Early onset or syndromic epilepsy
Gene: CACNB4
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
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
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
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
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
Tag Q4_23_expert_review tag was added to gene: CACNB4.
Tag refuted tag was added to gene: CACNB4.
Tag Q4_23_demote_red tag was added to gene: CACNB4.
Tag for-review was removed from gene: CACNB4.
Source Expert Review Green was added to CACNB4. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Phenotypes for gene: CACNB4 were changed from {Epilepsy, idiopathic generalized, susceptibility to, 9}, 607682; {Epilepsy, juvenile myoclonic, susceptibility to, 6}, 607682; Episodic ataxia, type 5, 613855; Intellectual disability to {Epilepsy, idiopathic generalized, susceptibility to, 9} OMIM:607682; {Epilepsy, juvenile myoclonic, susceptibility to, 6} OMIM:607682; Episodic ataxia, type 5 OMIM:613855; Intellectual disability
Tag for-review tag was added to gene: CACNB4.
Publications for gene: CACNB4 were set to 20561025; 20378313; 10762541; 32176688 25529582
Phenotypes for gene: CACNB4 were changed from to {Epilepsy, idiopathic generalized, susceptibility to, 9}, 607682; {Epilepsy, juvenile myoclonic, susceptibility to, 6}, 607682; Episodic ataxia, type 5, 613855; Intellectual disability
Publications for gene: CACNB4 were set to
Mode of inheritance for gene: CACNB4 was changed from to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Gene: cacnb4 has been classified as Amber List (Moderate Evidence).
Source Wessex and West Midlands GLH was added to CACNB4.
Source NHS GMS was added to CACNB4.
Arianna Tucci: one variant describes in one p
NIHRBR-RD Consortium SPEED_v3.0_20170404 was added to CACNB4. Panel: Genetic Epilepsy Syndromes
CACNB4 was added to Genetic Epilepsy Syndromes panel. Sources: Expert,Expert Review Red
CACNB4 was created by Sarah Leigh