Early onset or syndromic epilepsy
Gene: CUX2The mode of inheritance of this gene has been updated to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.Created: 11 Oct 2023, 11:59 a.m. | Last Modified: 11 Oct 2023, 11:59 a.m.
Panel Version: 4.110
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Almost all cases reported to date have a de novo E590K variant, there is currently no evidence supporting this gene being imprinted or for LOF variants being pathogenic. I suggest the inheritance model should be updated to be monoallelic, NOT imprinted.Created: 14 Nov 2022, 2:22 p.m. | Last Modified: 14 Nov 2022, 2:22 p.m.
Panel Version: 2.603
recurrent de novo variant reported (p.Glu590Lys)Nine de novo epilepsy cases (all the same variant) reported in PMID 29630738, plus another with the same variant subsequently identified in PMID 29795476Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.
Panel Version: 1.188
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Epileptic encephalopathy early infantile 67, 618141
Publications
Mode of pathogenicity
Other
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: Green.Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.
Panel Version: 1.189
Comment on list classification: Updated rating from Amber to Green following discussion with Sarah Leigh. A personal communication from the authors of PMID:29630738 confirm that the variants seen in 9 patients were de novo and therefore not Founder effect. Although there is no functional data and there is limited information about the patients in PMIDs:29630738, 23020937 and 23934111, overall there are sufficient cases (10 individuals from 4 papers including 2 large-scale studies) and 2 Green reviews to support inclusion on the panel as a Green gene. Plus CUX2 is now associated with an EIEE disorder in OMIM.Created: 24 Jun 2019, 11:48 a.m. | Last Modified: 24 Jun 2019, 11:48 a.m.
Panel Version: 1.65
A summary of evidence: ONE variant (Glu590Lys) reported from 9 patients in Chatron et al., 2018 (PMID:29630738) and 1 patient in Barington et al., 2018 (PMID:29795476). Barington et al claim their Danish patient is a third case as there are additionally two large scale reports from Rauch et al., 2012 (PMID:23020937) and the Epi4K Consortium (Allen et al., 2013, PMID:23934111)- there is sparse information about the patients in the large-scale papers, although the Epi4K patient is a German male. Two of the 9 patients in Chatron et al came from these large-scale studies. None of the papers perform functional studies. CUX2 was previously rated Amber as there was a question mark over the relatedness of patients in Chatron et al (this has been addressed by a pers.comm from Gemma Carvill).Created: 24 Jun 2019, 11:43 a.m. | Last Modified: 24 Jun 2019, 11:43 a.m.
Panel Version: 1.64
Re-assessing the rating of CUX2 following a new Green review by Deb Pals (the new review contains the same paper (PMID:29630738) as described by Konstantinos Varvagiannis). CUX2 is now associated with an OMIM disorder: Epileptic encephalopathy, early infantile, 67, 618141. The DD-Gene2Phenotype rating is still probable.Created: 24 Jun 2019, 11:39 a.m. | Last Modified: 24 Jun 2019, 11:39 a.m.
Panel Version: 1.64
Sarah received a reply to her query about the relatedness of patients in PMID:29630738. Gemma Carvill (personal communication, June 24th 2019) confirmed that the variant was de novo in all nine patients so not a Founder effect.Created: 24 Jun 2019, 11:38 a.m. | Last Modified: 24 Jun 2019, 11:38 a.m.
Panel Version: 1.64
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
infantile onset myoclonic DEE
Publications
Variants in this GENE are reported as part of current diagnostic practice
It is recommended that the mode of inheritance of CUX2 is changed from:
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted, based on the review by Tracy Lester (Genetics laboratory, Oxford UK)(14 Nov 2022).Created: 10 Jan 2023, 1:11 p.m. | Last Modified: 10 Jan 2023, 1:11 p.m.
Panel Version: 3.19
Comment when marking as ready: No associated with a phenotype in OMIM, but as a probable Gen2Phen gene for developmental epileptic encephalopathy. A single variant has been reported in at least 9 cases, however, at present it is unclear about whether or not the cases are related (the authors of PMID 29630738 have been contacted).Created: 25 Sep 2018, 2:07 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
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, 12:12 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes
Seizures; Intellectual disability; Autistic behavior
Publications
Tag Q1_23_MOI was removed from gene: CUX2. Tag Q1_23_NHS_review was removed from gene: CUX2.
Mode of inheritance for gene CUX2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Tag Q1_23_MOI tag was added to gene: CUX2. Tag Q1_23_NHS_review tag was added to gene: CUX2.
Phenotypes for gene: CUX2 were changed from Seizures; Epileptic encephalopathy, early infantile, 67, 618141; Infantile onset myoclonic epileptic encephalopathy to Developmental and epileptic encephalopathy 67, OMIM:618141; Infantile onset myoclonic epileptic encephalopathy
Source Wessex and West Midlands GLH was added to CUX2.
Source NHS GMS was added to CUX2.
Phenotypes for gene: CUX2 were changed from Seizures; Intellectual disability; Autistic behavior; Developmental epileptic encephalopathy to Seizures; Epileptic encephalopathy, early infantile, 67, 618141; Infantile onset myoclonic epileptic encephalopathy
Gene: cux2 has been classified as Green List (High Evidence).
Konstantinos Varvagiannis: Overall 10 unrelated individua
Gene: cux2 has been classified as Amber List (Moderate Evidence).
Gene: cux2 has been classified as Amber List (Moderate Evidence).
Phenotypes for gene: CUX2 were changed from Seizures; Intellectual disability; Autistic behavior to Seizures; Intellectual disability; Autistic behavior; Developmental epileptic encephalopathy
Gene: cux2 has been classified as Green List (High Evidence).
CUX2 was added to Genetic Epilepsy Syndromes panel. Sources: Literature
CUX2 was created by Konstantinos Varvagiannis