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Early onset or syndromic epilepsy v2.47 CUL3 Konstantinos Varvagiannis gene: CUL3 was added
gene: CUL3 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: CUL3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CUL3 were set to 32341456
Phenotypes for gene: CUL3 were set to Global developmental delay; Intellectual disability; Seizures; Abnormality of cardiovascular system morphology; Abnormality of the palate; Pseudohypoaldosteronism, type IIE - MIM #614496
Penetrance for gene: CUL3 were set to unknown
Review for gene: CUL3 was set to AMBER
Added comment: Epilepsy has been reported in at least 2 relevant individuals in the literature.
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Nakashima et al (2020 - PMID:32341456) provide clinical details on 3 unrelated individuals with de novo CUL3 variants.

Features included DD, variable degrees of ID (P1: severe, P3: mild, P2: NA although he displayed motor and severe speech and language delay and had severe learning difficulties). Two out of three had intractable seizures (onset 2 - 6 months). One presented with congenital heart defects (ASD, PV stenosis) and another submucosal palatoschisis/bifid uvula. There were no facial dysmorphisms reported.

CUL3 encodes Cullin-3, a core piece of the E3 ubiquitin ligase complex, thus playing a role in the ubiquitin-proteasome system. [ https://ghr.nlm.nih.gov/gene/CUL3 ]. Germline variants in some other Cullin family genes (eg. CUL4B, CUL7) cause disorders with ID as a feature.

The 3 individuals reported by Nakashima had variable previous investigations (karyotype, CMA, metabolic testing) which were non-diagnostic. Singleton or trio exome sequencing identified 2 frameshift and 1 missense variant (NM_003590.4:c.854T>C / p.Val285Ala), further confirmed with Sanger sequencing. De novo occurrence was confirmed by analysis of microsatellite markers in an individual with singleton ES.

While the frameshift variants were presumed to lead to NMD (not studied), studies in HEK293T cells suggested that the Val285Ala reduced binding ability with KEAP1, possibly leading to instability of the Cullin-RING ligase (CRL) complex and impairment of the ubiquitin-proteasome system.

In OMIM, the phenotype associated with heterozygous CUL3 mutations is Pseudohypoaldosteronism type IIE (PHA2E - # 614496). As OMIM and Nakashima et al comment, PHA2E-associated variants are clustered around exon 9, most lead to skipping of exon 9 and produce an in-frame deletion of 57 aa in the cullin homology domain. Few (probably 3) missense variants in exon 9 have also been reported. Individuals with PHA2E do not display DD/ID and conversely individuals with NDD did not display features of PHA2E.

Nakashima et al summarize the phenotypes associated with 12 further de novo CUL3 variants in the literature with most pLOF ones detected in individuals with autism and/or developmental disorders and in few cases with congenital heart disease. Few additional missense variants and a stoploss one have been reported in individuals with NDD and one in SCZ.

Heterozygous Cul3 (/tissue-specific) deletion in mice resulted in autism-like behavior. Cul3 deficient mice also demonstrated NMDAR hypofunction and decreased spine density. [PMIDs cited : 31455858, 31780330]

Overall haploinsufficiency is favored as the underlying mechanism of variants associated with NDD. Nakashima et al comment that the pathogenesis of missense variants remains unknown and/or that a dominant-negative effect on CRL may be possible.

Studies on larger cohorts reporting on individuals with relevant phenotypes due to de novo CUL3 variants (eg. DDD study - PMID: 28135719, Lelieveld et al - PMID: 27479843), are better summarized in denovo-db (after filtering for coding variants):

