ClinGen Dosage Sensitivity Curation Page

SYN1

  • Curation Status: Complete

Location Information

  • Xp11.3-p11.23
  • GRCh37/hg19 chrX: 47,431,300-47,479,256
  • View: NCBI | Ensembl | UCSC
  • GRCh38/hg38 chrX: 47,571,901-47,619,857
  • View: NCBI | Ensembl | UCSC
Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
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.
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.

Haploinsufficiency phenotype 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 emerging evidence that loss of function sequence variants in SYN1 can cause epilepsy with or without additional features such as learning disability, macrocephaly, or autism. However, entire or partial deletions of this gene have not yet 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.

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 score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

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).

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.