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Genetic epilepsy syndromes

Gene: CUX2

Green List (high evidence)

CUX2 (cut like homeobox 2)
EnsemblGeneIds (GRCh38): ENSG00000111249
EnsemblGeneIds (GRCh37): ENSG00000111249
OMIM: 610648, Gene2Phenotype
CUX2 is in 5 panels

5 reviews

Tracy Lester (Genetics laboratory, Oxford UK)

Green List (high evidence)

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 29795476
Created: 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

Rebecca Foulger (Genomics England curator)

I don't know

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

Deb Pal (King's College London)

Green List (high evidence)

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

Sarah Leigh (Genomics England Curator)

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.

Konstantinos Varvagiannis (Other)

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, 12:12 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Seizures; Intellectual disability; Autistic behavior

Publications

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Wessex and West Midlands GLH
  • NHS GMS
  • Expert Review Green
Phenotypes
  • Seizures
  • Epileptic encephalopathy, early infantile, 67, 618141
  • Infantile onset myoclonic epileptic encephalopathy
OMIM
610648
Clinvar variants
Variants in CUX2
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

6 Aug 2019, Gel status: 3

Added New Source

Rebecca Foulger (Genomics England curator)

Source Wessex and West Midlands GLH was added to CUX2.

6 Aug 2019, Gel status: 3

Added New Source

Rebecca Foulger (Genomics England curator)

Source NHS GMS was added to CUX2.

24 Jun 2019, Gel status: 3

Set Phenotypes

Rebecca Foulger (Genomics England curator)

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

24 Jun 2019, Gel status: 3

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

Gene: cux2 has been classified as Green List (High Evidence).

11 Dec 2018, Gel status: 2

Panel promoted to version 1.0

Sarah Leigh (Genomics England Curator)

Konstantinos Varvagiannis: Overall 10 unrelated individua

25 Sep 2018, Gel status: 2

Entity classified by Genomics England curator

Sarah Leigh (Genomics England Curator)

Gene: cux2 has been classified as Amber List (Moderate Evidence).

25 Sep 2018, Gel status: 2

Entity classified by Genomics England curator

Sarah Leigh (Genomics England Curator)

Gene: cux2 has been classified as Amber List (Moderate Evidence).

25 Sep 2018, Gel status: 3

Set Phenotypes

Sarah Leigh (Genomics England Curator)

Phenotypes for gene: CUX2 were changed from Seizures; Intellectual disability; Autistic behavior to Seizures; Intellectual disability; Autistic behavior; Developmental epileptic encephalopathy

25 Sep 2018, Gel status: 3

Entity classified by Genomics England curator

Sarah Leigh (Genomics England Curator)

Gene: cux2 has been classified as Green List (High Evidence).

19 Aug 2018, Gel status: 0

Added New Source

Konstantinos Varvagiannis (Other)

CUX2 was added to Genetic Epilepsy Syndromes panel. Sources: Literature

19 Aug 2018, Gel status: 0

Created

Konstantinos Varvagiannis (Other)

CUX2 was created by Konstantinos Varvagiannis