Expansion of GGC repeat in the human-specific NOTCH2NLC gene is associated with essential tremor
Expansion of GGC repeat in the human-specific NOTCH2NLC gene is associated with essential tremor
复制标题
人类特异性 NOTCH2NLC 基因中 GGC 重复序列的扩展与特发性震颤相关。
DOI：
10.1093/brain/awz372
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发表时间：
2020-01-01
期刊：
影响因子：
14.5
通讯作者：
Tang, Bei-Sha
中科院分区：
文献类型：
--
作者：
Sun, Qi-Ying;Xu, Qian;Tang, Bei-Sha
特发性震颤是最常见的运动障碍之一。尽管特发性震颤具有很高的患病率和遗传性，但其遗传病因仍然难以捉摸。到目前为止，只有少数基因/位点被确定，但这些基因尚未在其他特发性震颤家族或群体中复制。在这里，我们报告了一项对197个临床诊断为特发性震颤的中国血统的遗传研究。采用连锁分析、全外显子组测序、长读全基因组测序、重复引物聚合酶链反应和富gc聚合酶链反应相结合的综合策略，研究人员在11个特发性震颤家族（5.58%）中发现NOTCH2NLC基因5'区域的异常GGC重复扩增。临床发现GGC重复扩增异常的先证者震颤表型更为严重，日常生活能力活动能力较低。在这11个基本震颤阳性家族中也检测到明显的遗传预见性。这些结果提示NOTCH2NLC基因5′区GGC重复扩增异常与特发性震颤有关，为特发性震颤是一个具有较高临床和遗传异质性的家族疾病提供了强有力的证据。
Essential tremor is one of the most common movement disorders. Despite its high prevalence and heritability, the genetic aetiology of essential tremor remains elusive. Up to now, only a few genes/loci have been identified, but these genes have not been replicated in other essential tremor families or cohorts. Here we report a genetic study in a cohort of 197 Chinese pedigrees clinically diagnosed with essential tremor. Using a comprehensive strategy combining linkage analysis, whole-exome sequencing, long-read whole-genome sequencing, repeat-primed polymerase chain reaction and GC-rich polymerase chain reaction, we identified an abnormal GGC repeat expansion in the 5' region of the NOTCH2NLC gene that co-segregated with disease in 11 essential tremor families (5.58%) from our cohort. Clinically, probands that had an abnormal GGC repeat expansion were found to have more severe tremor phenotypes, lower activities of daily living ability. Obvious genetic anticipation was also detected in these 11 essential tremor-positive families. These results indicate that abnormal GGC repeat expansion in the 5' region of NOTCH2NLC gene is associated with essential tremor, and provide strong evidence that essential tremor is a family of diseases with high clinical and genetic heterogeneities.