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Genetic epilepsy syndromes

Gene: CACNA2D2

Green List (high evidence)

CACNA2D2 (calcium voltage-gated channel auxiliary subunit alpha2delta 2)
EnsemblGeneIds (GRCh38): ENSG00000007402
EnsemblGeneIds (GRCh37): ENSG00000007402
OMIM: 607082, Gene2Phenotype
CACNA2D2 is in 3 panels

6 reviews

Zerin Hyder (Genomics England)

Green List (high evidence)

CACNA2D2 biallelic variants are associated with cerebellar atrophy with seizures and variable developmental delay. 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). Animal models (Brodbeck et al., Brill et al) showed showed association of CACNA2D2 mutations with absence epilepsy, ataxia and paroxysmal dyskinesia. Multiple submissions to ClinVar of biallelic variants rated as pathogenic for epileptic encephalopathy. Suggest update to green on panel.
Created: 21 Nov 2019, 5:06 p.m. | Last Modified: 21 Nov 2019, 5:06 p.m.
Panel Version: 1.425

Phenotypes
epilepsy; ataxia; developmental delay; cerebellar atrophy

Publications

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Biallelic pathogenic CACNA2D2 variants cause Cerebellar atrophy with seizures and variable developmental delay (MIM 618501).

A recent OMIM update, a subsequent relevant publication by Punatha et al. as well as several additional LP/P variants in ClinVar for the phenotype of epileptic encephalopathy, support possible upgrade to green.

The following affected individuals appear to be relevant [NM_006030.3 used as RefSeq unless otherwise specified]:

[1] Edvardson et al. (PMID: 23339110) - 3 sibs born to consanguineous parents with EIEE, severe GDD / ID (inferred from the descritpion, at least for the oldest one), cerebellar atrophy and movement abnormalities. A CACNA2D2 variant (c.3137T>C / p.Leu1046Pro) was found in affected individuals by SNP-arrays and WES in one of them. Functional studies (reduction in current density of calcium channels in Xenopus laevis oocytes) supported the deleterious effect of the variant. A role of a rare hmz CESLR3 variant could not be ruled out.

[2] Pippucci et al. (PMID: 24358150) - 1 individual born to consanguineous parents, presenting with EE (onset at 1-2 m), severe GDD, cerebellar atrophy and choreiform movements. Homozygosity for a LoF variant (c.1294delA - p.Asn432fs) was found by WES. The role of the variant was further supported by expression studies (80% reduced mRNA levels, protein levels estimated at 3% of control / milder effect in htz parents). The proband was also hmz for a CESLR3 variant. Previous studies incl. 'high-resolution karyotype' and metabolic investigations.

[3] Butler et al. (PMID: 30410802) - A 5 y.o. male, with EE (seizure onset at 7m / GDD) and cerebellar atrophy. Compound heterozygosity for c.782C>T (p.Pro261Leu) and c.3137T>C (p.Leu1046Pro) was demonstrated by WES and supported by segregation studies.

[4] Valence et al. (PMID: 29997391) - Reported on a 20 y.o. male belonging to a cohort of 20 individuals with congenital ataxia, all from consaguineous families. This individual, who had cerebellar atrophy, ataxia, a single episode of febrile seizures and normal cognitive impairment was homozygosity for c.2971G>A (p.Asp991Asn). RT-PCR revealed presence of a normal length transcript as well as an additional, longer one, due to a concurrent splicing effect (activation of a cryptic donor splice site and retention of 4 bases of intronic sequence). Presence of both nl/abn length transcripts was presumed to explain the mild phenotype (variability also commented in OMIM).

[5] Punatha et al. (PMID: 31402629) - 3 affected individuals from 2 consanguineous families presenting with early onset EE (onset 1-7m), GDD/ID, cerebelar atrophy and ataxia. Sibs from the first family were homozygous for c.1778G>C (p.Arg593Pro). An affected 5 y.o. child from the 2nd family was homozygous for c.485_486delAT (p.Tyr162Ter). Mutations were found by WES in regions of AOH.

The following variants - not reported in the literature - have been submitted in ClinVar as LP / P for EE:
[VCV000645106.1] NM_006030.4:c.1389+2T>C - EIEE with suppression bursts - Likely Pathogenic (Invitae)
[VCV000570589.1] NM_006030.4:c.1956_1960del (p.Asn652fs) - EIEE - Pathogenic (Invitae)
[VCV000578284.1] NM_006030.4:c.1555C>T (p.Gln519Ter) - EIEE - Pathogenic (Invitae)
[VCV000653393.1] NM_006030.4:c.851dup (p.Ala286fs) - EIEE with suppression bursts - Pathogenic (Invitae)
[VCV000411003.1] NM_006030.4:c.485_486del (p.Tyr161_Tyr162insTer) - EIEE - Pathogenic (Invitae)

Additional ones have been reported as LP / P although the condition is not specified.
[VCV000620551.1] NM_006030.4:c.1023C>A (p.Cys341Ter) - Likely pathogenic (GeneDx)
[VCV000373439.2] NM_006030.4:c.1846-1G>A - Likely pathogenic (GeneDx)
[VCV000423330.2] NM_006030.4:c.200dup (p.His68fs) - Pathogenic (GeneDx).

The aforementioned laboratories include CACNA2D2 in gene panels for epilepsy (Invitae) and/or ID (GeneDx).

