Human Gene Module / Chromosome 12 / SYT1

SYT1synaptotagmin 1

SFARI Gene Score
S
Syndromic Syndromic
Autism Reports / Total Reports
2 / 12
Rare Variants / Common Variants
28 / 0
Aliases
SYT1, P65,  SVP65,  SYT
Associated Syndromes
Baker-Gordon syndrome, Baker-Gordon syndrome, DD, epilepsy/seizures, Baker-Gordon syndrome, DD, ID
Chromosome Band
12q21.2
Associated Disorders
-
Relevance to Autism

A de novo missense variant in the SYT1 gene that was predicted to be damaging was detected in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014). Baker et al., 2018 described 11 individuals with de novo SYT1 missense variants that presented with a neurodevelopmental disorder characterized by infantile hypotonia, congenital ophthalmic abnormalities, childhood-onset hyperkinetic movements disorder, motor stereotypies, and developmental delay; impaired social development was also a common feature, with six of these individuals reportedly showing poor or no eye contact, limited interest in social interactions, and an absence of normal imitative behaviors.

Molecular Function

The synaptotagmins are integral membrane proteins of synaptic vesicles thought to serve as Ca(2+) sensors in the process of vesicular trafficking and exocytosis. Calcium binding to synaptotagmin-1 participates in triggering neurotransmitter release at the synapse.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to SYT1 (12 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
2 Recent Recommendation SYT1-associated neurodevelopmental disorder: a case series Baker K , et al. (2018) No Impaired social development, motor stereotypies
3 Support Molecular Basis for Synaptotagmin-1-Associated Neurodevelopmental Disorder Bradberry MM et al. (2020) No -
4 Support - Pode-Shakked B et al. (2021) No -
5 Support - Melland H et al. (2022) No ASD, epilepsy/seizures
6 Support - Brea-Fernández AJ et al. (2022) No -
7 Support - Leite AJDC et al. (2022) No -
8 Support - Zhou X et al. (2022) Yes -
9 Support - Carlo Alberto Cesaroni et al. (2023) No Autistic features, stereotypy
10 Support - Milena Barbosa Porto et al. (2024) No -
11 Support - Maaike A van Boven et al. () No Autistic features
12 Support - Paul Yangho Park et al. (2024) No ASD or autistic features, DD
Rare Variants   (28)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.10G>A p.Glu4Lys missense_variant De novo - - 35982159 Zhou X et al. (2022)
- p.Asp366Glu missense_variant De novo - - 32362337 Bradberry MM et al. (2020)
c.844C>T p.Arg282Cys missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1094A>G p.Tyr365Cys missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.908T>A p.Met303Lys missense_variant De novo - - 30107533 Baker K , et al. (2018)
c.911A>G p.Asp304Gly missense_variant De novo - - 30107533 Baker K , et al. (2018)
c.1098C>A p.Asp366Glu missense_variant De novo - - 30107533 Baker K , et al. (2018)
c.1103T>C p.Ile368Thr missense_variant De novo - - 30107533 Baker K , et al. (2018)
c.1113C>G p.Asn371Lys missense_variant De novo - - 30107533 Baker K , et al. (2018)
c.476T>G p.Leu159Arg missense_variant De novo - - 35101335 Melland H et al. (2022)
c.587C>A p.Thr196Lys missense_variant De novo - - 35101335 Melland H et al. (2022)
c.625G>A p.Glu209Lys missense_variant De novo - - 35101335 Melland H et al. (2022)
c.655G>C p.Glu219Gln missense_variant De novo - - 35101335 Melland H et al. (2022)
c.907A>G p.Met303Val missense_variant De novo - - 35101335 Melland H et al. (2022)
c.925T>C p.Ser309Pro missense_variant De novo - - 35101335 Melland H et al. (2022)
c.1022A>G p.Asn341Ser missense_variant De novo - - 35101335 Melland H et al. (2022)
c.1094A>G p.Tyr365Cys missense_variant De novo - - 35101335 Melland H et al. (2022)
c.1103T>C p.Ile368Thr missense_variant De novo - - 35101335 Melland H et al. (2022)
c.1106G>A p.Gly369Asp missense_variant De novo - - 35101335 Melland H et al. (2022)
c.1103T>C p.Ile368Thr missense_variant De novo - - 35390071 Leite AJDC et al. (2022)
c.587C>G p.Thr196Arg missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.911A>G p.Asp304Gly missense_variant De novo - - 32362337 Bradberry MM et al. (2020)
c.1100_1102dup p.Lys367dup inframe_insertion De novo - - 35101335 Melland H et al. (2022)
c.1198C>T p.Arg400Ter stop_gained De novo - Simplex 34580403 Pode-Shakked B et al. (2021)
c.928G>C p.Asp310His missense_variant De novo - - 35322241 Brea-Fernández AJ et al. (2022)
c.1202C>T p.Pro401Leu missense_variant De novo - Simplex 38321119 Maaike A van Boven et al. ()
c.1103T>C p.Ile368Thr missense_variant De novo - Simplex 38283597 Milena Barbosa Porto et al. (2024)
c.1101_1103dup p.Lys367_Ile368insMet inframe_insertion De novo - - 38058756 Carlo Alberto Cesaroni et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
S

Syndromic

A de novo missense variant in the SYT1 gene that was predicted to be damaging was detected in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014). Baker et al., 2018 described 11 individuals with de novo SYT1 missense variants that presented with a neurodevelopmental disorder characterized by infantile hypotonia, congenital ophthalmic abnormalities, childhood-onset hyperkinetic movements disorder, motor stereotypies, and developmental delay; impaired social development was also a common feature, with six of these individuals reportedly showing poor or no eye contact, limited interest in social interactions, and an absence of normal imitative behaviors.

Score Delta: Score remained at S

criteria met
See SFARI Gene'scoring criteria
S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

4/1/2020
S
icon
S

Score remained at S

Description

A de novo missense variant in the SYT1 gene that was predicted to be damaging was detected in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014). Baker et al., 2018 described 11 individuals with de novo SYT1 missense variants that presented with a neurodevelopmental disorder characterized by infantile hypotonia, congenital ophthalmic abnormalities, childhood-onset hyperkinetic movements disorder, motor stereotypies, and developmental delay; impaired social development was also a common feature, with six of these individuals reportedly showing poor or no eye contact, limited interest in social interactions, and an absence of normal imitative behaviors.

Reports Added
[Molecular Basis for Synaptotagmin-1-Associated Neurodevelopmental Disorder2020]
10/1/2019
S
icon
S

Score remained at S

New Scoring Scheme
Description

A de novo missense variant in the SYT1 gene that was predicted to be damaging was detected in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014). Baker et al., 2018 described 11 individuals with de novo SYT1 missense variants that presented with a neurodevelopmental disorder characterized by infantile hypotonia, congenital ophthalmic abnormalities, childhood-onset hyperkinetic movements disorder, motor stereotypies, and developmental delay; impaired social development was also a common feature, with six of these individuals reportedly showing poor or no eye contact, limited interest in social interactions, and an absence of normal imitative behaviors.

Reports Added
[New Scoring Scheme]
Krishnan Probability Score

Score 0.76710780335399

Ranking 5/25841 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.
Original Source
ExAC Score

Score 0.83718035458995

Ranking 3706/18225 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
Original Source
Sanders TADA Score

Score 0.54218167880071

Ranking 545/18665 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).
Original Source
Zhang D Score

Score 0.17393467022902

Ranking 4735/20870 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.
Original Source
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