从头序列和拷贝数变异与抽动障碍强烈相关，并提示细胞极性在发病机制中的作用。
De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis.
机构信息
College of Biological Sciences, China Agricultural University, Beijing, China; National Institute of Biological Sciences, Beijing, China; Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA; Institute for Neurodegenerative Diseases, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA; Institute for Neurodegenerative Diseases, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
出版信息
Cell Rep. 2018 Sep 25;24(13):3441-3454.e12. doi: 10.1016/j.celrep.2018.08.082.
We previously established the contribution of de novo damaging sequence variants to Tourette disorder (TD) through whole-exome sequencing of 511 trios. Here, we sequence an additional 291 TD trios and analyze the combined set of 802 trios. We observe an overrepresentation of de novo damaging variants in simplex, but not multiplex, families; we identify a high-confidence TD risk gene, CELSR3 (cadherin EGF LAG seven-pass G-type receptor 3); we find that the genes mutated in TD patients are enriched for those related to cell polarity, suggesting a common pathway underlying pathobiology; and we confirm a statistically significant excess of de novo copy number variants in TD. Finally, we identify significant overlap of de novo sequence variants between TD and obsessive-compulsive disorder and de novo copy number variants between TD and autism spectrum disorder, consistent with shared genetic risk.
我们之前通过对 511 个三核苷酸重复扩展家族进行外显子测序，证实了从头出现的有害序列变异对抽动秽语综合征（TD）的贡献。在此，我们对另外 291 个 TD 三核苷酸重复扩展家族进行了测序，并对 802 个三核苷酸重复扩展家族的样本进行了分析。我们发现，从头出现的有害变异在单体型而非多体型家族中过度表达；我们鉴定出了一个高可信度的 TD 风险基因，CELSR3（钙粘蛋白 EGF LAG 七次跨膜 G 型受体 3）；我们发现，TD 患者中突变的基因富集了与细胞极性相关的基因，这表明存在一个共同的生物学途径；我们还证实了 TD 中存在显著的新生拷贝数变异过度现象。最后，我们发现 TD 与强迫症之间存在新生序列变异的显著重叠，TD 与自闭症谱系障碍之间存在新生拷贝数变异的显著重叠，这与共享的遗传风险一致。
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