Intellectual disabilityGene: CACNA1E Green List (high evidence)
Comment on list classification: New gene added by external expert and reviewed by curation team, appropriate phenotype, sufficient cases and external expert review all support gene-disease association and relevance to this panel to rate gene to Green.
Created: 21 Feb 2019, 2:31 p.m.
Comment on publications: added Helbig et al. publication that supports the gene-disease association, and upgrading of the gene to Green
Created: 21 Feb 2019, 2:29 p.m.
Comment on phenotypes: added phenotype info from OMIM and MIMid
Created: 21 Feb 2019, 2:25 p.m.
Green List (high evidence)
Helbig et al. (https://doi.org/10.1016/j.ajhg.2018.09.006) report on 30 individuals with pathogenic variants in CACNA1E.
The phenotype was consistent with a developmental and epileptic encephalopathy, with hypotonia, early-onset and refractory seizures, severe to profound developmental delay and intellectual disability. Additional relatively common features included hyperkinetic movement disorder (severe dystonia which was observed in 40%, other dyskinesias in another 20%), congenital joint contractures of variable degree and joint involvement (approx. 40% of individuals) and macrocephaly (approx. 40%). There were no common facial dysmorphic features observed.
Of note, epilepsy was not a feature in 4 cases (age 1 to 4 years) so few of these individuals may be investigated for their developmental delay/intellectual disability or other features.
All the 30 subjects described harbored a missense variant in CACNA1E which in all cases where parental studies were possible (29/30) occurred as a de novo event. There were 4 recurrent variants, explaining the phenotype in 20 patients in total while the rest of the individuals had private mutations. Functional studies were performed and suggested a gain-of-function effect for these variants (increased calcium inward currents).
Loss-of-function (LoF) variants:
Apart from the main cohort of patients, the authors note the presence of 3 individuals with such variants incl.:
- one individual with a nonsense variant present in the mosaic state (6/22 reads) in peripheral blood.
- one individual with a frameshift variant inherited from his unaffected parent.
- one individual with a nonsense variant for whom parental studies were not possible.
The authors comment that these indivdiduals presented with milder phenotype compared to those with missense variants. More information on these subjects is provided in the supplement as the article focuses on missense SNVs.
As the authors also note, several LoF variants exist in gnomAD, although the gene appears to be LoF intolerant (pLI=1).
Seems to be complete for missense SNVs and possibly incomplete for LoF ones.
A previous study by Heyne et al. (PMID: 29942082) implicated de novo variants (DNVs) in CACNA1E with neurodevelopmental disorders for the first time. This study however does not provide clinical details on the phenotype of the affected individuals, while it seems to present overlap as to the individuals reported (eg. includes subjects from the DDD study and others).
Details as to a few - possibly further - de novo coding variants reported to date can be found at the denovo-db:
As a result this gene can be considered for inclusion in this panel as green.
Sources: Expert Review, Literature
Created: 19 Oct 2018, 7:58 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Global developmental delay; Intellectual disability; Seizures; Dystonia; Congenital contracture; Macrocephaly
Mode of pathogenicity
Gene: cacna1e has been classified as Green List (High Evidence).
Publications for gene: CACNA1E were set to 29942082
Phenotypes for gene: CACNA1E were changed from Global developmental delay; Intellectual disability; Seizures; Dystonia; Congenital contracture; Macrocephaly to Global developmental delay; Intellectual disability; Seizures; Dystonia; Congenital contracture; Macrocephaly; Epileptic encephalopathy, early infantile, 69, 618285
gene: CACNA1E was added gene: CACNA1E was added to Intellectual disability. Sources: Expert Review,Literature Mode of inheritance for gene: CACNA1E was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: CACNA1E were set to 29942082 Phenotypes for gene: CACNA1E were set to Global developmental delay; Intellectual disability; Seizures; Dystonia; Congenital contracture; Macrocephaly Penetrance for gene: CACNA1E were set to Incomplete Mode of pathogenicity for gene: CACNA1E was set to Other Review for gene: CACNA1E was set to GREEN
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at [email protected]
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.