Gln | missense_variant | Familial | Maternal | Simplex | 36568968 | Parenti I et al. (2022) | |
| c.774G>T | p.Met258Ile | missense_variant | Familial | Maternal | Simplex | 36568968 | Parenti I et al. (2022) | |
| c.1072G>A | p.Asp358Asn | missense_variant | Familial | Maternal | Simplex | 36568968 | Parenti I et al. (2022) | |
| c.1729del | p.Ala577ProfsTer90 | frameshift_variant | Familial | Maternal | - | 36568968 | Parenti I et al. (2022) | |
| c.1121C>T | p.Ala374Val | missense_variant | Familial | Maternal | Multiplex | 36568968 | Parenti I et al. (2022) | |
| c.1259G>A | p.Arg420Gln | missense_variant | Familial | Maternal | Multiplex | 31969655 | Darvish H , et al. (2020) | |
| c.528-2A>T | - | splice_site_variant | Familial | Maternal | Extended multiplex | 36568968 | Parenti I et al. (2022) | |
| c.796G>A | p.Val266Met | missense_variant | Familial | Maternal | Multiplex | 31906484 | Ibarluzea N , et al. (2020) | |
| c.39del | p.Phe13LeufsTer10 | frameshift_variant | Familial | Maternal | Simplex | 36568968 | Parenti I et al. (2022) | |
| c.1663C>T | p.Gln555Ter | stop_gained | Familial | Maternal | Multi-generational | 21441247 | Fassio A , et al. (2011) | |
| c.1264C>T | p.Arg422Ter | stop_gained | Familial | Maternal | Extended multiplex | 36568968 | Parenti I et al. (2022) | |
| c.614_615insTGC | p.Leu205_Gln206insAla | inframe_insertion | De novo | - | Simplex | 36568968 | Parenti I et al. (2022) | |
| c.975del | p.Tyr326ThrfsTer2 | frameshift_variant | Familial | Maternal | Multiplex | 36568968 | Parenti I et al. (2022) | |
| c.1321dup | p.Ala441GlyfsTer243 | frameshift_variant | Familial | Maternal | Simplex | 36568968 | Parenti I et al. (2022) | |
| c.1258dup | p.Arg420ProfsTer264 | frameshift_variant | Familial | Maternal | Unknown | 36568968 | Parenti I et al. (2022) | |
| c.2del | p.Met1? | initiator_codon_variant | Familial | Maternal | Extended multiplex | 36568968 | Parenti I et al. (2022) | |
| c.236C>G | p.Ser79Trp | missense_variant | Familial | Maternal | Multi-generational | 28973667 | Guarnieri FC , et al. (2017) | |
| c.1794_1906del | p.Thr601GlufsTer45 | frameshift_variant | Familial | Maternal | Simplex | 36568968 | Parenti I et al. (2022) | |
| c.1001del | p.Asn334ThrfsTer74 | frameshift_variant | Familial | Maternal | Extended multiplex | 36568968 | Parenti I et al. (2022) | |
| c.1439dup | p.Leu481IlefsTer203 | frameshift_variant | Familial | Maternal | Extended multiplex | 36568968 | Parenti I et al. (2022) | |
| 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
Score Delta: Score remained at 1
criteria met
See SFARI Gene'scoring criteriaWe 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
3
1
Decreased from 3 to 1
1/1/2021
3
3
Decreased from 3 to 3
Description
Rare variants in the SYN1 gene have been identified with autism (PMID 21441247).
1/1/2020
3
3
Decreased from 3 to 3
Description
Rare variants in the SYN1 gene have been identified with autism (PMID 21441247).
10/1/2019
4
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
4
Decreased from 4 to 4
Description
Rare variants in the SYN1 gene have been identified with autism (PMID 21441247).
10/1/2017
4
4
Decreased from 4 to 4
Description
Rare variants in the SYN1 gene have been identified with autism (PMID 21441247).
7/1/2015
4
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
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
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.