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Genetic epilepsy syndromes

Gene: SNAP25

Green List (high evidence)

SNAP25 (synaptosome associated protein 25)
EnsemblGeneIds (GRCh38): ENSG00000132639
EnsemblGeneIds (GRCh37): ENSG00000132639
OMIM: 600322, Gene2Phenotype
SNAP25 is in 8 panels

4 reviews

Rebecca Foulger (Genomics England curator)

I don't know

Kept rating as Green based on Green post-Webex review from Helen Lord.
Created: 9 Sep 2019, 10:45 a.m. | Last Modified: 9 Sep 2019, 10:45 a.m.
Panel Version: 1.321
Review and rating collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene was added to the Genetic epilepsy syndromes panel after the initial panel was reviewed by West Midlands, Oxford and Wessex GLH: this gene was therefore reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.
Created: 5 Sep 2019, 2:26 p.m. | Last Modified: 5 Sep 2019, 2:26 p.m.
Panel Version: 1.262

Helen Lord (Oxford Medical Genetics Laboratories)

Green List (high evidence)

AD CMS18. Shen et al, 2014 (25381298) - girl who presented at birth with stifness, respiratory insuffic and mutiple joint contractures. Staring spells and EEG abnormalities also seen. De novo het missense variant, I67N - functional work done - suggest dom neg effect. Hamdan et al, 2017 (29100083) - missense de novo variant. Patient has epilepsy. Rohena et al, 2013 (25003006) - patient with generalised epilepsy - de novo missense variant detected. Helbig et al, 2016 (26795593) - epilepsy patient with de novo missense variant - same change as that reported by Rohena et al.
Created: 5 Sep 2019, 2:22 p.m. | Last Modified: 5 Sep 2019, 2:22 p.m.
Panel Version: 1.261

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Catherine Snow (Genomics England)

Sufficient number of individuals, with de novo varients, identified within a number of studies for SNAP25 to be included on the Epilepsy panel. SNAP25 is in OMIM but based on just one paper from one individual (PubMed: 25381298). SNAP25 is in Gene2Phenotype as "Disease: Epilepsy and intellectual disability". Severe ID and seizures consistent phenotype in all identified cases therefore rating as Green
Created: 27 Jun 2019, 10:30 a.m. | Last Modified: 27 Jun 2019, 10:30 a.m.
Panel Version: 0.32

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Probably 9 individuals with heterozygous SNAP25 pathogenic variants have been reported to date, most summarized in the first reference (NM_130811.2 used as reference for all variants below):
- Fukuda et al. (2018 - PMID: 29491473) 2 sibs (~11 and 2.5 y.o) with seizures and cerebellar ataxia but not ID. harboring c.176G>C (p.Arg59Pro) variant which was inherited from a mosaic unaffected parent.
- DDD study (2017 - PMID: 28135719) [also in Heyne et al. 2018 - PMID: 29942082] 3 inividuals (11 m - 7 y of age) with DD and seizures due to c.118A>G (p.Lys40Glu), c.127G>C (p.Gly43Arg) and c.520C>T (p.Gln174*) de novo variants.
- Hamdan et al. (2017 - PMID: 29100083) a 23 y.o. male with epilepsy and ID and c.496G>T (p.Asp166Tyr) de novo variant
- Shen et al. (2014 - PMID: 25381298) a 11 y.o. female with epilepsy and ID and c.200T>A (p.Ile67Asn) de novo variant
- Rohena et al. (2013 - PMID: 25003006) a 15 y.o. female with epilepsy and ID and c.142G>T (p.Val48Phe) de novo variant
- Decipher patient 292139, a male with c.212T>C (p.Met71Thr) with hypotonia, DD, poor coordination and additional features (epilepsy not reported).

Seizures of variable type [absence seizures, generalized tonic-clonic (most), focal clonic, myoclonic, etc] have been reported for most (8/9) of these individuals. DD was a feature in several subjects and intellectual outcome has been specifically commented on for 5 (2 without and 3 with ID - moderate/severe/not further specified).

