Holoprosencephaly and septo-optic dysplasia

Gene: CNOT1

I don't know

LIMITED by ClinGen for holoprosencephaly 12 with or without pancreatic agenesis, MONDO:0032787

ClinGen curation:
CNOT1 was originally reported in cases of holoprosencephaly and/or pancreatic agenesis/insufficiency in 2019 (PMID: 31006513, 31006510). One of the papers included 3 individuals with heterozygous p.Arg535Cys (PMID: 31006513), confirmed to be de novo in 2 individuals. One of these individuals was not scored due to a lack of documentation of holoprosencephaly. The other paper included 2 individuals with de novo p.Arg535Cys, both of whom with holoprosencephaly. A knock-in mouse model of this variant showed neurological and pancreatic abnormalities at E14.5, and this evidence was used to augment the genetic evidence. A mouse brain expression study (PMID: 31006510) was scored as functional evidence. In total, there is Limited evidence to support the gene-disease relationship between CNOT1 and holoprosencephaly with or without pancreatic agenesis. Of note, this gene has also been implicated in Vissers-Bodmer syndrome, which is characterized by global developmental delay and behavioral abnormalities apparent from infancy. As the condition is clinically distinct from holoprosencephaly and/or pancreatic agenesis/insufficiency, lacks specific structural brain anomalies, and likely has different molecular mechanisms, this will be/have been assessed separately.

Created: 19 Apr 2024, 4:34 a.m. | Last Modified: 19 Apr 2024, 4:34 a.m.

Panel Version: 1.14

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Holoprosencephaly 12 with or without pancreatic agenesis MONDO:0032787

Green List (high evidence)

PMID:32553196 : 39 individuals with heterozygous de novo CNOT1 variants, including missense, splice site, and
nonsense variants, who present with a clinical spectrum of intellectual disability, motor delay, speech delay, seizures, hypotonia, and behavioral problems.

Created: 6 Jul 2020, 6:04 a.m. | Last Modified: 6 Jul 2020, 6:04 a.m.

Panel Version: 0.3242

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Neurodevelopmental delay

Publications

• 32553196

Variants in this GENE are reported as part of current diagnostic practice

Green List (high evidence)

Three unrelated individuals reported. Functional studies in mouse
Sources: Literature

Created: 17 Jan 2020, 5:29 a.m.

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

Phenotypes
HOLOPROSENCEPHALY 12 WITH OR WITHOUT PANCREATIC AGENESIS; HPE12; OMIM# 618500

Publications

• PMID: 31006513

Variants in this GENE are reported as part of current diagnostic practice