Yun-Chao Wang, Yu Fan, Wen-Kai Yu, Si Shen, Jia-Di Li, Yuan Gao, Yan Ji, Yu-Sheng Li, Lu-Lu Yu, Zi-Chen Zhao, Shan-Shan Li, Yao Ding, Chang-He Shi, Yu-Ming Xu
{"title":"NOTCH2NLC在脑血管疾病患者中扩增GGC重复序列。","authors":"Yun-Chao Wang, Yu Fan, Wen-Kai Yu, Si Shen, Jia-Di Li, Yuan Gao, Yan Ji, Yu-Sheng Li, Lu-Lu Yu, Zi-Chen Zhao, Shan-Shan Li, Yao Ding, Chang-He Shi, Yu-Ming Xu","doi":"10.1136/svn-2022-001631","DOIUrl":null,"url":null,"abstract":"<p><strong>Objective: </strong>GGC repeat expansions in the human-specific <i>NOTCH2NLC</i> gene have been reported as the cause of neuronal intranuclear inclusion disease (NIID). Given the clinical overlap of cognitive impairment in NIID and cerebral small vessel disease (CSVD), both diseases have white matter hyperintensity on T2-fluid-attenuated inversion recovery sequences of brain MRI, and white matter hyperintensity is a primary neuroimaging marker of CSVD on MRI. Therefore, we hypothesised that the GGC repeat expansions might also contribute to CSVD. To further investigate the relationship between <i>NOTCH2NLC</i> GGC repeat expansions and CSVD, we performed a genetic analysis of 814 patients with the disease.</p><p><strong>Methods: </strong>We performed a comprehensive GGC repeat expansion screening in <i>NOTCH2NLC</i> from 814 patients with sporadic CSVD. Their Fazekas score was greater than or equal to 3 points. Repeat-primed PCR and fluorescence amplicon length analyses were performed to identify GGC repeat expansions, and whole-exome sequencing was used to detect any pathogenic mutation in previously reported genes associated with CSVD.</p><p><strong>Results: </strong>We identified nine (1.11%) patients with pathogenic GGC repeat expansions ranging from 41 to 98 repeats. The minor allele frequency of expanded GGC repeats in <i>NOTCH2NLC</i> was 0.55%.</p><p><strong>Conclusion: </strong>Our findings suggest that intermediate-length and longer-length GGC repeat expansions in <i>NOTCH2NLC</i> are associated with sporadic CSVD. This provides new thinking for studying the pathogenesis of CSVD.</p>","PeriodicalId":22021,"journal":{"name":"Stroke and Vascular Neurology","volume":"8 2","pages":"161-168"},"PeriodicalIF":4.4000,"publicationDate":"2023-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/70/3d/svn-2022-001631.PMC10176980.pdf","citationCount":"4","resultStr":"{\"title\":\"<i>NOTCH2NLC</i> expanded GGC repeats in patients with cerebral small vessel disease.\",\"authors\":\"Yun-Chao Wang, Yu Fan, Wen-Kai Yu, Si Shen, Jia-Di Li, Yuan Gao, Yan Ji, Yu-Sheng Li, Lu-Lu Yu, Zi-Chen Zhao, Shan-Shan Li, Yao Ding, Chang-He Shi, Yu-Ming Xu\",\"doi\":\"10.1136/svn-2022-001631\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Objective: </strong>GGC repeat expansions in the human-specific <i>NOTCH2NLC</i> gene have been reported as the cause of neuronal intranuclear inclusion disease (NIID). Given the clinical overlap of cognitive impairment in NIID and cerebral small vessel disease (CSVD), both diseases have white matter hyperintensity on T2-fluid-attenuated inversion recovery sequences of brain MRI, and white matter hyperintensity is a primary neuroimaging marker of CSVD on MRI. Therefore, we hypothesised that the GGC repeat expansions might also contribute to CSVD. To further investigate the relationship between <i>NOTCH2NLC</i> GGC repeat expansions and CSVD, we performed a genetic analysis of 814 patients with the disease.</p><p><strong>Methods: </strong>We performed a comprehensive GGC repeat expansion screening in <i>NOTCH2NLC</i> from 814 patients with sporadic CSVD. Their Fazekas score was greater than or equal to 3 points. Repeat-primed PCR and fluorescence amplicon length analyses were performed to identify GGC repeat expansions, and whole-exome sequencing was used to detect any pathogenic mutation in previously reported genes associated with CSVD.</p><p><strong>Results: </strong>We identified nine (1.11%) patients with pathogenic GGC repeat expansions ranging from 41 to 98 repeats. The minor allele frequency of expanded GGC repeats in <i>NOTCH2NLC</i> was 0.55%.</p><p><strong>Conclusion: </strong>Our findings suggest that intermediate-length and longer-length GGC repeat expansions in <i>NOTCH2NLC</i> are associated with sporadic CSVD. This provides new thinking for studying the pathogenesis of CSVD.</p>\",\"PeriodicalId\":22021,\"journal\":{\"name\":\"Stroke and Vascular Neurology\",\"volume\":\"8 2\",\"pages\":\"161-168\"},\"PeriodicalIF\":4.4000,\"publicationDate\":\"2023-04-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/70/3d/svn-2022-001631.PMC10176980.pdf\",\"citationCount\":\"4\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Stroke and Vascular Neurology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1136/svn-2022-001631\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Stroke and Vascular Neurology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1136/svn-2022-001631","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
NOTCH2NLC expanded GGC repeats in patients with cerebral small vessel disease.
Objective: GGC repeat expansions in the human-specific NOTCH2NLC gene have been reported as the cause of neuronal intranuclear inclusion disease (NIID). Given the clinical overlap of cognitive impairment in NIID and cerebral small vessel disease (CSVD), both diseases have white matter hyperintensity on T2-fluid-attenuated inversion recovery sequences of brain MRI, and white matter hyperintensity is a primary neuroimaging marker of CSVD on MRI. Therefore, we hypothesised that the GGC repeat expansions might also contribute to CSVD. To further investigate the relationship between NOTCH2NLC GGC repeat expansions and CSVD, we performed a genetic analysis of 814 patients with the disease.
Methods: We performed a comprehensive GGC repeat expansion screening in NOTCH2NLC from 814 patients with sporadic CSVD. Their Fazekas score was greater than or equal to 3 points. Repeat-primed PCR and fluorescence amplicon length analyses were performed to identify GGC repeat expansions, and whole-exome sequencing was used to detect any pathogenic mutation in previously reported genes associated with CSVD.
Results: We identified nine (1.11%) patients with pathogenic GGC repeat expansions ranging from 41 to 98 repeats. The minor allele frequency of expanded GGC repeats in NOTCH2NLC was 0.55%.
Conclusion: Our findings suggest that intermediate-length and longer-length GGC repeat expansions in NOTCH2NLC are associated with sporadic CSVD. This provides new thinking for studying the pathogenesis of CSVD.
期刊介绍:
Stroke and Vascular Neurology (SVN) is the official journal of the Chinese Stroke Association. Supported by a team of renowned Editors, and fully Open Access, the journal encourages debate on controversial techniques, issues on health policy and social medicine.