Intellectual disability - microarray and sequencing
Gene: CNOT3After NHS Genomic Medicine Service consideration, the mode of inheritance of this gene has not been changedCreated: 9 Mar 2022, 3:40 p.m. | Last Modified: 9 Mar 2022, 3:40 p.m.
Panel Version: 3.1510
Classified as a confirmed gene disease association for "CNOT3 syndrome" by Gen2Phen.Created: 25 Jun 2020, 10:51 a.m. | Last Modified: 25 Jun 2020, 10:51 a.m.
Panel Version: 3.100
The Green review by Konstantinos Varvagiannis supports the existing Green rating of CNOT3 on the ID panel.Created: 11 May 2020, 11:27 a.m. | Last Modified: 11 May 2020, 11:27 a.m.
Panel Version: 3.42
OMIM recently created an entry for this disorder : Intellectual developmental disorder with speech delay, autism, and dysmorphic facies (#618672).
The DDD study (2017 - PMID: 28135719) had identified 7 individuals with de novo CNOT3 variants (5 with missense and 2 with pLoF variants) with 5/7 presenting global developmental delay not further specified (suppl).
A recent study by Martin et al (2019 - PMID: 31201375) is the first description of the associated developmental phenotype. The authors report on 16 individuals, all harboring de novo missense or truncating CNOT3 variants. 8 of these individuals were identified by the DDD study (with other DDD cases not included).
Hypotonia, DD and ID, relatively small stature and behavioral problems (among others ASD in 6/16) were the most consistent features in their cohort. Some facial features (incl. anteverted nares, thin upper lip or low set eyebrows) were more common. Epilepsy was reported in few. As also commented in the respective OMIM entry, ID and other features were also present in subjects with missense variants.
CNOT3 encodes a subunit of the CCR4-NOT protein complex, the latter playing a role in transcriptional regulation (as well as post-transcriptional mRNA regulation) (Martin et al / Boland et al - PMID: 24121232 / OMIM).
The gene appears to be highly intolerant to both missense and LoF variants (z-score of 3.89 and pLI of 1 respectively). 7 different missense variants [3 affecting Arg188 : Arg188His (x2), Arg188Cys (x1)] and 8 different LoF variants are reported. As a result haploinsufficiency appears to be the likely mechanism.
Mutations in other genes encoding subunits of the complex (among others and CNOT2, CNOT1) cause neurodevelopmental disorders (genes rated green in the current panel).Created: 1 Dec 2019, 11:21 p.m. | Last Modified: 1 Dec 2019, 11:21 p.m.
Panel Version: 2.1134
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes
Intellectual developmental disorder with speech delay, autism, and dysmorphic facies, MIM 618672
Publications
Variants in this GENE are reported as part of current diagnostic practice
If I am reading the table in the DDD paper correctly, there are at least 2, if not 3, unrelated individuals reported with variants in this gene, and a further case in ClinVar from Ambry Genetics.Created: 23 Jul 2018, 2:17 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications
Variants in this GENE are reported as part of current diagnostic practice
This is a pertinent gene from the NIHR BioResource - Rare Diseases Study (NIHRBR-RD) BRIDGE Study : SPEED (Specialist Pathology: Evaluating Exomes in Diagnostics) which covers epilepsies, movement and microcephaly disorders, this gene is on the SPEED_NEURO_20170705 gene list. Evidences used for SPEED NEURO gene list: in_ddg2p_2_4_2017;in_ddg2p_2_4_2017_conf . Main mutation mechanism : NACreated: 27 Jul 2017, 5:22 p.m.
Mode of inheritance
Unknown
Publications
Comment on list classification: Changed Amber to Green from external expert review and further publication to support gene-disease associationCreated: 10 Aug 2018, 4:24 p.m.
Comment on phenotypes: added disease from gene2phenotype, this is confirmed G2P geneCreated: 10 Aug 2018, 4:20 p.m.
Comment on publications: Added publication suggested by reviewer to support gene-disease association, and upgrading of the gene to GreenCreated: 10 Aug 2018, 4:17 p.m.
Comment on list classification: This gene is from an expert list and needs further assessment by the Genomics England curation team to access inclusion and pertinence to this panel.Created: 28 Jul 2017, 9:54 a.m.
Source NHS GMS was added to CNOT3.
Mode of inheritance for gene: CNOT3 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CNOT3 were set to 25529582; 28135719
Phenotypes for gene: CNOT3 were changed from CNOT3 syndrome; intellectual disability, global developmental delay to CNOT3 syndrome; intellectual disability, global developmental delay; Intellectual developmental disorder with speech delay, autism, and dysmorphic facies, 618672
Source Victorian Clinical Genetics Services was added to CNOT3.
Gene: cnot3 has been classified as Green List (High Evidence).
Phenotypes for gene: CNOT3 were set to CNOT3 syndrome; intellectual disability, global developmental delay
Publications for gene: CNOT3 were set to 25529582; 28135719
Mode of inheritance for gene: CNOT3 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
12.03.2018: Due to major updates completed (Phase 1, 2 and 3), this panel was promoted to Version 2 in order to reflect the major updates since November 2017 which have resulted in reviews for 836 genes added by Genomics England Curators and the Clinical Team, 130 new Green genes added to the interpretation pipeline (from 751 to 881 Green genes), and the gene total has increased from 1879 to 1927.
This gene has been classified as Amber List (Moderate Evidence).
CNOT3 was added to Intellectual disabilitypanel. Sources: BRIDGE study SPEED NEURO Tier1 Gene
CNOT3 was created by BRIDGE