Intellectual disability
Gene: CUX2 Green List (high evidence)Comment on list classification: Following personal comunication with Gemma Louise Carvill, the variant was confirmed as de novo in all nine cases mentioned in PMID 29630738.Created: 25 Jun 2019, 8:36 a.m. | Last Modified: 25 Jun 2019, 8:36 a.m.
Panel Version: 2.884
Comment on list classification: More than three unrelated individuals reported in the literature, ID is part of the phenotype. Recent publications support gene-disease association and rating of this gene to Green. In addition to Chatron et al. (2018) who describes 9 unrelated patients with early infantile epileptic encephalopathy (there is no doubt these affected cases are not unrelated), Barington et al. (2018) PMID: 29795476 describes another unrelated patient with the same variant with early infantile epileptic encephalopathy caused by the same a de novo heterozygous E590K mutation in the CUX2 gene.Created: 31 Oct 2018, 4:59 p.m.
Comment on phenotypes: added phenotype from OMIM/MIMid and external reviewCreated: 31 Oct 2018, 4:56 p.m.
Comment on mode of inheritance: added MOI from publication and external reviewCreated: 31 Oct 2018, 4:54 p.m.
Comment on publications: added publications suggested by external reviewer which support gene-disease association and rating of this gene to Green. Intellectual disability is a prominent feature, all nine unrelated patients reported by PubMed: 29630738 had severe intellectual disability, and 7 were nonverbal.Created: 31 Oct 2018, 4:51 p.m.
Green List (high evidence)
Overall 10 unrelated individuals with seizures, intellectual disability and autistic features due to a recurrent de novo missense CUX2 SNV have been reported to date. //
PMID 29630738 describes in detail the phenotype of 7 males and 2 females with the recurrent p.Glu590Lys variant (NM_015267.3:c.1768G>A). 2 of these subjects were previously published in the context of larger studies (PMID: 23020937 and 23934111). Median age at seizure onset was 6 months (2 months - 9 years). 8 of these individuals had severe cognitive impairment, while the 9th individual was to young to assess. A few of these individuals were seizure-free at the time of inclusion while 4 (of the 9) individuals were identified by screening patient cohorts with intellectual disability with/without epilepsy (as in the case of PMID 23020937). As a result inclusion in the intellectual disability gene panel is also relevant despite epilepsy being commonly (but not always) the presenting feature. //
PMID 29795476 reports on a further individual with intellectual disability, seizures and ASD due to the de novo occurrence of the same variant. There are no shared authors between this article and PMID 29630738. //
As a result this gene could be considered for inclusion in this panel as green (or amber).Created: 19 Aug 2018, 12:10 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Phenotypes
Seizures; Intellectual disability; Autistic behavior
Publications
Red List (low evidence)
Red List (low evidence)
Expressed in the brain. Role in dendritogenesis and synaptogenesis. Candidate gene for ID in PMID: 26350204. No published cases related to ID and variants in this gene identified.Created: 27 Oct 2017, 2:46 p.m.
Publications
Red List (low evidence)
Gene: cux2 has been classified as Green List (High Evidence).
Gene: cux2 has been classified as Green List (High Evidence).
Phenotypes for gene: CUX2 were changed from to Epileptic encephalopathy, early infantile, 67, 618141; Seizures; Intellectual disability; Autistic behavior
Mode of inheritance for gene: CUX2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Publications for gene: CUX2 were set to 21331220; 26350204
12.03.2018: Due to major updates completed (Phase 1, 2 and 3), this panel was promoted to Version 2 in order to reflect the major updates since November 2017 which have resulted in reviews for 836 genes added by Genomics England Curators and the Clinical Team, 130 new Green genes added to the interpretation pipeline (from 751 to 881 Green genes), and the gene total has increased from 1879 to 1927.
Publications for gene CUX2 was set to ['21331220', '26350204']
The Gel status was updated for this whole panel
The Gel status was updated for this whole panel
CUX2 was created by ellenmcdonagh
CUX2 was added to Intellectual disabilitypanel. Sources: Expert Review Red
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).
OR
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).
OR
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.
AND
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
AND
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.