Autism spectrum disorder (ASD) is a neurodevelopmental disability with high heritability yet the genetic etiology remains elusive. Therefore, it is necessary to elucidate new genotype–phenotype relationships for ASD to improve both the etiological knowledge and diagnosis. In this work, a copy-number variant and whole-exome sequencing analysis were performed in an ASD patient with a complex neurobehavioral phenotype with epilepsy and attention deficit hyperactivity disorder. We identified rare recessive single nucleotide variants in the two genes, PLXNA2 encoding Plexin A2 that participates in neurodevelopment, and LRRC40, which encodes Leucine-rich repeat containing protein 40, a protein of unknown function. PLXNA2 showed the heterozygous missense variants c.614G>A (p.Arg205Gln) and c.4904G>A (p.Arg1635Gln) while LRRC40 presented the homozygous missense variant c.1461G>T (p.Leu487Phe). In silico analysis predicted that these variants could be pathogenic. We studied PLXNA2 and LRRC40 mRNA and proteins in fibroblasts from the patient and controls. We observed a significant PlxnA2 subcellular delocalization and very low levels of LRRC40 in the patient. Moreover, we found a novel interaction between PlxnA2 and LRRC40 suggesting that participate in a common neural pathway. This interaction was significant decreased in the patient's fibroblasts. In conclusion, our results identified PLXNA2 and LRRC40 genes as candidates in ASD providing novel clues for the pathogenesis. Further attention to these genes is warranted in genetic studies of patients with neurodevelopmental disorders, particularly ASD.

中文翻译：

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PLXNA2 和 LRRC40 作为自闭症谱系障碍的候选基因

自闭症谱系障碍（ASD）是一种具有高遗传性的神经发育障碍，但遗传病因仍然难以捉摸。因此，有必要阐明 ASD 新的基因型-表型关系，以提高病因学知识和诊断水平。在这项工作中，对一名患有癫痫和注意力缺陷多动障碍的复杂神经行为表型的 ASD 患者进行了拷贝数变异和全外显子组测序分析。我们在这两个基因中发现了罕见的隐性单核苷酸变异，PLXNA2编码参与神经发育的 Plexin A2，LRRC40编码富含亮氨酸重复序列的蛋白质 40，一种功能未知的蛋白质。PLXNA2显示杂合错义变体 c.614G>A (p.Arg205Gln) 和 c.4904G>A (p.Arg1635Gln)，而LRRC40显示纯合错义变体 c.1461G>T (p.Leu487Phe)。计算机分析预测这些变异可能是致病的。我们研究了患者和对照组成纤维细胞中的PLXNA2和LRRC40 mRNA 和蛋白质。我们在患者中观察到显着的 PlxnA2 亚细胞离域和极低水平的 LRRC40。此外，我们发现 PlxnA2 和 LRRC40 之间存在一种新的相互作用，表明它们参与了共同的神经通路。这种相互作用在患者的成纤维细胞中显着减少。总之，我们的结果确定了PLXNA2和LRRC40基因作为 ASD 的候选基因，为发病机制提供了新的线索。在对神经发育障碍，特别是 ASD 患者的基因研究中，需要进一步关注这些基因。