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Genetic epilepsy syndromes

Gene: CUL4B

Green List (high evidence)

CUL4B (cullin 4B)
EnsemblGeneIds (GRCh38): ENSG00000158290
EnsemblGeneIds (GRCh37): ENSG00000158290
OMIM: 300304, Gene2Phenotype
CUL4B is in 8 panels

2 reviews

Tracy Lester (Genetics laboratory, Oxford UK)

Green List (high evidence)

X-linked recessive syndromic mental retardation 15. Seizures isted as feature on OMIM - Vulto-van Silfhout et al, 2015 - 24 patients from 10 families - 32% had seizures & Ravn et al, 2012 - Danish monozygotic twins - both had seizures. Other reported cases with no seizures as well on OMIM.
Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.
Panel Version: 1.188

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Phenotypes
Mental retardation, X-linked, syndromic 15 (Cabezas type), 300354

Publications

Rebecca Foulger (Genomics England curator)

I don't know

As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Promoted from Amber to Green.
Created: 13 Aug 2019, 3:58 p.m. | Last Modified: 15 Aug 2019, 8:05 a.m.
Panel Version: 1.222
This gene was part of an initial gene list 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: John Taylor and Helen Lord. 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: Added CUL4B to the panel and rated Amber awaiting further clinical review. Seizures are noted in the literature in >30% of patients- although there are sufficient unrelated cases, the seizure phenotype is not consistent. Plus some of the cases recorded as seizures refer to febrile seizures, which are out of scope of this panel (e.g. PMID:17236139), and detailed information on seizures is not provided in most papers.
Created: 1 Jul 2019, 11:52 a.m. | Last Modified: 1 Jul 2019, 11:52 a.m.
Panel Version: 1.84
PMID:20014135: Isifor et al., 2010 report a de novo deletion of CUL4B in a boy with syndromic ID. Seizures were not reported.
Created: 1 Jul 2019, 11:48 a.m. | Last Modified: 1 Jul 2019, 11:48 a.m.
Panel Version: 1.83
PMID:20002452: Badura-Stronka et al., 2010 report a CUL4B nonsense variant in 3 brothers with X-linked ID.
2 brothers had a single seizure, in the setting of infection. Therefore not appropriate in the context of this epilepsy panel.
Created: 1 Jul 2019, 11:48 a.m. | Last Modified: 1 Jul 2019, 11:48 a.m.
Panel Version: 1.83
PMID:17273978: Zou et al., 2007 analyse a previously reported (PMID:8135271) family (5 individuals) with X-linked ID and implicate p.R388X nonsense variant in CUL4B as the cause. 4/5 patients had seizures according to the summaries in PMID:20014135 and PMID:22182342.
Created: 1 Jul 2019, 11:48 a.m. | Last Modified: 1 Jul 2019, 11:48 a.m.
Panel Version: 1.83
PMID:22182342: Ravn et al., 2012 report a monozygotic Danish twin pair with a CUL4B deletion. Seizures are reported in both patients but no further details on the seizures are given. Ravn et al also summarise previous studies and note seizures in 14/22 patients. However this includes the febrile seizures noted in PMID:17236139 (Tarpet et al 2007).
Created: 1 Jul 2019, 11:48 a.m. | Last Modified: 1 Aug 2019, 12:50 p.m.
Panel Version: 1.185
PMID:17236139: Tarpet et al., 2007 report CUL4B variants in 8/250 families with X-linked mental retardation. Segregation analysis is performed for all 8 families. Seizures (before age 2) reported in 8/11 affected males (Table 2). However the seizures are reported to be usually single febrile fits. The authors also note that further evidence is required to confirm that the missense variants are disease causing (e.g. in Family 432 it is possible that C638C>T (T213I) is a rare variant because ethically-matched controls were unavailable).
Created: 1 Jul 2019, 11:48 a.m. | Last Modified: 1 Jul 2019, 11:48 a.m.
Panel Version: 1.83
PMID:25385192: Vulto-van Silfhout et al, 2015 identified CUL4B variants in 8/407 families with X-linked mental retardation. Plus CUL4B variants in an additional 3 patients (2 families) with malformations of cortical development. Ten different variants were identified in the 10 families (5 truncating, 2 splice, 1 in-frame deletion, 1 in-frame duplication, 1 missense). Across the 10 families with CUL4B variants, 7/22 (32%) of the individuals had seizures, though the phenotype was not always consistent between family members: In both family 1 (N151) and family 5 (D173), 1 of 3 individuals had seizures. The authors note that previously 17/30 (57%) of individuals with CUL4B variants were reported to have seizures.
Created: 1 Jul 2019, 11:48 a.m. | Last Modified: 1 Jul 2019, 11:48 a.m.
Panel Version: 1.83
Seizures listed amongst the phenotypes of MENTAL RETARDATION SYNDROMIC X-LINKED CABEZAS TYPE in Gene2Phenotype. Seizures (onset <2 years) listed amongst the phenotypes in OMIM for Mental retardation, X-linked, syndromic 15 (Cabezas type), MIM:300354.
Created: 1 Jul 2019, 11:47 a.m. | Last Modified: 1 Jul 2019, 11:47 a.m.
Panel Version: 1.83
Added to Genetic epilepsy syndromes panel based on gene list submitted by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group.
Sources: NHS GMS, Literature
Created: 1 Jul 2019, 11:46 a.m.

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Phenotypes
Mental retardation, X-linked, syndromic 15 (Cabezas type), 300354; seizures

Publications

Details

Mode of Inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females
Sources
  • Expert Review Green
  • Wessex and West Midlands GLH
  • Literature
  • NHS GMS
Phenotypes
  • Mental retardation, X-linked, syndromic 15 (Cabezas type), 300354
  • seizures
OMIM
300304
Clinvar variants
Variants in CUL4B
Penetrance
None
Publications
Panels with this gene

History Filter Activity

15 Aug 2019, Gel status: 3

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

Gene: cul4b has been classified as Green List (High Evidence).

13 Aug 2019, Gel status: 3

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

Gene: cul4b has been classified as Green List (High Evidence).

6 Aug 2019, Gel status: 2

Added New Source

Rebecca Foulger (Genomics England curator)

Source Wessex and West Midlands GLH was added to CUL4B.

1 Jul 2019, Gel status: 2

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

Gene: cul4b has been classified as Amber List (Moderate Evidence).

1 Jul 2019, Gel status: 1

Set publications

Rebecca Foulger (Genomics England curator)

Publications for gene: CUL4B were set to 25385192; 17236139

1 Jul 2019, Gel status: 1

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes

Rebecca Foulger (Genomics England curator)

gene: CUL4B was added gene: CUL4B was added to Genetic epilepsy syndromes. Sources: NHS GMS,Literature Mode of inheritance for gene: CUL4B was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: CUL4B were set to 25385192; 17236139 Phenotypes for gene: CUL4B were set to Mental retardation, X-linked, syndromic 15 (Cabezas type), 300354; seizures