A role for the CACNA2D2 is supported by :
- The highly overlapping features (with the exception of the milder phenotype reported by Valence et al.) incl. early onset of seizures, GDD, cerebellar atrophy in all (9/9 incl. the individual reported by Valence, as evaluated Punatha et al). Ataxia was a feature in many (with movement abnormalities also in the remaining ones).
- The role of the gene encoding the alpha-2-delta-2 auxiliary subunit of high voltage-gated calcium channels. Auxiliary subunits modulate calcium current and channel activation and inactivation kinetics, and may be involved in proper assembly and membrane localization of the channels (summary by Edvardson and OMIM).
- Functional / expression studies for some of the variants (as in Refs 1,2,4).
- Relevant expression patterns (notably in cerebellum) [GTEx project]
- Mouse models recapitulating the human phenotypes (summarized by Edvardson et al) : The 'ducky' mouse model (due to biallelic Cacna2d2 mutations) presenting absence epilepsy, spike-wave seizures and ataxia. Dysgenesis of the cerebellum is among the neuropathological findings (PMIDs cited : 11487633, 11756448, 4177347). The 'entla' mouse model (also AR due to an in-frame duplication) presents also epilepsy and ataxia (PMID : 14660671). Targeted knockout in another mouse model resulted also in ataxic gait, seizure susceptibility and cerebellar anomalies/degeneration (PMID: 15331424).

[Please consider inclusion in other relevant panels eg. for cerebellar anomalies / ataxia].
Created: 15 Sep 2019, 7:29 p.m. | Last Modified: 15 Sep 2019, 7:29 p.m.
Panel Version: 1.329

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Cerebellar atrophy with seizures and variable developmental delay (MIM 618501)

Publications

Variants in this GENE are reported as part of current diagnostic practice

Rebecca Foulger (Genomics England curator)

I don't know

As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Promoted from Amber to Green.
Created: 25 Nov 2019, 8:30 p.m. | Last Modified: 25 Nov 2019, 8:30 p.m.
Panel Version: 1.431
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: Alison Callaway and John Taylor. 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

Tracy Lester (Genetics laboratory, Oxford UK)

I don't know

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
? Epileptic encephalopathy

Publications

Sarah Leigh (Genomics England Curator)

Comment when marking as ready: Not associated with phenotype in OMIM or in Gen2Phen. Both variant reported have been refuted in OMIM and are now listed as VUS, however, the mouse model reported in PMID 11487633 does provide some evidence for involvement of this gene in epilepsy.
Created: 12 Nov 2018, 5:46 p.m.

Zornitza Stark (Australian Genomics)

I don't know

Two unrelated individuals reported in the literature, plus functional evidence. Probably merits Amber.
Created: 8 Aug 2018, 3:41 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

Variants in this GENE are reported as part of current diagnostic practice

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Wessex and West Midlands GLH
  • NHS GMS
  • Victorian Clinical Genetics Services
Phenotypes
  • Absence epilepsy
  • Cerebellar atrophy with seizures and variable developmental delay, 618501
Tags
watchlist
OMIM
607082
Clinvar variants
Variants in CACNA2D2
Penetrance
None
Publications
Panels with this gene

History Filter Activity

25 Nov 2019, Gel status: 3

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for gene: CACNA2D2 were changed from Absence epilepsy to Absence epilepsy; Cerebellar atrophy with seizures and variable developmental delay, 618501

25 Nov 2019, Gel status: 3

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

Gene: cacna2d2 has been classified as Green List (High Evidence).

6 Aug 2019, Gel status: 2

Added New Source

Rebecca Foulger (Genomics England curator)

Source Wessex and West Midlands GLH was added to CACNA2D2.

6 Aug 2019, Gel status: 2

Added New Source

Rebecca Foulger (Genomics England curator)

Source NHS GMS was added to CACNA2D2.

11 Dec 2018, Gel status: 2

Panel promoted to version 1.0

Sarah Leigh (Genomics England Curator)

Zornitza Stark: Two unrelated individuals repo

12 Nov 2018, Gel status: 2

Added Tag

Sarah Leigh (Genomics England Curator)

Tag watchlist tag was added to gene: CACNA2D2.

12 Nov 2018, Gel status: 2

Entity classified by Genomics England curator

Sarah Leigh (Genomics England Curator)

Gene: cacna2d2 has been classified as Amber List (Moderate Evidence).

12 Nov 2018, Gel status: 2

Set publications

Sarah Leigh (Genomics England Curator)

Publications for gene: CACNA2D2 were set to 24358150; 23339110; 11487633

12 Nov 2018, Gel status: 2

Set Phenotypes

Sarah Leigh (Genomics England Curator)

Phenotypes for gene: CACNA2D2 were changed from to Absence epilepsy

12 Nov 2018, Gel status: 2

Set publications

Sarah Leigh (Genomics England Curator)

Publications for gene: CACNA2D2 were set to

12 Nov 2018, Gel status: 2

Set mode of inheritance

Sarah Leigh (Genomics England Curator)

Mode of inheritance for gene: CACNA2D2 was changed from to BIALLELIC, autosomal or pseudoautosomal

25 Jun 2018, Gel status: 2

Added New Source

Sarah Leigh (Genomics England Curator)

Expert Review Amber was added to CACNA2D2. Panel: Genetic Epilepsy Syndromes

25 Jun 2018, Gel status: 1

Added New Source

Sarah Leigh (Genomics England Curator)

CACNA2D2 was added to Genetic Epilepsy Syndromes panel. Sources: Victorian Clinical Genetics Services

25 Jun 2018, Gel status: 1

Created

Sarah Leigh (Genomics England Curator)

CACNA2D2 was created by Sarah Leigh