Intellectual disability - microarray and sequencing
Gene: CUL3
Associated with relevant phenotype in OMIM and as definitive Gen2Phen gene. At least seven variants have been reported in publications (PMIDs: 32341456;25969726;31696658;33097317;30311385) in at least seven unrelated cases, together with a case reported by Julie Evans (South West Genomic Laboratory Hub) all being diagnosed with Neurodevelopmental disorder with or without autism or seizures, OMIM:619239. Severe intellectual disability (ID) was observed in two of these cases, mild in three cases and unclassified ID in another case. Seizures were also evident in three cases and a febrile seizure was reported in another case.Created: 9 Jun 2022, 5:53 p.m. | Last Modified: 9 Jun 2022, 5:53 p.m.
Panel Version: 3.1599
Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.Created: 9 Jun 2022, 5:29 p.m. | Last Modified: 9 Jun 2022, 5:29 p.m.
Panel Version: 3.1599
We have an additional case with a de novo consensus splice variant that we assessed as likely pathogenic. Our patient has intellectual disability, autism and possible seizures.Created: 28 May 2022, 10:20 a.m. | Last Modified: 28 May 2022, 10:20 a.m.
Panel Version: 3.1593
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Intellectual disability; seizures; autism
The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.Created: 30 Jan 2023, 5:50 p.m. | Last Modified: 30 Jan 2023, 5:50 p.m.
Panel Version: 4.53
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
Please consider upgrade to amber / green rating.
---
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
Tag Q3_22_rating was removed from gene: CUL3. Tag Q3_22_NHS_review was removed from gene: CUL3.
Source NHS GMS was added to CUL3. Source Expert Review Green was added to CUL3. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Tag Q3_22_rating tag was added to gene: CUL3. Tag Q3_22_NHS_review tag was added to gene: CUL3.
Gene: cul3 has been classified as Amber List (Moderate Evidence).
Publications for gene: CUL3 were set to 32341456; 25969726; 31696658; 33097317
Phenotypes for gene: CUL3 were changed from Global developmental delay; Intellectual disability; Autism Spectrum Disorder; Seizures; Abnormality of cardiovascular system morphology; Abnormality of the palate; Pseudohypoaldosteronism, type IIE, 614496 to Neurodevelopmental disorder with or without autism or seizures, OMIM:619239
Publications for gene: CUL3 were set to 32341456; 25969726
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
Publications for gene: CUL3 were set to
Mode of inheritance for gene: CUL3 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Gene: cul3 has been classified as Amber List (Moderate Evidence).
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