Regulation of neuronal connectivity and synaptic communication are key to proper functioning of the brain. The Netrin-G subfamily and their cognate receptors are vertebrate-specific synaptic cell adhesion molecules with a role in synapse establishment and function, which seem to have co-evolved to contribute to higher brain functions. We identified a homozygous frameshift variant in NTNG2 (NM_032536.3: c.376dup), encoding Netrin-G2, in eight individuals from four families with global developmental delay, hypotonia, secondary microcephaly, and autistic features. Comparison of haplotypes established this as a founder variant. Previous studies showed that Ntng2-knockout mice have impaired visual, auditory, and motor coordination abilities required for demanding tasks, as well as possible spatial learning and memory deficits. Knockout of Ntng2 in a cellular model resulted in short neurites, and knockout of its trans-synaptic partner Ngl2/Lrrc4 in mice revealed autistic-like behavior and reduced NMDAR synaptic plasticity. The Ngl2/Lrrc4-knockout mouse phenotype was rescued by NMDAR activation, suggesting a mechanistic link to autism spectrum disorder. We thus propose NTNG2 as a candidate disease gene and provide further support for the involvement of Netrin-G2 in neuropsychiatric phenotypes.

中文翻译：

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具有发育延迟，肌张力减退和自闭症特征的个体中，NTNG2的纯合移码变体，编码突触细胞粘附分子。

神经元连通性和突触通讯的调节是大脑正常运作的关键。Netrin-G亚家族及其同源受体是脊椎动物特有的突触细胞粘附分子，在突触的建立和功能中起着作用，似乎共同进化为大脑的更高功能做出了贡献。我们在来自全球发育延迟，肌张力减退，继发性小头畸形和自闭症特征的四个家庭的八个人中，鉴定了编码Netrin-G2的NTNG2（NM_032536.3：c.376dup）纯合移码变异。单倍型的比较将其确定为创始人变异。先前的研究表明Ntng2-基因敲除小鼠的视力，听觉和运动协调能力受损，无法满足要求苛刻的任务以及可能的空间学习和记忆障碍。在细胞模型中敲除Ntng2导致神经突短，敲除小鼠的反式突触伴侣Ngl2 / Lrrc4则表现出自闭症样行为并降低NMDAR突触可塑性。所述Ngl2 / LRRC4敲除小鼠的表型是通过NMDAR活化救出，提示一种机械连结自闭症谱系障碍。因此，我们提出NTNG2作为候选疾病基因，并为Netrin-G2参与神经精神病学表型提供进一步的支持。