• 3
    Haplo
    Score
  • 0
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
SYN1 (HGNC:11494) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
synapsin I
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
MRX50
Alias symbols
No aliases found
%HI
9.89(Read more about the DECIPHER Haploinsufficiency Index)
pLI
0.99(Read more about gnomAD pLI score)
LOEUF
0.25(Read more about gnomAD LOEUF score)
Cytoband
Xp11.3-p11.23
Genomic Coordinates
GRCh37/hg19: chrX:47431300-47479256 NCBI Ensembl UCSC
GRCh38/hg38: chrX:47571901-47619857 NCBI Ensembl UCSC
MANE Select Transcript
NM_006950.3 ENST00000295987.13 (Read more about MANE Select)
Function
Neuronal phosphoprotein that coats synaptic vesicles, and binds to the cytoskeleton. Acts as a regulator of synaptic vesicles trafficking, involved in the control of neurotransmitter release at the pre-synaptic terminal (PubMed:21441247, PubMed:23406870). Also involved in the regulation of axon outgrowth and synaptogenesis (By similarity). The complex formed with NOS1 and CAPON proteins is necessary for specific nitric-oxid functions at a presynaptic level (By similarity). {ECO:0000250|UniProtKB... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-32275
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
Sufficient Evidence for Haploinsufficiency (3)
Triplosensitivity:
No Evidence for Triplosensitivity (0)
Last Evaluated:
07/12/2022

Haploinsufficiency (HI) Score Details

HI Score:
3
HI Evidence Strength:
Sufficient Evidence for Haploinsufficiency (Disclaimer)
HI Disease:
  • X-linked complex neurodevelopmental disorder Monarch
HI Evidence:
  • PUBMED: 14985377
    Garcia et al. (2004) reported a four generation family with multiple males. Some males had epilepsy and normal intelligence and others have various combinations of epilepsy, learning difficulties, macrocephaly, and aggressive behavior. One patient had a diagnosis of autism. All affected males and female carriers were found to have a nonsense variant; however, it was not present in 287 control chromosomes.
  • PUBMED: 21441247
    Fassio et al. (2011) described a nonsense variant in all affected individuals from a large four generation French-Canadian family segregating partial epilepsy with variable learning disabilities and behavioral disorders. Two patients also had autism. Additionally, three missense variants were found in 1.0 and 3.5% of French-Canadian individuals with autism and epilepsy, respectively. Three out of four variants were clustered in the SynI D-domain which is target of multiple molecular interactions and signal transduction pathways, and were associated with functional defects in nerve terminal function. The nonsense variant was found to impair binding and phosphorylation capacity and disrupt normal trafficking of synaptic vesicles in neurons. The missense variants did not result in impaired binding or phosphorylation but did cause impaired synaptic vesicle trafficking. The authors showed that Syn KO mice exhibited various impairments in cognitive and social behavior compatible with an autism spectrum phenotype in human.
  • PUBMED: 34243774
    Xiong et al. 2021 reported 2 probands, one with missense and the other with a nonsense variant in the SYN1 gene that was identified by Trio-WES. The first proband was a 6-year-old male patient presenting with a profound global developmental delay, two febrile convulsions and bilateral esotropia. He had no history of behavioural abnormalities. The variant was detected in the patient in a hemizygous state and in his mother, grandmother and great grandmother in a heterozygous state but was absent from his unaffected brother. The second proband was an 8.5-year-old boy presenting with intellectual disability, epilepsy, abnormal social behaviour and ametropia. The variant was identified in his mother in a heterozygous state and absent from his father.
  • PUBMED: 34078716
    Accogli et al. 2021 reported 12 patients from 10 unrelated families with different nonsense (6 variants) and missense variants (4 variants) in the SYN1 gene. They presented with bathing epilepsy, varying degrees of intellectual disability (2 had normal intelligence), ASD and ADHD. Two of the affected patients were females and the rest were males and this was attributed to the skewed X-inactivation. The affected females also had intellectual disabilities and unprovoked seizures. The mothers were carriers in all 10 families.
  • PUBMED: 30390306
    Peron el al. 2018 (PMID: 30390306) reported a splice site variant in a male patient with a reflex seizure induced by contact with water and normal but below-average intelligence (IQ 80) and learning disability. A maternal uncle with the same variant had the same type of seizure and mild intellectual disability. The mother and the grandmother were carriers.
HI Evidence Comments:
Synapsin 1 (SYN1) is an X-linked gene encoding for a neuron-specific phosphoprotein implicated in the regulation of neurotransmitter release and synaptogenesis. There is evidence that loss of function sequence variants in SYN1 can cause a complex neurodevelopmental phenotype including epilepsy, learning disability, macrocephaly, and/or autism. To date, no entire or partial deletions of this gene have been reported in the literature. Additional publications: Guarnieri et al (2017) (PMID: 28973667): A missense variant in the B domain region of SYN1 in a family with multiple affected males with non-syndromic X-linked intellectual disability. Expression of the human Synapsin I missense variant (S79W) in Syn1 knockout hippocampal neurons caused aberrant accumulation of small clear vesicles in the soma, increased clustering of synaptic vesicles at presynaptic terminals and increased frequency of excitatory spontaneous release events. In addition, the presence of this variant strongly reduced the mobility of synaptic vesicles, with possible implications for the regulation of neurotransmitter release and synaptic plasticity. The authors suggested that alterations of synaptic vesicle trafficking were one possible cause of this disease, and distinct variants in SYN1 may lead to distinct brain pathologies. Rossi et al (2017) (PMID 28330790 ): A missense variant in SYN1 in a male patient with autism spectrum disorder using exome sequencing.
NOTE:

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

Triplosensitivity (TS) Score Details

TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)
TS Evidence Comments:
There have been no reports of focal duplications of SYN1. El-Hattab et al. (2011) report a male patient with developmental disabilities who had a 1.3 Mb duplication that contained more than 30 genes, including SYN1. The patient was adopted so parental studies were unavailable. Quantitative PCR failed to detect SYN1 expression in blood, possibly due to normal expression differences between tissues (PMID: 20662849).
NOTE:

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

Genomic View

Select assembly: (NC_000023.10) (NC_000023.11)