Early onset or syndromic epilepsy

Gene: SCN9A

Red List (low evidence)

Fasham et al, 2020 - paper showing no association with SCN9A and monogenic human epilepsy disorders - to remove gene from epilepsy panel.

Created: 27 Jan 2021, 3:47 p.m. | Last Modified: 27 Jan 2021, 3:47 p.m.

Panel Version: 2.274

Publications

• 33216760

I don't know

Three more cases in the literature (including twin sisters). Two of the families had the p.(G327E) variant and the other had a frameshift. Have not assessed these variants using ACMG, but think this gene should be at least on the watchlist.

Created: 22 Nov 2019, 9:58 a.m. | Last Modified: 22 Nov 2019, 9:58 a.m.

Panel Version: 1.425

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Publications

• 30834459
• 29500686

Red List (low evidence)

As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Demoted SCN9A from Green to Amber.

Created: 25 Nov 2019, 8:41 p.m. | Last Modified: 25 Nov 2019, 8:41 p.m.

Panel Version: 1.435

Added a Red review to highlight the comment from Diane Cairns (Manchester University NHS, North West GLH) that it would be acceptable to remove this gene from the Epilepsy Panel.

Created: 7 Oct 2019, 9:47 a.m. | Last Modified: 7 Oct 2019, 9:47 a.m.

Panel Version: 1.351

Diane Cairns (Manchester University NHS, North West GLH) comments that "I have looked into the variants that we found on our Epilepsy panel in the FLNA, SCN9A and KCNA1 genes. Using ACGS guidelines these variants are all Class 3 or below, we therefore feel that it would be acceptable to remove these genes from the Epilepsy Panel." (personal communication via email to Jane Deller, 2019-09-04)

Created: 5 Sep 2019, 2:52 p.m. | Last Modified: 5 Sep 2019, 2:52 p.m.

Panel Version: 1.262

As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is sufficient evidence to rate this gene Green. Kept rating as Green.

Created: 15 Aug 2019, 10:08 a.m. | Last Modified: 15 Aug 2019, 10:08 a.m.

Panel Version: 1.230

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: Amber.

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

Panel Version: 1.189

I don't know

AD febrile seizures (type 7 and 3B), AD EIEE 6 (also AD primary erythermalgia, AD paraoxysmal extreme pain disorder and AR HSAN2D - all 'pain' phenotype not epilepsy). AD febrile seizures: Singh et al, 2009, large Utah family - identified a het missense variant and in 2 unrelated probands 2 diff het missense variants identified. No functional work done. AD EIEE6: Singh et al 2009, 2 patients with Dravet syndrome het mutation in SCN9A (K655R). One of these patients also had an SCN1A variant, which was also detected in a patient with AD febrile seizures. Possible that SCN9A gene is a modifier of Dravet syndrome as 9/109 patients with dravet syndrome also had an SCN9A variant including 6 patients who were double heterozygous for SCN9A and SCN1A mutations and 3 patients with only het SCN9A mutations - consistent with multifactoral inheritance.

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
Epilepsy, generalized, with febrile seizures plus, type 7,613863; Erythermalgia, primary,133020; Febrile seizures, familial,613863; HSAN2D,243000; Insensitivity to pain, congenital,243000; Paroxysmal extreme pain disorder,167400; Small fiber neuropathy,133020

Publications

• 19763161
• 23895530

Red List (low evidence)

This gene should remain Red on this panel.

Created: 28 Jan 2021, 3:55 p.m. | Last Modified: 28 Jan 2021, 3:55 p.m.

Panel Version: 2.278

Comment on list classification: Evidence presented by PMID 33216760 disputes the association between SCN9A and epilepsy, inparticular the serendipitous identification of the SCN9A p.(Asn641Tyr) variant within the Wisconsin Amish community with no epilepsy in their phenotypes. The authors report this lack of gene disease association was also evident in the UK Biobank.

Created: 28 Jan 2021, 11:36 a.m. | Last Modified: 28 Jan 2021, 11:36 a.m.

Panel Version: 2.276

Associated with phenotype in OMIM and not in Gen2Phen. At least 6 variants identified in unrelated cases, 2 variants in Epilepsy, generalized, with febrile seizures plus, type 7 613863 (including affected members of a large family in Utah), 2 in unrelated cases of Febrile seizures, familial, 3B 613863 (PMID 19763161) and 2 in unrelated cases with variable epilepsy phenotypes (PMID 29500686).

Created: 4 Apr 2018, 3:29 p.m.

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

Red List (low evidence)

Red List (low evidence)

Red List (low evidence)

Red List (low evidence)

Added the watchlist tag.

Created: 8 Dec 2016, 10:29 a.m.

Comment on list classification: Insufficient data to report diagnostically in a monogenic setting

Created: 8 May 2016, 7:01 p.m.