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Eur J Hum Genet. 2019 Nov;27(11):1677-1682. doi: 10.1038/s41431-019-0413-6. Epub 2019 Jun 14.

De novo variants in CNOT3 cause a variable neurodevelopmental disorder.

Author information

Institute of Genetic Medicine, Newcastle upon Tyne, England.
Institute of Genetic Medicine, Newcastle upon Tyne, England.
Medical Genetics Department, Rare Diseases and Personalized Medicine, Montpellier University Hospital, Montpellier, France.
Department of Clinical Genetics, Leiden University Medical Center, Leiden, Netherlands.
Wessex Clinical Genetics, Princess Anne Hospital, Southampton, England.
Division Biomedical Genetics, Genetics Department, University Medical Center Utrecht, Utrecht, Netherlands.
Centre de Génétique, Centre de Référence Maladies Rares, Anomalies du Développement et Syndromes Malformatifs, Hôpital d'enfants, Dijon, France.
West of Scotland Clinical Genetics Service, Queen Elizabeth University Hospital, Glasgow, Scotland.
Bristol Regional Genetics Service, St Michael's Hospital, Bristol, England.
Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Sciences Centre, Division of Evolution and Genomic Sciences School of Biological Sciences University of Manchester, Manchester, England.
Peninsula Clinical Genetics, Royal Devon and Exeter Hospital, Exeter, England.
Department of Child Neurology, HAGA/Juliana Children's Hospital, The Hague, Netherlands.
Lab. de diagnostic génétique des HUS, Strasbourg, France.


As a result of exome-based sequencing work performed by the DDD study, de novo variants in CNOT3 have emerged as a newly recognised cause of a developmental disorder. This paper describes molecular and clinical details of 16 probands with developmental disorders and de novo CNOT3 variants. It is the first such description of the developmental phenotype associated with CNOT3 variants. Eight of these cases were discovered as part of the DDD study, while the other eight were found as a result of large-scale sequencing work performed by other groups. A highly specific phenotype was not recognised in these 16 cases. The most consistent phenotypic features seen in subjects with de novo variants in CNOT3 were hypotonia, relatively small stature, developmental delay, behavioural problems and intellectual disability. There is no easily recognisable facial phenotype, but some common dysmorphic features such as anteverted nares, thin upper lip and low set eyebrows were shared among some of the probands. Haploinsufficiency appears to be the most likely mechanism of action, with eight cases found to have protein-truncating variants. Of the other eight cases (all missense variants), three share an amino acid substitution at the same position which may therefore represent an important functional domain.

[Available on 2020-11-01]

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