Hereditary ataxia

Gene: CACNA2D2

Comment on list classification: New gene added to panel by Genomics England clinical team recommendation and upgraded Grey to Green. There is enough evidence to support a Green rating on this panel, confirming biallelic CACNA2D2 variants and pertinent to the corresponding phenotype of Cerebellar anomalies/ataxia/epilepsy/ID.

Created: 10 Jan 2020, 5:26 p.m. | Last Modified: 10 Jan 2020, 5:26 p.m.

Panel Version: 1.204

Green List (high evidence)

CACNA2D2 biallelic variants are associated with cerebellar atrophy with seizures and variable developmental delay (6 publications of affected families in the literature). Most patients also have onset of severe refractory seizures in the first year of life and show global developmental delay, compatible with epileptic encephalopathy (summary by Edvardson et al., 2013). However, at least 1 patient with normal cognitive development and only 1 febrile seizure has been reported (Valence et al., 2019), suggesting significant clinical variability of this disorder (OMIM 618501).

Mouse models including The 'ducky' mouse model (due to biallelic Cacna2d2 mutations) presented with absence epilepsy, spike-wave seizures and ataxia. Dysgenesis of the cerebellum is among the neuropathological findings (Brodbeck et al. (2002)). Mutations of the same gene in two other mouse models shows an association with ataxic gait, seizure susceptibility and cerebellar anomalies/degeneration.

Multiple submissions to ClinVar of biallelic variants rated as pathogenic for epileptic encephalopathy. Suggest update to green on panel.
Sources: Other

Created: 21 Nov 2019, 5:17 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
epilepsy; ataxia; developmental delay; cerebellar atrophy

Publications

• PMID: 30410802, PMID: 31402629, PMID: 24358150, PMID: 23339110, PMID: 29997391
• PMID : 14660671
• PMID: 15331424