Early onset or syndromic epilepsy

Gene: SCAMP5

Green List (high evidence)

The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.

Created: 1 Feb 2023, 9:39 a.m. | Last Modified: 1 Feb 2023, 9:39 a.m.

Panel Version: 3.29

Green List (high evidence)

PMID 33390987: Four unrelated individuals reported with same de novo missense variant, p. Gly180Trp. The onset age of seizures was ranged from 6 to 15 months. Patients had different types of seizures, including focal seizures, generalized tonic-clonic seizures and tonic seizure. One patient showed typical autism spectrum disorder (ASD) symptoms. Electroencephalogram (EEG) findings presented as focal or multifocal discharges, sometimes spreading to generalization. Brain magnetic resonance imaging (MRI) abnormalities were present in each patient. Severe intellectual disability and language and motor developmental disorders were found in our patients, with all patients having poor language development and were nonverbal at last follow-up. All but one of the patients could walk independently in childhood, but the ability to walk independently in one patient had deteriorated with age. All patients had abnormal neurological exam findings, mostly signs of extrapyramidal system involvement. Dysmorphic features were found in 2/4 patients, mainly in the face and trunk.

PMID 31439720: 2 unrelated individuals with ASD, ID and seizures, with the same heterozygous de novo variant in SCAMP5 (p.Gly302Trp). Western blot analysis of proteins overexpressed in the Drosophila fat body showed strongly reduced levels of the SCAMP p.Gly302Trp protein compared with the wild-type protein, indicating that the mutant either reduced expression or increased turnover of the protein. The expression of the fly homologue of the human SCAMP5 p.Gly180Trp mutation caused similar eye and neuronal phenotypes as the expression of SCAMP RNAi, suggesting a dominant-negative effect.

Created: 16 Jan 2021, 1:12 a.m. | Last Modified: 16 Jan 2021, 1:12 a.m.

Panel Version: 2.255

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Intellectual disability; seizures; autism

Publications

• 31439720
• 33390987

Mode of pathogenicity
Other

Green List (high evidence)

The mode of inheritance of this gene has been updated following NHS Genomic Medicine Service approval.

Created: 3 Mar 2022, 5:34 p.m. | Last Modified: 3 Mar 2022, 5:34 p.m.

Panel Version: 2.491

Not associated with relevant phenotype in OMIM or Gen2Phen (18/02/2021). At single heterozygous variant (NM_001178111.1: c.538G>T, p.Gly180Trp) has been reported to be associated with intellectual disability; seizures; autism in at least six unrelated cases (PMID 33390987; 31439720).

Created: 18 Feb 2021, 3:16 p.m. | Last Modified: 18 Feb 2021, 3:16 p.m.

Panel Version: 2.303

Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.

Created: 18 Feb 2021, 3:05 p.m. | Last Modified: 18 Feb 2021, 3:05 p.m.

Panel Version: 2.303

Comment on phenotypes: OMIM does not have a phenotype associated with variants in this gene (18/02/21).

Created: 18 Feb 2021, 3:03 p.m. | Last Modified: 18 Feb 2021, 3:03 p.m.

Panel Version: 2.302

Comment on mode of pathogenicity: Heterozygous c.538G>T, p.Gly180Trp seeming to have a dominant-negative effect resulting in autistic spectrum disorder, intellectual disability and seizures. While homozygous c.271C>T, p.R91W seems to have a loss of function effect resulting in early onset epilepsy and Parkinson’s disease.

Created: 24 Mar 2020, 1:39 p.m. | Last Modified: 24 Mar 2020, 1:39 p.m.

Panel Version: 2.20

PMID 32020363 reports a homozygous variant (NM_001178111:c.271C>T, p.R91W rs747966691) in two sibs of a Chinese consanguienious family, with early onset epilepsy and Parkinson’s disease (the heterozygous parents had a normal phenotype). The p.R91W knock-in mouse showed typical early-onset epilepsy and functional studies showed dysfunction of SCAMP5 shifted the excitation/inhibition balance of the neuronal network in the brain. The patients with this variant did not show signs of autism, intellectual disability, or other growth and developmental disorders.

Created: 24 Mar 2020, 1:21 p.m. | Last Modified: 24 Mar 2020, 1:21 p.m.

Panel Version: 2.18

Comment on list classification: Not associated with phenotype in OMIM (last edited on 10/06/2014) or in Gen2Phen. Two variants have been identified in three unrelated cases (one monoallelic, one biallelic). Supportive functional studies have been reported.
It would appear that the two variants reported so far in this gene result in differing mode of pathogenicity and phenotypic features. With heterozygous c.538G>T, p.Gly180Trp seeming to have a dominant-negative effect resulting in autistic spectrum disorder, intellectual disability and seizures. While homozygous c.271C>T, p.R91W seems to have a loss of function effect resulting in early onset epilepsy and Parkinson’s disease. This may be due to different functional domains of the mature protein being altered.
Based on this evidence, SCAMP5 is rated as Amber, with a Watchlist tag. This status may change if further cases are reported.

