Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA; Rare Disease Institute, Genetics and Metabolism, Children's National Health System, Washington, DC 20036, USA.
Am J Hum Genet. 2019 May 2;104(5):990-993. doi: 10.1016/j.ajhg.2019.03.017. Epub 2019 Apr 18.
Holoprosencephaly is the incomplete separation of the forebrain during embryogenesis. Both genetic and environmental etiologies have been determined for holoprosencephaly; however, a genetic etiology is not found in most cases. In this report, we present two unrelated individuals with semilobar holoprosencephaly who have the identical de novo missense variant in the gene CCR4-NOT transcription complex, subunit 1 (CNOT1). The variant (c.1603C>T [p.Arg535Cys]) is predicted to be deleterious and is not present in public databases. CNOT1 has not been previously associated with holoprosencephaly or other brain malformations. In situ hybridization analyses of mouse embryos show that Cnot1 is expressed in the prosencephalic neural folds at gestational day 8.25 during the critical period for subsequent forebrain division. Combining human and mouse data, we show that CNOT1 is associated with incomplete forebrain division.
无脑回畸形是胚胎发育过程中前脑未完全分离。无脑回畸形的病因既有遗传因素也有环境因素，但大多数情况下并未发现遗传病因。本报告介绍了 2 例无关联的半侧无脑回畸形患者，他们均存在 CCR4-NOT 转录复合物亚基 1（CNOT1）基因的新发错义变异。该变异（c.1603C>T [p.Arg535Cys]）预测为有害变异，且不在公共数据库中。此前 CNOT1 并未与无脑回畸形或其他脑畸形相关联。对小鼠胚胎进行原位杂交分析显示，Cnot1 在妊娠第 8.25 天的前脑神经褶中表达，这是后续前脑分裂的关键时期。结合人和小鼠的数据，我们表明 CNOT1 与前脑不完全分裂有关。
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