Childhood onset dystonia, chorea or related movement disorder

Gene: CACNB4

Red List (low evidence)

Comment on list classification: There is only one family reported with monoallelic CACNB4 variants and episodic ataxia. Other two families were reported with epilepsy. There is also one family reported with biallelic CACNB4 variants and a phenotype including movement disorder. Hence, this gene should be recommended for demotion from green to red in the next GMS update.

In addition, the mode of inheritance should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal'.

Created: 29 Sep 2025, 1:19 p.m. | Last Modified: 29 Sep 2025, 1:19 p.m.

Panel Version: 7.6

PMID:10762541 (2000) reported the identification of two different monoallelic variants (p.Arg482Ter and p.Cys104Phe) in CACNB4 gene in three unrelated families. The p.Arg482Ter variant was reported in a patient with juvenile myoclonic epilepsy. The missense p.Cys104Phe variant was identified both in a German family with generalized epilepsy and praxis-induced seizures and in a French Canadian family with episodic ataxia. In addition, p.Cys104Phe has been identified in over 1,000 alleles in gnomAD - https://gnomad.broadinstitute.org/variant/2-151880879-C-A?dataset=gnomad_r4.

There are no other patients reported with monoallelic CACNB4 variants in published scientific literature.

Monoallelic CACNB4 variants have been associated with both episodic ataxia and epilepsy phenotypes in OMIM (MIMs #613855 & #607682, phenotypes accessed on 29 September 2025) and with CACNB4-related juvenile myoclonic epilepsy in Gene2Phenotype (with 'limited' rating on the DD panel).

PMID:32176688 (2020) reported two siblings with intellectual disability, psychomotor retardation, blindness, epilepsy, movement disorder and cerebellar atrophy. They were identified with rare homozygous variants in the genes LTBP1, EMILIN1, CACNB4, MINAR1, DHX38 and MYO15 by whole-exome sequencing. The authors identified using in silico tools, animal model, clinical, and genetic data that the p.Leu126Pro variant in CACNB4 gene to be likely pathogenic.

Biallelic CACNB4 variants have not yet been associated with any phenotypes either in OMIM or in Gene2Phenotype.

Created: 29 Sep 2025, 1:04 p.m. | Last Modified: 29 Sep 2025, 1:24 p.m.

Panel Version: 7.6

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
?Episodic ataxia, type 5, OMIM:613855; episodic ataxia type 5, MONDO:0013464; {Epilepsy, idiopathic generalized, susceptibility to, 9}, OMIM:607682; {Epilepsy, juvenile myoclonic, susceptibility to, 6}, OMIM:607682; epilepsy, idiopathic generalized, susceptibility to, 9, MONDO:0011892; neurodevelopmental disorder, MONDO:0700092

Publications

• 10762541
• 32176688

Comment on phenotypes: OMIM phenotypes correct at 30th September 2025

Created: 30 Sep 2025, 2:42 p.m. | Last Modified: 30 Sep 2025, 2:42 p.m.

Panel Version: 7.7

The mode of inheritance of this gene was proposed to be changed to Both mono and biallelic in 2022 but since there is no new evidence since it was last considered by the GMS, it has been decided to keep it as just monoallelic.

Created: 30 Jan 2023, 6:27 p.m. | Last Modified: 5 Feb 2023, 6:31 p.m.

Panel Version: 2.11

Green List (high evidence)

NHSGenomic Medicine Service consideration - limited evidence for biallelic mode of inheritance.

Created: 19 Jun 2022, 11:23 p.m. | Last Modified: 19 Jun 2022, 11:23 p.m.

Panel Version: 1.237

After NHSGenomic Medicine Service consideration, the mode of inheritance of this gene has not been changed

Created: 19 Jun 2022, 11:23 p.m. | Last Modified: 19 Jun 2022, 11:23 p.m.

Panel Version: 1.237

PMID 10762541 reports monoallelic variants associated with Idiopathic Generalized Epilepsy and Episodic Ataxia and PMID 32176688 reports biallelic variants associated with severe neurodevelopmental disorder and impairs channel and non-channel functions. Therefore recommend the MOI be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.

Created: 28 Jan 2021, 3:46 p.m. | Last Modified: 28 Jan 2021, 3:46 p.m.

Panel Version: 1.76

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: 28 Jan 2021, 3:32 p.m. | Last Modified: 28 Jan 2021, 3:32 p.m.

Panel Version: 1.74

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Publications

• 32176688

Red List (low evidence)

One multigenerational family reported with episodic ataxia and supportive animal model data.

Created: 5 Sep 2020, 4:31 a.m. | Last Modified: 5 Sep 2020, 4:31 a.m.

Panel Version: 1.49

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Episodic ataxia, type 5, MIM#613855

Publications

• 10762541
• 9628818
• 27003325

Green List (high evidence)