Created: 24 Mar 2020, 12:57 p.m. | Last Modified: 30 Mar 2020, 11:57 a.m.

Panel Version: 2.25

Comment on mode of inheritance: Based on the reporting of a de novo heterozygous varaiant (NM_001178111.1:c.538G>T) in two unrelated cases (PMID: 31439720) and a homozygous variant (NM_001178111:c.271C>T, rs747966691) in two members of a Chinese consanguienious family (PMID: 32020363).

Created: 24 Mar 2020, 12:51 p.m. | Last Modified: 24 Mar 2020, 12:51 p.m.

Panel Version: 2.16

Comment on mode of pathogenicity: A dominant negative effect is predicted.

Created: 27 Nov 2019, 5:02 p.m. | Last Modified: 27 Nov 2019, 5:02 p.m.

Panel Version: 1.477

Comment on list classification: Gene added by external Reviewer, and promoted to Amber due to review and overall evidence.

Created: 27 Nov 2019, 5:01 p.m. | Last Modified: 27 Nov 2019, 5:01 p.m.

Panel Version: 1.476

I don't know

PMID: 31439720 (Hubert et al. 2019) reported on 2 unrelated individuals with severe ID, seizures, behavioral and brain MRI abnormalities (white matter hyperintensity and mesial temporal sclorosis), both harboring the same missense SCAMP5 mutation as a de novo event (NM_001178111.1:c.538G>T or p.Gly180Trp).

Previously aCGH +/- metabolic workup were non diagnostic.

The occurrence of the same de novo variant in both as well as the similar presentation (incl. MRI images) suggested SCAMP5 as the most probable candidate gene, despite presence of few other variants in both.

SCAMP5 is highly expressed in brain (https://www.proteinatlas.org/ENSG00000198794-SCAMP5) and previous studies have suggested a role in synaptic vesicle trafficking (PMIDs cited: 29562188, 25057210, etc).

Cultured skin fibroblasts from affected individuals failed to express SCAMP5.

Scamp is the Drosophila orthologue, with previous studies having demonstrated that mutants display defects in climbing, olfactory-assisted memory and susceptibility to heat induced seizures (PMIDs cited: 25478561, 19144841). Expression of the Scamp Gly302Trp variant in Drosophila ('equivalent' to the SCAMP5 Gly180Trp) revealed strongly reduced levels for the variant compared with wt upon Western Blot, either due to reduced expression or due to increased turnover. Overall the effect of Gly302Trp expression was similar to Scamp knockdown by RNAi (eg. rough eye phenotype, reduced ability to climb the walls of a graded tube after tapping, less/no flies reaching adult stage) but significantly different compared to wt.

As a result, a dominant-negative effect was presumed.
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PMID: 20071347 (Castermans et al. 2010) is cited as a previous report of a relevant affected individual. In this study a 40 y.o. male with early DD, mild ID (IQ of 63) and ASD was found to harbor a de novo apparently balanced t(1;15) translocation affecting CLIC4 and PPCDC (both not associated with ID). [1-Mb resolution aCGH revealed no relevant CNVs].

Studies were however focused on SCAMP5 given that the gene is located downstream of / proximal to PPCDC, has brain-enriched expression as well as involvement in synaptic trafficking and demonstrated:
- Less than 50% expression upon quantitative RT-PCR in patients leukocytes, compared to control.
- Silencing and overexpression of Scamp5 in mouse β-TC3 cells resulted in increased and suppressed respectively secretion of large dense-core vesicles (LDCVs).
- Given conservation of some components involved in secretion of dense core granules (DCGs) in platelets and LDCVs in neuronal cells, study of patient platelets - where SCAMP5 was confirmed to be expressed - suggested an altered pattern of DCGs.
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SCAMP5 is not associated with any phenotype in OMIM/G2P/SysID and not commonly included in gene panels for ID.
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Overall, this gene could be considered for inclusion in the ID and epilepsy panels probably with amber (# of unrelated individuals, 1 recurrent de novo variant and 1 regulatory effect, gene expressed in brain with a role in synaptic vesicle trafficking) or red rating (pending further evidence).
Sources: Literature

Created: 11 Nov 2019, 5:20 p.m.

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

Phenotypes
Global developmental delay; Intellectual disability; Seizures; Abnormality of nervous system morphology; Behavioral abnormality

Publications

• 31439720
• 20071347

Mode of pathogenicity
Other