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. This curation was approved by the Brain Malformation Panel on 2/14/2023.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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