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Early onset or syndromic epilepsy v4.110 CUX2 Arina Puzriakova Tag Q1_23_MOI was removed from gene: CUX2.
Tag Q1_23_NHS_review was removed from gene: CUX2.
Early onset or syndromic epilepsy v4.110 CUX2 Arina Puzriakova reviewed gene: CUX2: Rating: ; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v4.109 CUX2 Arina Puzriakova Mode of inheritance for gene CUX2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v3.19 CUX2 Sarah Leigh Tag Q1_23_MOI tag was added to gene: CUX2.
Tag Q1_23_NHS_review tag was added to gene: CUX2.
Early onset or syndromic epilepsy v3.19 CUX2 Sarah Leigh edited their review of gene: CUX2: Added comment: 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).; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v2.603 CUX2 Tracy Lester edited their review of gene: CUX2: Added comment: 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.; Changed mode of pathogenicity: Other; Changed publications to: 29795476, 29630738
Early onset or syndromic epilepsy v2.428 TNPO2 Arina Puzriakova gene: TNPO2 was added
gene: TNPO2 was added to Genetic epilepsy syndromes. Sources: Literature
Q3_21_rating tags were added to gene: TNPO2.
Mode of inheritance for gene: TNPO2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TNPO2 were set to 34314705
Phenotypes for gene: TNPO2 were set to Intellectual disability; Dysmorphic features; Microcephaly; Seizures; Hypotonia
Review for gene: TNPO2 was set to GREEN
Added comment: Goodman et al., 2021 (PMID: 34314705) reported on 15 unrelated individuals with different variants in this gene (14 de novo, 1 mosaic in mother; 12 SNVs, 3 in-frame deletions, 1 deletion-insertion). All had GDD and all those who were assessed also had ID (9/9), ranging from mild to severe. ID also suspected but not investigated in another 3 cases. 6 had seizures starting between 1 and 2.5 years of age. 5 individuals had microcephaly (HC ranging -2.77 to -4.53 SD). Other less common features were also observed such as variable brain, gastrointestinal and ophthalmologic abnormalities.

Notably 6 individuals had additional SNVs/CNVs of uncertain significance, some of which include known ID genes (e.g. SETBP1, CUX2, ARMC9, PDE4D), but were discounted due to lack of explanation of the overall patient phenotype.

Some functional studies conducted in Drosophila demonstrated that patient-associated variants caused neurodevelopmental defects that were dosage and location (of variant within protein) dependent.
Sources: Literature
Early onset or syndromic epilepsy v2.370 CUX2 Arina Puzriakova 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
Early onset or syndromic epilepsy v1.191 CUX2 Rebecca Foulger Source Wessex and West Midlands GLH was added to CUX2.
Early onset or syndromic epilepsy v1.190 CUX2 Rebecca Foulger Source NHS GMS was added to CUX2.
Early onset or syndromic epilepsy v1.189 CUX2 Rebecca Foulger edited their review of gene: CUX2: Added comment: 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. ; Changed rating: AMBER
Early onset or syndromic epilepsy v1.188 CUX2 Tracy Lester reviewed gene: CUX2: Rating: GREEN; Mode of pathogenicity: ; Publications: 29795476, 29630738 ; Phenotypes: Epileptic encephalopathy early infantile 67, 618141; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.66 CUX2 Rebecca Foulger 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
Early onset or syndromic epilepsy v1.65 CUX2 Rebecca Foulger Classified gene: CUX2 as Green List (high evidence)
Early onset or syndromic epilepsy v1.65 CUX2 Rebecca Foulger Added comment: 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.
Early onset or syndromic epilepsy v1.65 CUX2 Rebecca Foulger Gene: cux2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.64 CUX2 Rebecca Foulger commented on gene: CUX2: 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).
Early onset or syndromic epilepsy v1.64 CUX2 Rebecca Foulger commented on gene: CUX2: 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.
Early onset or syndromic epilepsy v1.64 CUX2 Rebecca Foulger commented on gene: CUX2
Early onset or syndromic epilepsy v1.13 CUX2 Deb Pal reviewed gene: CUX2: Rating: GREEN; Mode of pathogenicity: None; Publications: 29630738; Phenotypes: infantile onset myoclonic DEE; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Early onset or syndromic epilepsy v0.442 CUX2 Sarah Leigh Marked gene: CUX2 as ready
Early onset or syndromic epilepsy v0.442 CUX2 Sarah Leigh Added comment: 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).
Early onset or syndromic epilepsy v0.442 CUX2 Sarah Leigh Gene: cux2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.442 CUX2 Sarah Leigh Classified gene: CUX2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v0.442 CUX2 Sarah Leigh Gene: cux2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v0.441 CUX2 Sarah Leigh Phenotypes for gene: CUX2 were changed from Seizures; Intellectual disability; Autistic behavior to Seizures; Intellectual disability; Autistic behavior; Developmental epileptic encephalopathy
Early onset or syndromic epilepsy v0.440 CUX2 Sarah Leigh Classified gene: CUX2 as Green List (high evidence)
Early onset or syndromic epilepsy v0.440 CUX2 Sarah Leigh Gene: cux2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy CUX2 Konstantinos Varvagiannis Added gene to panel