Holoprosencephaly

Gene: CNOT1

Amber List (moderate evidence)

CNOT1 (CCR4-NOT transcription complex subunit 1)
EnsemblGeneIds (GRCh38): ENSG00000125107
EnsemblGeneIds (GRCh37): ENSG00000125107
OMIM: 604917, Gene2Phenotype
CNOT1 is in 5 panels

2 reviews

Louise Daugherty (Genomics England Curator)

As discussed with the GMS Neurology Specialist Test Group webex call 11th July 2019: The Specialist Test Group all agreed that there is only enough evidence to rate this gene Amber
Created: 29 Jul 2019, 2:15 p.m. | Last Modified: 29 Jul 2019, 2:15 p.m.
Panel Version: 1.20

Rebecca Foulger (Genomics England curator)

Keep as amber on advice from Helen Brittain (Genomics England Clinical Fellow), and added watchlist tag; this might be a specific variant-related phenotype.
Created: 18 Jun 2019, 2:28 p.m.
Comment on list classification: Added to panel as an Amber gene based on the DD-G2P Disease confidence rating of 'probable' for 'pancreatic agenesis and holoprosencephaly syndrome'. Sufficient cases of holoprosencephaly from the literature in unrelated patients with the p.Arg535Cys variant (two/three in PMID:31006513, and two in PMID:31006510). But De Franco et al., 2019 (PMID:31006513) suggest that a mutation-specific mechanism rather than LOF is responsible for the pancreatic and holoprosencephaly phenotype since the DDD study identified de novo CNOT1 variants in three individuals with developmental delay but none of them had holoprosencephaly or diabetes.
Created: 13 May 2019, 12:25 p.m.
Added CNOT1 to the Holoprosencephaly panel based on recent (2019) literature evidence: De Franco et al., 2019 (PMID:31006513) investigated a cohort of 107 individuals with pancreatic agenesis and definite/possible holoprosencephaly, and identified a heterozygous missense variant in CNOT1 (NM_016284.4; c.1603C>T (p.Arg535Cys)) in three unrelated individuals. Definite holoprosencephaly was recorded in 2 of the cases: P01 had Partial holoprosencephaly, PO2 had Semi-lobar holoprosencephaly, PO3 had dysmorphic features consistent with possible holoprosencephaly (prominent central incisors and occiput, highly arched palate, and low-set ears). All three individuals also had pancreatic agenesis. The variant occured de novo in at least two individuals (maternal DNA was unavailable for proband 1).

Kruszka et al., 2019 (PMID:31006510) applied WES to 134 trios with Holoprosencephaly, and identified two unrelated individuals with semilobar holoprosencephaly and the identical de novo missense variant in the gene CNOT1. (c.1603C>T [p.Arg535Cys]). Additional phenotypes include developmental delay and neonatal diabetes (in proband 1).

Not yet associated with a disorder in OMIM, but a new gene:disorder association for CNOT1 was added to DDG2P on 25/04/2019: pancreatic agenesis and holoprosencephaly syndrome. Disease confidence rating in DDG2P: probable. DDG2P mutation consequence: all missense/in frame. DDG2P mode of inheritance: monoallelic.
Sources: Literature
Created: 13 May 2019, 12:19 p.m.

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

Phenotypes
pancreatic agenesis and holoprosencephaly syndrome

Publications

Mode of pathogenicity
Other

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
Phenotypes
  • Holoprosencephaly 12, with or without pancreatic agenesis, 618500
  • pancreatic agenesis and holoprosencephaly syndrome
Tags
watchlist
OMIM
604917
Clinvar variants
Variants in CNOT1
Penetrance
None
Publications
Mode of Pathogenicity
Other
Panels with this gene

History Filter Activity

19 Aug 2019, Gel status: 2

Set Phenotypes

Louise Daugherty (Genomics England Curator)

Phenotypes for gene: CNOT1 were changed from pancreatic agenesis and holoprosencephaly syndrome to Holoprosencephaly 12, with or without pancreatic agenesis, 618500; pancreatic agenesis and holoprosencephaly syndrome

29 Jul 2019, Gel status: 2

Added New Source

Louise Daugherty (Genomics England Curator)

Source NHS GMS was added to CNOT1.

18 Jun 2019, Gel status: 2

Added Tag

Rebecca Foulger (Genomics England curator)

Tag watchlist tag was added to gene: CNOT1.

13 May 2019, Gel status: 2

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

Gene: cnot1 has been classified as Amber List (Moderate Evidence).

13 May 2019, Gel status: 1

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set mode of pathogenicity

Rebecca Foulger (Genomics England curator)

gene: CNOT1 was added gene: CNOT1 was added to Holoprosencephaly. Sources: Literature Mode of inheritance for gene: CNOT1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: CNOT1 were set to 31006513; 31006510 Phenotypes for gene: CNOT1 were set to pancreatic agenesis and holoprosencephaly syndrome Mode of pathogenicity for gene: CNOT1 was set to Other