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Intellectual disability

Gene: CUL3

Amber List (moderate evidence)

CUL3 (cullin 3)
EnsemblGeneIds (GRCh38): ENSG00000036257
EnsemblGeneIds (GRCh37): ENSG00000036257
OMIM: 603136, Gene2Phenotype
CUL3 is in 6 panels

2 reviews

Arina Puzriakova (Genomics England Curator)

Comment on list classification: Upgraded from Red to Amber, as some cases reported with severe features of ID but not yet reaching the threshold for inclusion. Additional cases/publications would also enable clarification regarding the contribution of seizures to this phenotype.
Created: 2 Oct 2020, 10:23 a.m. | Last Modified: 2 Oct 2020, 10:23 a.m.
Panel Version: 3.364
Literature search showed that CUL3 variants are often found in ASD patients, however the association with ID is much less discernible. Only two cases reported to date with severe ID features, but the same two individuals were also the only ones to present early-onset seizures. Therefore, it is difficult to distinguish whether these findings were independent of one another.
Created: 2 Oct 2020, 10:16 a.m. | Last Modified: 2 Oct 2020, 10:16 a.m.
Panel Version: 3.363
- PMID: 25969726 (2015) - Determined as a candidate gene following discovery of a de novo missense variant (c.2156A>G, p.H719R) in an autistic patient with mild ID, sleep disturbances, ADHD, and no seizures. No functional analysis was undertaken.
Created: 2 Oct 2020, 9:58 a.m. | Last Modified: 2 Oct 2020, 10:15 a.m.
Panel Version: 3.363

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

Phenotypes
Autism spectrum disorder; Intellectual disability

Publications

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Please consider upgrade to amber / green rating.
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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

Overall, this gene can be considered for inclusion in the ID (amber/green), epilepsy (amber) and/or ASD panels.
Created: 8 May 2020, 9:30 a.m. | Last Modified: 8 May 2020, 9:30 a.m.
Panel Version: 3.39

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

Phenotypes
Global developmental delay; Intellectual disability; Seizures; Abnormality of cardiovascular system morphology; Abnormality of the palate; Pseudohypoaldosteronism, type IIE - MIM #614496

Publications

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Amber
  • Victorian Clinical Genetics Services
Phenotypes
  • Global developmental delay
  • Intellectual disability
  • Autism Spectrum Disorder
  • Seizures
  • Abnormality of cardiovascular system morphology
  • Abnormality of the palate
  • Pseudohypoaldosteronism, type IIE, 614496
OMIM
603136
Clinvar variants
Variants in CUL3
Penetrance
None
Publications
Panels with this gene

History Filter Activity

2 Oct 2020, Gel status: 2

Set Phenotypes

Arina Puzriakova (Genomics England Curator)

Phenotypes for gene: CUL3 were changed from to Global developmental delay; Intellectual disability; Autism Spectrum Disorder; Seizures; Abnormality of cardiovascular system morphology; Abnormality of the palate; Pseudohypoaldosteronism, type IIE, 614496

2 Oct 2020, Gel status: 2

Set publications

Arina Puzriakova (Genomics England Curator)

Publications for gene: CUL3 were set to

2 Oct 2020, Gel status: 2

Set mode of inheritance

Arina Puzriakova (Genomics England Curator)

Mode of inheritance for gene: CUL3 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

2 Oct 2020, Gel status: 2

Entity classified by Genomics England curator

Arina Puzriakova (Genomics England Curator)

Gene: cul3 has been classified as Amber List (Moderate Evidence).

28 Sep 2018, Gel status: 1

Created, Added New Source, Set mode of inheritance

Louise Daugherty (Genomics England Curator)

gene: CUL3 was added gene: CUL3 was added to Intellectual disability. Sources: Victorian Clinical Genetics Services Mode of inheritance for gene: CUL3 was set to