Submission Details

CNOT1 was first reported in relation to an autosomal dominant complex neurodevelopmental disorder in 2020 (Vissers et al., PMID: 32553196). Individuals present with a clinical spectrum of intellectual disability, motor delay, speech delay, seizures, hypotonia, and behavioral problems. Individuals with CNOT1 p.Arg535Cys variants have been reported with holoprosencephaly and pancreatic agenesis without neurodevelopmental delay (De Franco et al., PMID: 31006513). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in phenotypic variability. Therefore, probands with this variant have not been included in this curation. Thirty-nine variants (missense, in-frame indel, nonsense, frameshift, large deletion) that have been reported in thirty-seven probands in one publication (PMID: 32553196) are included in this curation. More evidence is available in the publication, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be de novo haploinsufficiency.

This gene-disease relationship is also supported by experimental evidence. A GAL4-UAS Drosophila model designed with reportedly pathogenic CNOT1 variants demonstrated memory deficits, which were rescued when wild-type CNOT1 was introduced (PMID: 32553196).

In summary, there is definitive evidence to support the relationship between CNOT1 and an autosomal dominant complex neurodevelopmental disorder. This gene-disease relationship was first evaluated by the Intellectual Disability and Autism Gene Curation Expert Panel on April 4, 2023 with a classification of strong (SOP 9). This relationship was then reevaluated by the Intellectual Disability and Autism Gene Curation Expert Panel on September 19, 2023 and upgraded to a classification of definitive given that three years have now passed since the first report of this gene-disease relationship (SOP 9).

CNOT1 was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2020 (Vissers et al., PMID: 32553196). Individuals present with a clinical spectrum of intellectual disability, motor delay, speech delay, seizures, hypotonia, and behavioral problems. Individuals with CNOT1 p.Arg535Cys variants have been reported with holoprosencephaly and pancreatic agenesis without neurodevelopmental delay (De Franco et al., PMID: 31006513). Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found differences in phenotypic variability. Therefore, probands with this variant have not been included in this curation.

Thirty-nine variants (missense, in-frame indel, nonsense, frameshift, large deletion) that have been reported in thirty-seven probands in one publication (PMID: 32553196) are included in this curation. More evidence is available in the publication, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity appears to be de novo haploinsufficiency.

This gene-disease relationship is also supported by experimental evidence. A GAL4-UAS Drosophila model designed with reportedly pathogenic CNOT1 variants demonstrated memory deficits, which were rescued when wild-type CNOT1 was introduced (PMID: 32553196).

In summary, there is definitive evidence to support the relationship between CNOT1 and autosomal dominant complex neurodevelopmental disorder. This gene-disease relationship was first evaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on April 4, 2023 with a classification of strong (SOP 9). This relationship was reevaluated on September 19, 2023 and upgraded to a classification of definitive given that three years have now passed since the first report of this gene-disease relationship (SOP 9).