期刊
BRAIN
卷 143, 期 -, 页码 222-233出版社
OXFORD UNIV PRESS
DOI: 10.1093/brain/awz372
关键词
essential tremor; long-read whole-genome sequencing; NOTCH2NLC; GGC repeat expansion; neuronal intranuclear inclusion disease
资金
- National Natural Sciences Foundation of China [81430023]
- National Key Plan for Scientific Research and Development of China [2016YFC1306000, 2017YFC0909100]
- National Key R&D Program of China [2018YPC1312003]
Essential tremor is one of the must 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-real whole-genuine 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 it 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 that essential tremor is a family of disease with high clinical and genetic heterogeneities.
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