Intellectual disability - microarray and sequencing
Gene: CACNA2D2Comment on list classification: Kept rating Amber as severe GDD is a neurodegenerative manifestation that is secondary to the onset of seizures, which represent the key phenotypic feature of this disorder.
This gene is Green on the Genetic epilepsy syndromes (v2.170) panel, which should be a sufficient route for detecting these cases.Created: 14 Oct 2020, 9:11 a.m. | Last Modified: 14 Oct 2020, 9:11 a.m.
Panel Version: 3.438
We have rated this Green as most affected individuals have been reported as having some DD/ID.Created: 30 Jan 2020, 1:01 a.m. | Last Modified: 30 Jan 2020, 1:01 a.m.
Panel Version: 3.0
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Cerebellar atrophy with seizures and variable developmental delay, MIM#618501
Variants in this GENE are reported as part of current diagnostic practice
Comment on list classification: Gene was added to panel and rated Amber by Konstantinos Varvagiannis. Updated rating from Grey to Amber: phenotype is relevant to panel (MIM:618501) but developmental delay is variable amongst patients, and therefore Amber rating most appropriate.Created: 20 Sep 2019, 8:46 p.m. | Last Modified: 20 Sep 2019, 8:46 p.m.
Panel Version: 2.1039
Gene reviewed for the epilepsy panel. Due to the phenotype of EE, with variable GDD (severe in many cases) and/or ID (either specifically commented on or inferred in some cases, although not universal) this gene might also be relevant for the current panel. CACNA2D2 is also included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx) as well as the SysID database. There is no associated phenotype in G2P.
Copied from the epilepsy panel:
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].
Sources: LiteratureCreated: 15 Sep 2019, 7:51 p.m.
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
Gene: cacna2d2 has been classified as Amber List (Moderate Evidence).
Gene: cacna2d2 has been classified as Amber List (Moderate Evidence).
Phenotypes for gene: CACNA2D2 were changed from Cerebellar atrophy with seizures and variable developmental delay (MIM 618501) to Cerebellar atrophy with seizures and variable developmental delay, 618501
gene: CACNA2D2 was added gene: CACNA2D2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: CACNA2D2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CACNA2D2 were set to 23339110; 24358150; 30410802; 29997391; 31402629; 11487633; 11756448; 4177347; 14660671; 15331424 Phenotypes for gene: CACNA2D2 were set to Cerebellar atrophy with seizures and variable developmental delay (MIM 618501) Penetrance for gene: CACNA2D2 were set to Complete Review for gene: CACNA2D2 was set to AMBER gene: CACNA2D2 was marked as current diagnostic