González-Morón Dolores, Vishnopolska Sebastián, Consalvo Damián, Medina Nancy, Marti Marcelo, Córdoba Marta, Vazquez-Dusefante Cecilia, Claverie Santiago, Rodríguez-Quiroga Sergio Alejandro, Vega Patricia, Silva Walter, Kochen Silvia, Kauffman Marcelo Andrés
Consultorio y laboratorio de Neurogenética, Centro Universitario de Neurología "José María Ramos Mejía" y División Neurología, Hospital JM Ramos Mejía, Facultad de Medicina, UBA, Buenos Aires, Argentina.
IBCN "Eduardo de Robertis", Facultad de Medicina, UBA-CONICET, Buenos Aires, Argentina.
PLoS One. 2017 Sep 27;12(9):e0185103. doi: 10.1371/journal.pone.0185103. eCollection 2017.
Neuronal migration disorders are a clinically and genetically heterogeneous group of malformations of cortical development, frequently responsible for severe disability. Despite the increasing knowledge of the molecular mechanisms underlying this group of diseases, their genetic diagnosis remains unattainable in a high proportion of cases. Here, we present the results of 38 patients with lissencephaly, periventricular heterotopia and subcortical band heterotopia from Argentina. We performed Sanger and Next Generation Sequencing (NGS) of DCX, FLNA and ARX and searched for copy number variations by MLPA in PAFAH1B1, DCX, POMT1, and POMGNT1. Additionally, somatic mosaicism at 5% or higher was investigated by means of targeted high coverage NGS of DCX, ARX, and PAFAH1B1. Our approach had a diagnostic yield of 36%. Pathogenic or likely pathogenic variants were identified in 14 patients, including 10 germline (five novel) and 4 somatic mutations in FLNA, DCX, ARX and PAFAH1B1 genes. This study represents the largest series of patients comprehensively characterized in our population. Our findings reinforce the importance of somatic mutations in the pathophysiology and diagnosis of neuronal migration disorders and contribute to expand their phenotype-genotype correlations.
神经元迁移障碍是一组临床和遗传异质性的皮质发育畸形，常导致严重残疾。尽管对这组疾病的分子机制的了解越来越多，但在很大比例的病例中，其基因诊断仍然无法实现。在此，我们展示了来自阿根廷的38例无脑回畸形、脑室周围异位和皮质下带异位患者的研究结果。我们对DCX、FLNA和ARX进行了桑格测序和新一代测序（NGS），并通过多重连接依赖探针扩增（MLPA）检测PAFAH1B1、DCX、POMT1和POMGNT1的拷贝数变异。此外，通过对DCX、ARX和PAFAH1B1进行靶向高覆盖NGS来研究5%或更高比例的体细胞镶嵌现象。我们的方法诊断率为36%。在14例患者中鉴定出致病或可能致病的变异，包括FLNA、DCX、ARX和PAFAH1B1基因中的10个种系变异（5个新变异）和4个体细胞突变。本研究是对我们人群进行全面特征分析的最大系列患者。我们的研究结果强化了体细胞突变在神经元迁移障碍病理生理学和诊断中的重要性，并有助于扩展其表型-基因型相关性。