http://denovo-db.gs.washington.edu/denovo-db/QueryVariantServlet?searchBy=Gene&target=cul3
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Please consider inclusion in other panels if appropriate (e.g. for ASD).
Sources: Literature
Early onset or syndromic epilepsy v1.233 CUL4B Rebecca Foulger Marked gene: CUL4B as ready
Early onset or syndromic epilepsy v1.233 CUL4B Rebecca Foulger Gene: cul4b has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.222 CUL4B Rebecca Foulger changed review comment from: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019: Agreed that there is enough evidence to rate this gene Green. Promoted from Amber to Green.; to: 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.
Early onset or syndromic epilepsy v1.215 CUL4B Rebecca Foulger Classified gene: CUL4B as Green List (high evidence)
Early onset or syndromic epilepsy v1.215 CUL4B Rebecca Foulger Gene: cul4b has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.214 CUL4B Rebecca Foulger commented on gene: CUL4B: As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019: Agreed that there is enough evidence to rate this gene Green. Promoted from Amber to Green.
Early onset or syndromic epilepsy v1.191 CUL4B Rebecca Foulger Source Wessex and West Midlands GLH was added to CUL4B.
Early onset or syndromic epilepsy v1.189 CUL4B Rebecca Foulger edited their review of gene: CUL4B: Added comment: 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. ; Changed rating: AMBER
Early onset or syndromic epilepsy v1.188 CUL4B Tracy Lester reviewed gene: CUL4B: Rating: GREEN; Mode of pathogenicity: ; Publications: 22182342, 17236139 ; Phenotypes: Mental retardation, X-linked, syndromic 15 (Cabezas type), 300354; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Early onset or syndromic epilepsy v1.185 CUL4B Rebecca Foulger changed review comment from: 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 seizues in 14/22 patients. However this includes the febrile seizures noted in PMID:17236139 (Tarpet et al 2007).; to: 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).
Early onset or syndromic epilepsy v1.185 CUL4B Rebecca Foulger changed review comment from: PMID:22182342: Ravn et al., 2012 report a monozygotic Danish twin pair with a CUL4B deletion. Seizures is reported in both patients but no further details on the seizures are given. Ravn et al also summarise previous studies and note seizues in 14/22 patients. However this includes the febrile seizures noted in PMID:17236139 (Tarpet et al 2007).; to: 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 seizues in 14/22 patients. However this includes the febrile seizures noted in PMID:17236139 (Tarpet et al 2007).
Early onset or syndromic epilepsy v1.84 CUL4B Rebecca Foulger Classified gene: CUL4B as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.84 CUL4B Rebecca Foulger Added comment: 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.
Early onset or syndromic epilepsy v1.84 CUL4B Rebecca Foulger Gene: cul4b has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.83 CUL4B Rebecca Foulger commented on gene: CUL4B: PMID:20014135: Isifor et al., 2010 report a de novo deletion of CUL4B in a boy with syndromic ID. Seizures were not reported.
Early onset or syndromic epilepsy v1.83 CUL4B Rebecca Foulger commented on gene: CUL4B: 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.
Early onset or syndromic epilepsy v1.83 CUL4B Rebecca Foulger changed review comment from: 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; to: 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.
Early onset or syndromic epilepsy v1.83 CUL4B Rebecca Foulger commented on gene: CUL4B: 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
Early onset or syndromic epilepsy v1.83 CUL4B Rebecca Foulger commented on gene: CUL4B: PMID:22182342: Ravn et al., 2012 report a monozygotic Danish twin pair with a CUL4B deletion. Seizures is reported in both patients but no further details on the seizures are given. Ravn et al also summarise previous studies and note seizues in 14/22 patients. However this includes the febrile seizures noted in PMID:17236139 (Tarpet et al 2007).
Early onset or syndromic epilepsy v1.83 CUL4B Rebecca Foulger commented on gene: CUL4B: 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).
Early onset or syndromic epilepsy v1.83 CUL4B Rebecca Foulger commented on gene: CUL4B: 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.
Early onset or syndromic epilepsy v1.83 CUL4B Rebecca Foulger commented on gene: CUL4B: 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.
Early onset or syndromic epilepsy v1.83 CUL4B Rebecca Foulger Publications for gene: CUL4B were set to 25385192; 17236139
Early onset or syndromic epilepsy v1.82 CUL4B Rebecca Foulger 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
Added comment: 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