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Intellectual disability

Gene: CNOT3

Green List (high evidence)

CNOT3 (CCR4-NOT transcription complex subunit 3)
EnsemblGeneIds (GRCh38): ENSG00000088038
EnsemblGeneIds (GRCh37): ENSG00000088038
OMIM: 604910, Gene2Phenotype
CNOT3 is in 4 panels

4 reviews

Konstantinos Varvagiannis (Other)

Green List (high evidence)

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

Zornitza Stark (Australian Genomics)

Green List (high evidence)

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

BRIDGE consortium (NIHRBR-RD)

Green List (high evidence)

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 : NA
Created: 27 Jul 2017, 5:22 p.m.

Mode of inheritance
Unknown

Publications

Louise Daugherty (Genomics England Curator)

Comment on list classification: Changed Amber to Green from external expert review and further publication to support gene-disease association
Created: 10 Aug 2018, 4:24 p.m.
Comment on phenotypes: added disease from gene2phenotype, this is confirmed G2P gene
Created: 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 Green
Created: 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.

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Victorian Clinical Genetics Services
  • Expert Review Green
Phenotypes
  • CNOT3 syndrome
  • intellectual disability, global developmental delay
OMIM
604910
Clinvar variants
Variants in CNOT3
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

28 Sep 2018, Gel status: 4

Added New Source

Louise Daugherty (Genomics England Curator)

Source Victorian Clinical Genetics Services was added to CNOT3.

10 Aug 2018, Gel status: 3

Entity classified by Genomics England curator

Louise Daugherty (Genomics England Curator)

Gene: cnot3 has been classified as Green List (High Evidence).

10 Aug 2018, Gel status: 2

Set Phenotypes

Louise Daugherty (Genomics England Curator)

Phenotypes for gene: CNOT3 were set to CNOT3 syndrome; intellectual disability, global developmental delay

10 Aug 2018, Gel status: 2

Set publications

Louise Daugherty (Genomics England Curator)

Publications for gene: CNOT3 were set to 25529582; 28135719

10 Aug 2018, Gel status: 2

Set mode of inheritance

Louise Daugherty (Genomics England Curator)

Mode of inheritance for gene: CNOT3 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

12 Mar 2018, Gel status: 2

Panel promoted to version 2.0

Ellen McDonagh (Genomics England Curator)

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.

28 Jul 2017, Gel status: 2

Gene classified by Genomics England curator

Louise Daugherty (Genomics England Curator)

This gene has been classified as Amber List (Moderate Evidence).

27 Jul 2017, Gel status: 0

Added New Source

BRIDGE consortium (NIHRBR-RD)

CNOT3 was added to Intellectual disabilitypanel. Sources: BRIDGE study SPEED NEURO Tier1 Gene

27 Jul 2017, Gel status: 0

Created

BRIDGE consortium (NIHRBR-RD)

CNOT3 was created by BRIDGE