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.
Created: 13 May 2019, 12:19 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
pancreatic agenesis and holoprosencephaly syndrome
Mode of pathogenicity
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
Source NHS GMS was added to CNOT1.
Tag watchlist tag was added to gene: CNOT1.
Gene: cnot1 has been classified as Amber List (Moderate Evidence).
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