Neonatal diabetes
Gene: CNOT1The to_be_confirmed_NHSE tag has been added, as further NHSE review is required before promoting this gene to green.Created: 31 Jan 2023, 4:43 p.m. | Last Modified: 31 Jan 2023, 4:43 p.m.
Panel Version: 3.3
Comment on list classification: Promoting from red to amber with a recommendation for consideration of green rating following expert GMS review, however the pancreatic agenesis is associated with one missense variant only.Created: 27 Sep 2022, 12:45 p.m. | Last Modified: 27 Sep 2022, 12:57 p.m.
Panel Version: 2.45
Comment on mode of pathogenicity: Only one missense variant reported in all cases. All de novo.Created: 27 Sep 2022, 12:43 p.m. | Last Modified: 27 Sep 2022, 12:43 p.m.
Panel Version: 2.42
Associated with Holoprosencephaly 12, with or without pancreatic agenesis, 618500 (AD) in OMIM and HOLOPROSENCEPHALY 12 WITH OR WITHOUT PANCREATIC AGENESIS (strong) in Gene2Phenotype.
3 publications reporting 6 unrelated probands with the same de novo missense variant in CNOT and a holoprosencephaly phenotype. 5/6 also had pancreatic agenesis.
PMID:35481434 - Cospain et al 2022 - report 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.
PMID:31006513 - de Franco et al 2019 - looked at an international cohort of 107 individuals diagnosed with pancreatic agenesis and identified 3 unrelated individuals with CNOT1 variant c.1603C>T [p.Arg535Cys]. In 2 patients it was confirmed as de novo (maternal DNA not available for the 3rd). 2 of the patients had definite holoprosencephaly and one had possible holoprosencephaly. They report that the DDD study5 has identified other de novo CNOT1 variants in three individuals with developmental delay (2 missense and 1 nonsense) but none of them had holoprosencephaly or diabetes. Mice heterozygous for p.Arg535Cys variant showed no phenotype, but homozygotes (embryonically lethal) were found to have significant reduction in the size of the pancreas and neurological abnormalities.
PMID:31006510 - Kruszka et al 2019 - 2 unrelated individuals with semilobar holoprosencephaly with de novo variants in CNOT1 (c.1603C>T [p.Arg535Cys]) identified by WES. Both probands also presented with hearing loss and global developmental delay. Proband 1 also had diabetes insipidus, neonatal diabetes mellitus requiring insulin, pancreatic exocrine insufficiency requiring enzyme therapy.Created: 27 Sep 2022, 12:38 p.m. | Last Modified: 27 Sep 2022, 12:38 p.m.
Panel Version: 2.40
Review on behalf of Jayne Houghton and Kevin Colclough, Exeter Genomics Laboratory, SWGLH. De Franco et al 2019 Am J Hum Genet PMID:31006513, Cospain et al 2022, Pediatr Dev Pathol PMID:35481434, Kruszka et al 2019 Am J Hum Genet PMID:31006510) have reported a variant specific novel genetic syndrome of pancreatic agenesis and holoprosencephaly. The variant (c.1603C>T, p.(Arg535Cys) identified in CNOT1 has been reported in patients presenting with low birth weight (IUGR) as a result of reduced insulin secretion in utero, neonatal diabetes, pancreatic agenesis (defined as requiring both endocrine and exocrine replacement therapy) and holoprosencephaly. A mouse model of this specific variant supports CNOT1 playing a critical role in pancreatic and neurological development.Created: 14 Sep 2022, 4:42 p.m. | Last Modified: 14 Sep 2022, 4:42 p.m.
Panel Version: 2.40
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes
Neonatal diabetes, pancreatic agenesis and holoprosencephaly.
Publications
Tag Q3_22_rating was removed from gene: CNOT1. Tag Q3_22_NHS_review was removed from gene: CNOT1. Tag Q3_22_expert_review was removed from gene: CNOT1.
Tag to_be_confirmed_NHSE tag was added to gene: CNOT1.
Tag Q3_22_NHS_review tag was added to gene: CNOT1.
Tag Q3_22_rating tag was added to gene: CNOT1. Tag Q3_22_expert_review tag was added to gene: CNOT1.
Gene: cnot1 has been classified as Amber List (Moderate Evidence).
Phenotypes for gene: CNOT1 were changed from to Holoprosencephaly 12, with or without pancreatic agenesis, OMIM:618500; holoprosencephaly 12 with or without pancreatic agenesis, MONDO:0032787
Publications for gene: CNOT1 were set to
Mode of pathogenicity for gene: CNOT1 was changed from to Other
Mode of inheritance for gene: CNOT1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
gene: CNOT1 was added gene: CNOT1 was added to Diabetes - neonatal onset. Sources: Expert review Mode of inheritance for gene: CNOT1 was set to