SNAP25 encodes a (t-)SNARE protein essential for synaptic vesicle exocytosis. Mutations in genes for other components of the SNARE complex (eg. STXBP1) have been associated with epilepsy and/or ID.

SNAP25a and SNAP25b are the 2 major protein isoforms [corresponding transcripts: ENST00000304886 (NM_003081) and ENST00000254976 (NM_130811) respectively]. These isoforms are produced by utilization of alternative exons 5 (5a or 5b) though the amino-acid sequence encoded by these exons appears to be identical except for 9 residues. Most variants reported to date affect both transcripts (and protein isoforms) although 2 were specific for ENST00000254976 (or SNAP25b isoform - Fukuda et al. and Shen et al.).

Mouse Snap25 has also 2 isoforms. Both are predominantly localized in embryonic and adult mouse brains. Snap25a is produced before Snap25b though the latter becomes the major isoform early postnatally (by the second week) [PMIDs cited: 7878010, 21526988].

Based on the phenotype of some individuals with chromosome 20 deletions in Decipher (note: only 3 deletions spanning SNAP25 however appear currently, the phenotype is not specified and 2 of them are >4.5Mb) or the pLI of 0.96 in gnomAD, haploinsufficiency has been proposed as a likely mechanism. A dominant-negative effect was however suggested for the Ile67Asn studied by Shen et al. Functional studies have not been performed for other variants.

Animal models discussed:
- Snap25 null drosophila show complete loss of synaptic transmission upon electroretinogram recordings (PMID cited: 12242238).
- In mice, elimination of Snap25b expression resulted in developmental defects, seizures and impaired short-term synaptic plasticity (PMID cited: 19043548).
- Mice with a 4.6 Mb deletion encompassing 12 genes (incl. Snap25) display seizure predisposition (PMID cited: 23064108).
- Heterozygosity for Ile67Thr in (blind-drunk mutant) mice results in impaired vesicle trafficking, impaired sensorimotor gating and ataxia (PMID cited:17283335).

In OMIM, heterozygous SNAP25 mutations are associated with ?Myasthenic syndrome, congenital, 18 (with intellectual disability and ataxia). SNAP25 is part of the DD panel, associated with "Epilepsy and intellectual disability" (disease confidence: probable).

This gene is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc).

As a result SNAP25 can be considered for inclusion in the epilepsy and ID panels as green (or amber).
Sources: Literature
Created: 20 Apr 2019, 9:47 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
?Myasthenic syndrome, congenital 18, 616330

Publications

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Wessex and West Midlands GLH
  • NHS GMS
  • Expert Review
  • Expert Review Green
  • Expert Review Green
  • Expert Review
Phenotypes
  • ?Myasthenic syndrome, congenital 18, 616330
  • ?Myasthenic syndrome, congenital, 18
OMIM
600322
Clinvar variants
Variants in SNAP25
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

17 Sep 2019, Gel status: 3

Added New Source

Rebecca Foulger (Genomics England curator)

Source Wessex and West Midlands GLH was added to SNAP25.

17 Sep 2019, Gel status: 3

Added New Source

Rebecca Foulger (Genomics England curator)

Source NHS GMS was added to SNAP25.

22 Jul 2019, Gel status: 3

Added New Source, Added New Source, Set Phenotypes, Set publications, Status Update

Catherine Snow (Genomics England)

Source Expert Review Green was added to SNAP25. Source Expert Review was added to SNAP25. Added phenotypes ?Myasthenic syndrome, congenital, 18 for gene: SNAP25 Publications for gene SNAP25 were changed from 29491473; 28135719; 29100083; 25381298; 25003006 to 29100083; 28135719; 25003006; 29491473; 25381298; 30914295 Rating Changed from No List (delete) to Green List (high evidence)

20 Apr 2019, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance

Konstantinos Varvagiannis (Other)

gene: SNAP25 was added gene: SNAP25 was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: SNAP25 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: SNAP25 were set to 29491473; 28135719; 29100083; 25381298; 25003006 Phenotypes for gene: SNAP25 were set to ?Myasthenic syndrome, congenital 18, 616330 Penetrance for gene: SNAP25 were set to Complete Review for gene: SNAP25 was set to GREEN