Laboratory of Neurogenetics and Molecular Medicine - IPER, Institut de Recerca Sant Joan de Déu, Barcelona, Spain.
Movement Disorders Unit, Department of Pediatric Neurology, Institut de Recerca Sant Joan de Déu, CIBERER-ISCIII and European Reference Network for Rare Neurological Diseases (ERN-RND), Barcelona, Spain.
Autism Res. 2021 Jun;14(6):1088-1100. doi: 10.1002/aur.2502. Epub 2021 Mar 22.
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. LAY SUMMARY: Genomics is improving the knowledge and diagnosis of patients with autism spectrum disorder (ASD) yet the genetic etiology remains elusive. Here, using genomic analysis together with experimental functional studies, we identified in an ASD complex patient the PLXNA2 and LRRC40 recessive genes as ASD candidates. Furthermore, we found that the proteins of these genes interact in a common neural network. Therefore, more attention to these genes is warranted in genetic studies of patients with neurodevelopmental disorders, particularly ASD.
自闭症谱系障碍 (ASD) 是一种具有高遗传性的神经发育障碍，但遗传病因仍不清楚。因此，有必要阐明 ASD 的新基因型-表型关系，以提高病因学知识和诊断水平。在这项工作中，我们对一名具有癫痫和注意缺陷多动障碍等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 编码功能未知的富含亮氨酸重复蛋白 40。PLXNA2 显示杂合错义变异 c.614G>A(p.Arg205Gln)和 c.4904G>A(p.Arg1635Gln)，而 LRRC40 则表现为纯合错义变异 c.1461G>T(p.Leu487Phe)。计算机分析预测这些变异可能是致病性的。我们研究了患者和对照的成纤维细胞中的 PLXNA2 和 LRRC40 mRNA 和蛋白质。我们观察到患者的 PlxnA2 亚细胞定位明显改变，LRRC40 水平非常低。此外，我们发现了 PlxnA2 和 LRRC40 之间的新相互作用，表明它们参与了一个共同的神经通路。这种相互作用在患者的成纤维细胞中显著降低。总之，我们的研究结果确定了 PLXNA2 和 LRRC40 基因是 ASD 的候选基因，为发病机制提供了新的线索。在神经发育障碍患者的遗传研究中，特别是 ASD，进一步关注这些基因是必要的。
解析：这段文本是一篇学术论文的摘要，讨论了自闭症谱系障碍（ASD）的遗传病因学。翻译时，需要注意一些医学术语的准确性和流畅性。
