NCKAP1 Disruptive Variants Lead to a Neurodevelopmental Disorder with Core Features of Autism
NCKAP1 Disruptive Variants Lead to a Neurodevelopmental Disorder with Core Features of Autism
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NCKAP1 破坏性变异会导致具有自闭症核心特征的神经发育障碍。
DOI：
10.1016/j.ajhg.2020.10.002
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发表时间：
2020-11-05
影响因子：
9.8
通讯作者：
Xia, Kun
中科院分区：
文献类型：
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作者：
Guo, Hui;Zhang, Qiumeng;Xia, Kun
NCKAP1/NAP1调节神经元细胞骨架动力学，对发育中的大脑神经元分化至关重要。在自闭症谱系障碍（ASD）和智力残疾患者中发现了NCKAP1的有害变异；然而，其临床意义尚不清楚。为了确定其意义，我们收集了来自20个不相关家族的21名受影响个体的基因型和表型数据，这些家族预测NCKAP1有害变异。这包括16个具有新生（n = 8）、遗传（n = 6）或遗传未知（n = 2）截断变异的个体，2个具有结构性变异的个体，3个具有潜在破坏性的新生错义变异的个体。我们报告了NCKAP1在神经发育障碍患者中的新发和超罕见的有害变异负担，需要进一步的复制。ASD或自闭症特征、语言和运动迟缓以及智力或学习障碍的可变表达是常见的临床特征。在遗传病例中，有证据表明有害变异与神经精神疾病分离。基于现有的人脑转录组学数据，我们发现NCKAP1在产前和产后都广泛且高表达，并且在兴奋性神经元和放射状胶质细胞中表达富集，而在抑制性神经元中表达缺失。小鼠子宫内电穿孔实验显示，Nckap1功能的丧失促进了早期皮层发育过程中的神经元迁移。综上所述，这些数据支持破坏性NCKAP1变异在神经发育迟缓/自闭症中的作用，可能是通过干扰皮层发育早期的神经元迁移。
NCKAP1/NAP1 regulates neuronal cytoskeletal dynamics and is essential for neuronal differentiation in the developing brain. Deleterious variants in NCKAP1 have been identified in individuals with autism spectrum disorder (ASD) and intellectual disability; however, its clinical significance remains unclear. To determine its significance, we assemble genotype and phenotype data for 21 affected individuals from 20 unrelated families with predicted deleterious variants in NCKAP1. This includes 16 individuals with de novo (n = 8), transmitted (n = 6), or inheritance unknown (n = 2) truncating variants, two individuals with structural variants, and three with potentially disruptive de novo missense variants. We report a de novo and ultra-rare deleterious variant burden of NCKAP1 in individuals with neurodevelopmental disorders which needs further replication. ASD or autistic features, language and motor delay, and variable expression of intellectual or learning disability are common clinical features. Among inherited cases, there is evidence of deleterious variants segregating with neuropsychiatric disorders. Based on available human brain transcriptomic data, we show that NCKAP1 is broadly and highly expressed in both prenatal and postnatal periods and demostrate enriched expression in excitatory neurons and radial glias but depleted expression in inhibitory neurons. Mouse in utero electroporation experiments reveal that Nckap1 loss of function promotes neuronal migration during early cortical development. Combined, these data support a role for disruptive NCKAP1 variants in neurodevelopmental delay/autism, possibly by interfering with neuronal migration early in cortical development.