De novo variants in CNOT3 cause a variable neurodevelopmental disorder
De novo variants in CNOT3 cause a variable neurodevelopmental disorder
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DOI：
10.1038/s41431-019-0413-6
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发表时间：
2019-11-01
影响因子：
5.2
通讯作者：
van Haeringen, A.
中科院分区：
文献类型：
--
作者：
Martin, R.;Splitt, M.;van Haeringen, A.
由于DDD研究进行的基于外显子组的测序工作，CNOT3的新生变异已经成为一种发育障碍的新认识原因。本文描述了16例发育障碍和新生CNOT3变异先证者的分子和临床细节。这是首次对与CNOT3变异相关的发育表型进行这样的描述。其中8例是作为DDD研究的一部分发现的，而其他8例是由其他小组进行的大规模测序工作发现的。在这16例中没有发现高度特异性的表型。在CNOT3从头变异的受试者中，最一致的表型特征是张力低下、相对较小的身材、发育迟缓、行为问题和智力残疾。没有容易识别的面部表型，但一些常见的畸形特征，如前倾的鼻子，薄的上唇和低的眉毛在一些先证者中是共享的。单倍不足似乎是最可能的作用机制，有8例发现有蛋白质截断变异。在其他8例（所有错义变体）中，3例在相同位置共享氨基酸取代，因此可能代表一个重要的功能域。
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.