Early onset or syndromic epilepsy

Gene: CACNB4

Red List (low evidence)

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

Created: 2 May 2024, 1:13 p.m. | Last Modified: 6 May 2024, 9:09 p.m.

Panel Version: 5.6

Red List (low evidence)

This gene-disease relationship has been assessed as REFUTED by ClinGen, summary:

In 2019, Heyne et al (PMID:31056551) evaluated variants reportedly associated with neurodevelopmental disorders that were also included on gene panels targeted for epilepsy from 2013 to 2017. Authors compared variant frequencies of the genes compared to controls. As a result, CACNB4 showed identical frequencies of ultra-rare variants in cases compared to the controls. This evidence demonstrates that removing a gene with no diagnostic yield, such as CACNB4, from panels would increase diagnostic yield over time and this publication has been utilized as evidence to refute remaining evidence in addition to the other reasons described in more detail below.

The available genetic evidence for the gene-disease relationship between CACNB4 and epilepsy phenotypes includes 7 probands across 4 publications (PMIDs:10762541, 18755274, 27959697, 32042491). However, all genetic evidence has been discarded. In three cases (PMID:10762541), confirmation selective gel electrophoresis (CSGE) was used to identify variants in CACNB4. CSGE is a screening method used to detect variation in only the gene of interest; therefore, there is no way to confirm that the probands did not have another genetic cause to explain their phenotype. In two cases (PMIDs:18755274, 27959697), another variant was identified in a known disease-causing gene. And in two cases (PMID:32042491), there is greater than one individual present in gnomAD (v2.1.1).

Experimental evidence is also available in the literature including protein interaction, functional alteration, and a mouse model; however, in the absence of genetic evidence, no experimental evidence will be counted.

In summary, the evidence supporting the relationship between CACNB4 and autosomal dominant epilepsy has been updated to refuted following recuration and no valid evidence remains. New evidence would be needed to support this claim. This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel on July 5, 2022 (SOP Version 9).

Created: 24 Aug 2023, 5:29 a.m. | Last Modified: 24 Aug 2023, 5:29 a.m.

Panel Version: 4.87

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
{Epilepsy, juvenile myoclonic, susceptibility to, 6}, MIM# 607682; {Epilepsy, idiopathic generalized, susceptibility to, 9}, MIM#607682

I don't know

PMID 35813387 - Naseer et al, 2022: WES i one family and targeted sequencing of SCN1A and CACNB4 in 25 sporadic epilepsy patients. 3 different unrelated patients found to have the c.78_79insG variant in CACNB4. Do mention that tecently het CACNB4 mutations are not linked with epilepsy [Heyne et al 2019] and that het mutated animal model did not show any tyoe of deformities [Coba et al, 2012].

Also PMID32176688 - see previous occurence where identifed homozygously.

Created: 7 Feb 2024, 3:42 p.m. | Last Modified: 7 Feb 2024, 3:42 p.m.

Panel Version: 4.163

Coste de Bagneaux 2020, 2 siblings with intellectual disability, psychomotr retardation, blindness, epilepsy, movement disorder and cerebellar atrophy - rare hom missense variant identified L126P which thought to be likely pathoegenic using in silico tools, animal model, clinical and genetic data (This variant is thought to be impairing both channel and non channel functions of B4b).

Created: 27 Jan 2021, 4:03 p.m. | Last Modified: 27 Jan 2021, 4:03 p.m.

Panel Version: 2.274

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Publications

• 35813387

Red List (low evidence)

The gene disease association between CACNB4 and epilepsy has been refuted by ClinGen Epilepsy Gene Curation Expert Panel on July 5, 2022 (SOP Version 9)(https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_d2fad131-8e91-4874-9394-8b86d6d62abb-2022-07-05T160000.000Z?page=1&size=25&search= )

Created: 28 Nov 2023, 11:51 a.m. | Last Modified: 28 Nov 2023, 11:51 a.m.

Panel Version: 4.133

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

There is enough evidence for this gene to be rated GREEN for epilepsy at the next major review.

Created: 6 Jul 2020, 5:22 p.m. | Last Modified: 6 Jul 2020, 5:22 p.m.

Panel Version: 2.107

Comment on list classification: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene. At least 3 variants reported in at least 3 unrelated cases, together with supportive functional data.

Created: 6 Jul 2020, 5:10 p.m. | Last Modified: 6 Jul 2020, 5:10 p.m.

Panel Version: 2.103

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: 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 episodic ataxia type 5, and AD epilepsy. Escagy et al, 2000 - women with juvenille epilepsy - het nonsense variant and in an affected father and son a het missense variant.

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, idiopathic generalized, susceptibility to, 9}, 607682; {Epilepsy, juvenile myoclonic, susceptibility to, 6}, 607682; Episodic ataxia, type 5, 613855

Publications

• 10762541

Red List (low evidence)

Publications

• 20561025
• 20378313
• 10762541

Red List (low evidence)

Red List (low evidence)

Red List (low evidence)

Red List (low evidence)