De novo variants in CNOT3 cause a variable neurodevelopmental disorder

Martin, R. J.; Splitt, Miranda; Geneviève, David; Aten, Emmelien; Collins, Amanda; Bie, Charlotte I. de; Faivre, Laurence; Foulds, Nicola; Giltay, Jacques C.; Ibitoye, Rita; Joss, Shelagh; Kennedy, Joanna; Kerr, Bronwyn; Kivuva, Emma; Koopmans, Marije; Newbury‐Ecob, Ruth; Jean-Marçais, Nolwenn; Peeters, Els; Smithson, Sarah; Tomkins, Susan; Tran-Mau-Them, Frédéric; Piton, Amélie; Haeringen, Arie van

doi:10.1038/s41431-019-0413-6

Cited by 21 publications

(42 citation statements)

References 11 publications

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“…To briefly mention a few such examples, Next-Generation sequencing studies in children affected by NDD/ID identified several additional underlying RNA helicase genes including DDX59, DHX16, DHX34, DHX37 and DDX54, further implicating the role of this gene family in neuronal development and function, though the molecular processes impacted by their variants have not been characterized [93,94]. De novo mutations in genes encoding several subunits of the CCR4-NOT deadenylase (Figure 1) including CNOT1, CNOT2 and CNOT3 have been linked to variable NDD [95][96][97][98][99]. While CNOT4 is not yet associated with any human pathology, it is highly intolerant to loss-of-function with no truncated variants in the general population, suggesting that they could have severe consequences.…”

Section: Resultsmentioning

confidence: 99%

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Mutations in genes encoding regulators of mRNA decapping and translation initiation: links to intellectual disability

Weil

Piton

Lessel

et al. 2020

Biochemical Society Transactions

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Intellectual disability (ID) affects at least 1% of the population, and typically presents in the first few years of life. ID is characterized by impairments in cognition and adaptive behavior and is often accompanied by further delays in language and motor skills, as seen in many neurodevelopmental disorders (NDD). Recent widespread high-throughput approaches that utilize whole-exome sequencing or whole-genome sequencing have allowed for a considerable increase in the identification of these pathogenic variants in monogenic forms of ID. Notwithstanding this progress, the molecular and cellular consequences of the identified mutations remain mostly unknown. This is particularly important as the associated protein dysfunctions are the prerequisite to the identification of targets for novel drugs of these rare disorders. Recent Next-Generation sequencing-based studies have further established that mutations in genes encoding proteins involved in RNA metabolism are a major cause of NDD. Here, we review recent studies linking germline mutations in genes encoding factors mediating mRNA decay and regulators of translation, namely DCPS, EDC3, DDX6 helicase and ID. These RNA-binding proteins have well-established roles in mRNA decapping and/or translational repression, and the mutations abrogate their ability to remove 5′ caps from mRNA, diminish their interactions with cofactors and stabilize sub-sets of transcripts. Additional genes encoding RNA helicases with roles in translation including DDX3X and DHX30 have also been linked to NDD. Given the speed in the acquisition, analysis and sharing of sequencing data, and the importance of post-transcriptional regulation for brain development, we anticipate mutations in more such factors being identified and functionally characterized.

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Section: Resultsmentioning

confidence: 99%

“…Intellectual disability, syndromic (618672) AD missense or truncating [99] though recent reports suggest it may operate only transiently [15,16]. Nonetheless, given the shared importance of the cap/poly(A) tail and their binding factors, the translation state of an mRNA is likely to impact its decay rate.…”

Section: Ddx54mentioning

confidence: 99%

Mutations in genes encoding regulators of mRNA decapping and translation initiation: links to intellectual disability

Weil

Piton

Lessel

et al. 2020

Biochemical Society Transactions

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“…Different abnormalities in brain magnetic resonance imaging (MRI) including partial agenesis of the corpus callosum and parenchymal atrophy were present in some patients, whereas major organ malformations were not considered typical 1 . So far, only de novo pathogenic variants in CNOT3 have been reported and inheritance was not observed 1 . We here describe the first two families with a parent‐to‐child transmission of CNOT3 ‐related developmental phenotypes.…”

Section: Introductionmentioning

confidence: 90%

“…Recently a novel developmental disorder caused by de novo pathogenic variants of CNOT3 (CCR4‐NOT Transcription Complex Subunit 3) has been described in 16 patients (OMIM #618672, intellectual developmental disorder with speech delay, autism, and dysmorphic facies) 1 . CNOT3 is part of the CCR4‐NOT protein complex, a global regulator of protein biosynthesis 2 .…”

Section: Introductionmentioning

confidence: 99%

“…The phenotype of the reported patients included a developmental delay and variable degree of learning difficulties, short stature, and muscular hypotonia. Different abnormalities in brain magnetic resonance imaging (MRI) including partial agenesis of the corpus callosum and parenchymal atrophy were present in some patients, whereas major organ malformations were not considered typical 1 . So far, only de novo pathogenic variants in CNOT3 have been reported and inheritance was not observed 1 .…”

Section: Introductionmentioning

confidence: 99%

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Inherited cases of CNOT3‐associated intellectual developmental disorder with speech delay, autism, and dysmorphic facies

et al. 2020

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De novo pathogenic variants in CNOT3 have recently been reported in a developmental delay disorder (intellectual developmental disorder with speech delay, autism, and dysmorphic facies [IDDSADF, OMIM: #618672]). The patients present with a variable degree of developmental delay and behavioral problems. To date, all reported disease-causing variants occurred de novo and no parent-child transmission was observed. We report for the first time autosomal dominant transmissions of the CNOT3-associated developmental disorder in two unrelated families. The clinical characteristics in our patients match the IDDSADF features reported so far and suggest substantial variability of the phenotype within the same family.

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CNOT2 haploinsufficiency in a 40‐year‐old man with intellectual disability, autism, and seizures

Royer‐Bertrand¹,

Cisarova²,

Bütschi³

et al. 2021

American J of Med Genetics Pt A

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De novo variants in CNOT3 cause a variable neurodevelopmental disorder

Cited by 21 publications

References 11 publications

Mutations in genes encoding regulators of mRNA decapping and translation initiation: links to intellectual disability

Mutations in genes encoding regulators of mRNA decapping and translation initiation: links to intellectual disability

Inherited cases of CNOT3‐associated intellectual developmental disorder with speech delay, autism, and dysmorphic facies

CNOT2 haploinsufficiency in a 40‐year‐old man with intellectual disability, autism, and seizures

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