The CACNB4 gene encodes the beta-4 subunit of voltage-gated calcium channel complex proteins. In available literature, variants in CACNB4 have been reported in relation to episodic ataxia type 5, juvenile myoclonic epilepsy, and idiopathic generalized epilepsy. This gene was originally analyzed in June 2018 and was disputed at the time of curation due to a lack of clinical evidence to support the gene-disease relationship. In July 2022, CACNB4 was recurated by the ClinGen Epilepsy Gene Curation Expert Panel.
Since the original curation, contradictory evidence has emerged. 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).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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