Early onset or syndromic epilepsy

Gene: SEMA6B

Comment on publications: PMID:35604360 reported new unrelated cases identified with heterozygous variants in SEMA6B. Out of 16 patients referred for ID clinic, 10 of them had epilepsy or myoclonus.

Functional studies of selected variants and shRNA knock down studies showed mislocalisation and abnormal protein function.

Created: 1 Mar 2023, 3:32 p.m. | Last Modified: 1 Mar 2023, 3:32 p.m.

Panel Version: 3.93

Comment on publications: PMID:35604360 reported new unrelated cases identified with heterozygous variants in SEMA6B. Out of 16 patients referred for ID clinic, 10 of them had epilepsy or myoclonus.

Functional studies of selected variants and shRNA knock down studies showed mislocalisation and abnormal protein function.

Created: 1 Mar 2023, 3:32 p.m. | Last Modified: 1 Mar 2023, 3:32 p.m.

Panel Version: 3.92

Comment on publications: PMID:35604360 reported new unrelated cases identified with heterozygous variants in SEMA6B. Out of 16 patients referred for ID clinic, 10 of them had epilepsy or myoclonus.

Functional studies of selected variants and shRNA knock down studies showed mislocalisation and abnormal protein function.

Created: 1 Mar 2023, 3:31 p.m. | Last Modified: 1 Mar 2023, 3:31 p.m.

Panel Version: 3.92

The rating 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

I don't know

Hamanaka et al 2020 - Only seen in 4 individuals in 3 unrelated cases - all truncating de novo variants in the last exon - escape from NMD. They observed statistically significant enrichment of DNVs in NMD regions of 346 DEE trios. Although epilepsy is an initial feature, not sure there is enough evidence to make green?

Created: 31 Jan 2021, 8:32 p.m. | Last Modified: 31 Jan 2021, 8:32 p.m.

Panel Version: 2.281

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Publications

• 32169168

Comment on list classification: Changed rating from Green to Amber so that Green genes on this panel reflect the NHS signed-off version. This will be reviewed at the next GMS panel update (added 'for-review' tag).

Created: 20 Oct 2020, 2:11 p.m. | Last Modified: 20 Oct 2020, 2:11 p.m.

Panel Version: 2.186

Comment on list classification: Gene was added to panel and rated Green by Zornitza Stark. Sufficient cases with seizure phenotype in PMID:32169168 plus mouse model. Not yet associated with a disorder in G2P but relevant OMIM phenotype. Therefore updated rating from Grey to Green.

Created: 1 Jun 2020, 4:09 p.m. | Last Modified: 1 Jun 2020, 4:10 p.m.

Panel Version: 2.80

Comment on mode of pathogenicity: The authors of PMID:32169168 suggest a dominant-negative or gain-of-function effect rather than haploinsufficiency.

Created: 1 Jun 2020, 4:08 p.m. | Last Modified: 1 Jun 2020, 4:08 p.m.

Panel Version: 2.79

PMID:32169168. In 4 unrelated patients (2 Japanese, 1 Israeli and 1 Malaysian) with progressive myoclonic epilepsy, Hamanaka et al. (2020) identified de novo heterozygous frameshift mutations in the last exon of the SEMA6B gene. Variants were predicted to result in truncated proteins. Truncating variants in this region of the gene were not observed in the gnomAD database, although truncating variants in other regions of the gene were observed in gnomAD. The authors postulated a dominant-negative or gain-of-function effect rather than haploinsufficiency. In an animal model, the authors found that zebrafish with truncating sema6b variants were more susceptible to seizures.

Created: 1 Jun 2020, 4:07 p.m. | Last Modified: 1 Jun 2020, 4:08 p.m.

Panel Version: 2.78

Green List (high evidence)

Five individuals from unrelated families reported with de novo variants in the last exon, escaping NMD.
Sources: Literature

Created: 20 Apr 2020, 2:40 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Progressive myoclonic epilepsy

Publications

• 32169168