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.

NCKAP1 / NAP1调节神经元的细胞骨架动力学，对于发育中的大脑神经元分化至关重要。在患有自闭症谱系障碍（ASD）和智力障碍的个体中，已经鉴定出NCKAP1的有害变异。但是，其临床意义仍不清楚。为了确定其重要性，我们收集了来自20个无关家庭的21个受影响个体的基因型和表型数据，并预测了NCKAP1的有害变异。这包括16个具有从头突变（n = 8），已传播（n = 6）或遗传未知（n = 2）截断变体的个体，两个具有结构变体的个体和三个具有潜在破坏性的从头错义变体的个体。我们报告神经发育障碍患者的NCKAP1的从头开始的超罕见有害变体负担，需要进一步复制。ASD或自闭症特征，语言和运动延迟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，有证据表明有害变体与神经精神病疾病隔离。基于可用的人类大脑转录组数据，我们显示NCKAP1在产前和产后均广泛表达，并且在兴奋性神经元和radial神经胶质细胞中富集表达，而在抑制性神经元中表达却减少。子宫内的老鼠电穿孔实验表明，Nckap1功能丧失可促进早期皮质发育过程中的神经元迁移。结合起来，这些数据可能通过干扰皮质发育早期的神经元迁移来支持破坏性NCKAP1变异体在神经发育延迟/自闭症中的作用。