Early onset or syndromic epilepsy

Gene: SCN8A

Green List (high evidence)

Agree that evidence suggests that rare cases of biallelic inheritance of SCN8A variants have been reported with an epilepsy phenotype.

Created: 7 Jan 2022, 4:13 p.m. | Last Modified: 7 Jan 2022, 4:13 p.m.

Panel Version: 2.483

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Publications

• 31625145

Added 'for-review' tag as the MOI has changed since previous sign-off of this panel (version 2.2) and requires review by the Specialist Test Group.

Created: 21 Oct 2020, 4:42 p.m. | Last Modified: 21 Oct 2020, 4:42 p.m.

Panel Version: 2.201

The to_be_confirmed_NHSE tag has been added, as further NHSE review is required.

Created: 15 Mar 2022, 3:41 p.m. | Last Modified: 15 Mar 2022, 3:41 p.m.

Panel Version: 2.498

Comment on mode of inheritance: The mode of inheritance has been reverted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown from BOTH monoallelic and biallelic, autosomal or pseudoautosomal, while the strength of the evidence is reviewed.

Created: 11 Jan 2022, 11:09 a.m. | Last Modified: 11 Jan 2022, 11:14 a.m.

Panel Version: 2.485

Comment on mode of pathogenicity: Based on report in PMID 31625145, reporting biallelic loss of function SCN8A variants in three cases in two families with severe developmental and epileptic encephalopathy. This differs from the previosly reported gain of function, monoallelic variants (PMID 24194747;22365152).

Created: 26 Mar 2020, 3:49 p.m. | Last Modified: 26 Mar 2020, 3:49 p.m.

Panel Version: 2.25

Comment on mode of inheritance: Based on report in PMID 31625145, reporting biallelic loss of function SCN8A variants in three cases in two families with severe developmental and epileptic encephalopathy.

Created: 26 Mar 2020, 9:44 a.m. | Last Modified: 26 Mar 2020, 9:44 a.m.

Panel Version: 2.23

Green List (high evidence)

Note recent publication of bi-allelic variants causing epilepsy in three individuals from two families. Mono-allelic variants are typically GoF, whereas these variants were shown to be LoF. Parents are said to have had mild learning difficulties. Consider changing mode of inheritance and pathogenicity and associated pipeline settings.

Created: 21 Jan 2020, 10:34 a.m. | Last Modified: 21 Jan 2020, 10:34 a.m.

Panel Version: 2.0

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Epileptic encephalopathy, early infantile, 13, MIM# 614558; dominant and recessive

Publications

• 31625145

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 cognitive impairment with/without cerebellar ataxia, AD EIEE 13, AD benign familial infantile seizures. Lots of mutations reported - mostly missense on HGMD pro in assocation with an epilepsy phentoye. Several cases on OMIM with variants detected, arisen de novo. Functional studies have been undertaken for some variants: Veeramah et al, 2012 & de Kovel et al, 2014.

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
?Cognitive impairment with or without cerebellar ataxia,614306; Epileptic encephalopathy, early infantile,614558; Seizures, benign familial infantile,617080

Publications

• 22365152
• 24194747

Green List (high evidence)

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

Phenotypes
Cognitive impairment with or without cerebellar ataxia; Intellectual disability; Epileptic encephalopathy, early infantile, 13

Publications

• Trudeau et al (2004) J Med Genet 43: 527_530
• O'Brien and Meisler (2013) Frontiers in Genet 4(213): 1-9
• Veeramah et al (2012) Am J Hum Genet 90: 502_510

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

Green List (high evidence)

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

Phenotypes
Cognitive impairment with or without cerebellar ataxia; Intellectual disability; Epileptic encephalopathy, early infantile, 13

Publications

• Trudeau et al (2004) J Med Genet 43: 527_530
• O'Brien and Meisler (2013) Frontiers in Genet 4(213): 1-9
• Veeramah et al (2012) Am J Hum Genet 90: 502_510

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

Green List (high evidence)

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

Phenotypes
Cognitive impairment with or without cerebellar ataxia; Intellectual disability; Epileptic encephalopathy, early infantile, 13

Publications

• Trudeau et al (2004) J Med Genet 43: 527_530
• O'Brien and Meisler (2013) Frontiers in Genet 4(213): 1-9
• Veeramah et al (2012) Am J Hum Genet 90: 502_510

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

Green List (high evidence)

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Cognitive impairment with or without cerebellar ataxia; Intellectual disability; Epileptic encephalopathy, early infantile, 13

Publications

• Trudeau et al (2004) J Med Genet 43: 527 530
• O'Brien and Meisler (2013) Frontiers in Genet 4(213): 1-9
• Veeramah et al (2012) Am J Hum Genet 90: 502 510

Mode of pathogenicity
loss-of-function (truncating variants and curated list of variants)

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

Comment when marking as ready: Confirmed DD gene and all 4 reviewers agree this should be green. Mode of inheritance confirmed. Mutation consequence summary from G2P is dominant negative.

Created: 21 Jan 2016, 12:53 p.m.

Comment on mode of inheritance: Confirmed and not on imprinted gene list.

Created: 21 Jan 2016, 11:57 a.m.