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Abstract：
Gilles de la Tourette syndrome (GTS) is a neurodevelopmental psychiatric disorder with complex and elusive etiology with a significant role of genetic factors. The aim of this study was to identify structural variants that could be associated with familial GTS. The study group comprised 17 multiplex families with 80 patients. Structural variants were identified from whole-genome sequencing data and followed by co-segregation and bioinformatic analyses. The localization of these variants was used to select candidate genes and create gene sets, which were subsequently processed in gene ontology and pathway enrichment analysis. Seventy putative pathogenic variants shared among affected individuals within one family but not present in the control group were identified. Only four private or rare deletions were exonic in LDLRAD4, B2M, USH2A, and ZNF765 genes. Notably, the USH2A gene is involved in cochlear development and sensory perception of sound, a process that was associated previously with familial GTS. In addition, two rare variants and three not present in the control group were co-segregating with the disease in two families, and uncommon insertions in GOLM1 and DISC1 were co-segregating in three families each. Enrichment analysis showed that identified structural variants affected synaptic vesicle endocytosis, cell leading-edge organization, and signaling for neurite outgrowth. The results further support the involvement of the regulation of neurotransmission, neuronal migration, and sound-sensing in GTS.
摘要：
GillesdelaTourette综合征（GTS）是一种神经发育性精神障碍，病因复杂而难以捉摸，遗传因素起着重要作用。这项研究的目的是鉴定可能与家族性GTS相关的结构变体。研究组包括17个多重家庭和80名患者。从全基因组测序数据中鉴定结构变体，然后进行共分离和生物信息学分析。这些变体的定位被用来选择候选基因并创建基因集，随后在基因本体论和途径富集分析中进行了处理。确定了一个家庭内受影响的个体共有70种推定的致病变异，但对照组中不存在。在LDLRAD4，B2M中只有四个私人或罕见的缺失是外显子，USH2A,和ZNF765基因。值得注意的是,USH2A基因参与耳蜗发育和声音的感觉感知，以前与家族性GTS相关的过程。此外,对照组中有两个罕见的变异体和三个不存在的变异体在两个家庭中与疾病分离，GOLM1和DISC1中罕见的插入在三个家庭中共同分离。富集分析表明，鉴定的结构变体影响突触小泡内吞作用，细胞前沿组织，以及神经突生长的信号。结果进一步支持神经传递调节的参与，神经元迁移，和GTS中的声音感应。
