Holoprosencephaly - NOT chromosomal

Gene: CNOT1

Green List (high evidence)

The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.

Created: 31 Jan 2023, 5:59 p.m. | Last Modified: 31 Jan 2023, 5:59 p.m.

Panel Version: 3.4

Comment on list classification: Leaving the rating as Amber for now, however an additional case with the same variant as other cases and a holoprosencephaly phenotype has been reported, and so the rating should reviewed by the GMS.

Created: 27 Sep 2022, 12:47 p.m. | Last Modified: 27 Sep 2022, 12:47 p.m.

Panel Version: 2.29

Another case with the same variant reported in PMID:35481434 - Cospain et al 2022 - a foetus with semi-lobar HPE diagnosed at ultrasound and total pancreas agenesis identified at general autopsy. WES found the CNOT1 missense c.1603C>T, p.(Arg535Cys), occurring de novo.

Created: 27 Sep 2022, 12:39 p.m. | Last Modified: 27 Sep 2022, 12:39 p.m.

Panel Version: 2.27

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

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

• 31006513
• 31006510

Mode of pathogenicity
Other