Analysis of de novo variants identified in patients from the Deciphering Developmental Disorders (DDD) Study cohort, along with meta-analysis of probands from previously published studies, identified CNOT3 as a gene exceeding genome-wide significance (P<7.0E-07) (Deciphering Developmental Disorders Study, 2017). Of the seven cases with de novo variants in the CNOT3 gene from the DDD cohort, four (DECIPHER IDs 257816, 259521, 262450, and 263217) were reported to have the Human Phenotype Ontology (HPO) term "Autism spectrum disorder". Other recurrent HPO terms used in cases with CNOT3 variants were abnormal axial skeleton morphology and global developmental delay. A de novo frameshift variant in CNOT3 had previously been observed in an ASD proband from the Simons Simplex Collection (O'Roak et al., 2012). A second de novo frameshift variant in CNOT3 was identified in an ASD proband from a simplex family from the ASD: Genomes to Outcome Study cohort by whole genome sequencing as part of the MSSNG initiative in Yuen et al., 2017. Based on the discovery of two de novo LoF variants in this gene in ASD probands, a probability of LoF intolerance rate (pLI) > 0.9, and higher-than-expected mutation rate (false discovery rate < 15%), CNOT3 was classified as an ASD candidate gene in Yuen et al., 2017. Resequencing of 64 candidate neurodevelopmental disorder risk genes by molecular inversion probes in ORoak et al., 2014 identified a third de novo LoF variant in the CNOT3 gene in an ASD proband from The Autism Simplex Collection (TASC). Detailed phenotypic characterization of the seven previously described individuals with de novo CNOT3 variants from the 2017 Deciphering Developmental Disorders Study report and nine previously unpublished individuals with de novo CNOT3 variants in Martin et al., 2019 found that eight individuals presented with either autism, autism spectrum disorder, or PDD-NOS. Two additional de novo loss-of-function variants, as well as two rare and potentially damaging missense variants, in the CNOT3 gene were reported in ASD probands from the Autism Sequencing Consortium, the MSSNG cohort, and the SPARK cohort in Zhou et al., 2022; a two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in this report identified CNOT3 as a gene reaching exome-wide significance (P < 2.5E-06).
Molecular Function
This gene encodes for a component of the CCR4-NOT complex which is one of the major cellular mRNA deadenylases and is linked to various cellular processes including bulk mRNA degradation, miRNA-mediated repression, translational repression during translational initiation and general transcription regulation.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Prevalence and architecture of de novo mutations in developmental disorders
