Early onset or syndromic epilepsy

Gene: STXBP1

The mode of inheritance of this gene has been updated to BOTH monoallelic and biallelic, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.

Created: 11 Oct 2023, noon | Last Modified: 11 Oct 2023, noon

Panel Version: 4.110

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Comment on mode of inheritance: Due to the report of biallelic STXBP1 variants in a family with encephalopathy, developmental delay, intellectual disability and epilepsy (PMID: 31855252), the mode of inheritance for this gene should be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.

Created: 28 Feb 2023, 3:43 p.m. | Last Modified: 28 Feb 2023, 3:43 p.m.

Panel Version: 3.86

PMID: 31855252 reports a homozygous STXBP1 variant (NM_001032221.6(STXBP1):c.1336C>T (p.Leu446Phe)) in two sisters with developmental and epileptic encephalopathy 4 (OMIM:612164). Their mother and unaffected sister were heterozygous for NM_001032221.6(STXBP1):c.1336C>T (p.Leu446Phe)(the father was deceased). Functional studies showed that this variant had a lesser effect on protein stability in comparison with the heterozygous variants previously reported. However, patch clamp recordings demonstrated that p.Leu446Phe causes a 2-fold increase in evoked
synaptic transmission, leading to the conclusion that this variant was having a gain-of-function effect.
Although the majority of STXBP1 variants are heterozygous, with a loss-of -function effect, the results published in PMID: 31855252, suggest that there maybe further complexity to mechanisms involved in the development of developmental and epileptic encephalopathy 4.
PMID: 35190816 used a computational approach, together with biomedical ontologies, to characterize phenotypic features in STXBP1-related disorders, such that groups of HPO terms could be associated with certain STXBP1 variants.

Created: 28 Feb 2023, 3:37 p.m. | Last Modified: 28 Feb 2023, 3:37 p.m.

Panel Version: 3.85

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Publications

• 31855252
• 35190816

Green List (high evidence)

Please note recent report of BIALLELIC variants in this gene causing EE through GoF in two families and consider changing mode of inheritance/pathogenicity and associated pipeline settings.

Created: 21 Jan 2020, 10:31 a.m. | Last Modified: 21 Jan 2020, 10:31 a.m.

Panel Version: 2.0

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Epileptic encephalopathy, early infantile, 4, MIM#612164

Publications

• 31855252

Mode of pathogenicity
Other

Variants in this GENE are reported as part of current diagnostic practice

I don't know

Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: John Taylor and Helen Lord. Suggested gene rating: Green.

Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.

Panel Version: 1.189

Green List (high evidence)

AD Early infantile epileptic encephalopathy - lots of types of seizures reported in association with variants in this gene. Lots of reported variants on OMIM and HGMD Pro.

Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.

Panel Version: 1.188

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Epileptic encephalopathy, early infantile, 612164

Publications

• 18469812
• 19557857

Green List (high evidence)

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Red List (low evidence)

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

Phenotypes
Epileptic encephalopathy, early infantile, 4

Publications

• Saitsu et al (2008) Nature Genet 40 (6): 782-788

Variants in this GENE are reported as part of current diagnostic practice

Red List (low evidence)

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

Phenotypes
Epileptic encephalopathy, early infantile, 4

Publications

• Saitsu et al (2008) Nature Genet 40 (6): 782-788

Variants in this GENE are reported as part of current diagnostic practice

Red List (low evidence)

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

Phenotypes
Epileptic encephalopathy, early infantile, 4

Publications

• Saitsu et al (2008) Nature Genet 40 (6): 782-788

Variants in this GENE are reported as part of current diagnostic practice

Comment on mode of inheritance: Monoallelic confirmed on G2P and OMIM. Not on the imprinted gene list.

Created: 29 Jan 2016, 12:46 p.m.

Comment on list classification: Reviewers later agreed that this gene should be green. It is a confirmed DD gene for Epileptic encephalopathy.

Created: 29 Jan 2016, 12:33 p.m.