Department of Neurology (J.-Y.L., M.Y., Y.D., F.H., F.-F.Z., L.-X.Z., J.N., L.-Y.C., Y.-C.Z.), Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing, China.
Medical Research Center (D.-D.Z.), Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing, China.
Stroke. 2021 Dec;52(12):3918-3925. doi: 10.1161/STROKEAHA.120.032265. Epub 2021 Aug 18.
Researches on rare variants of in the general Chinese population are lacking. This study aims to describe the spectrum of rare variants by whole-exome sequencing in a Chinese community-based cohort and to investigate the association between rare variants and age-related cerebral small vessel disease.
The cross-sectional study comprised 1065 participants who underwent whole-exome sequencing and brain magnetic resonance imaging. variants with minor allele frequency<1% in all 4 public population databases (1000 Genomes, ESP6500siv2_ALL, GnomAD_ALL, and GnomAD_EAS) were defined as rare variants. Multivariable linear and logistic regressions were used to investigate the associations between rare variants and volume of white matter hyperintensities and cerebral small vessel disease burden. Clinical and imaging characteristics of rare variant carriers were summarized.
Sixty-five rare variants were identified in 147 of 1065 (13.8%) participants, including 57 missense single nucleotide polymorphisms (SNPs), 5 SNPs in splice branching sites, and 3 frameshift deletions. A significantly higher volume of white matter hyperintensities and heavier burden of cerebral small vessel disease was found in carriers of rare EGFr (epidermal growth factor-like repeats)-involving variants, but not in carriers of EGFr-sparing variants. The carrying rate of rare EGFr-involving variants in participants with dementia or stroke was significantly higher than those without dementia or stroke (12.4% versus 6.6%, =0.041). Magnetic resonance imaging signs suggestive of CADASIL were found in 3.4% (5/145) rare EGFr cysteine-sparing variant carriers but not in 2 cysteine-altering variant carriers.
Carriers of rare variants involving the EGFr domain may be genetically predisposed to age-related cerebral small vessel disease in the general Chinese population.
在普通中国人群中，关于 的罕见变异的研究较少。本研究旨在通过全外显子组测序描述中国人群中 的罕见变异谱，并探讨罕见 变异与年龄相关性脑小血管病之间的关系。
这项横断面研究纳入了 1065 名接受全外显子组测序和脑磁共振成像的参与者。将在 4 个公共人群数据库（1000 Genomes、ESP6500siv2_ALL、GnomAD_ALL 和 GnomAD_EAS）中频率<1%的 变异定义为罕见变异。采用多变量线性和逻辑回归分析来探讨罕见 变异与脑白质高信号体积和脑小血管病负担之间的关系。总结了罕见 变异携带者的临床和影像学特征。
在 1065 名参与者中的 147 名（13.8%）中发现了 65 个罕见的 变异，包括 57 个错义单核苷酸多态性（SNP）、5 个剪接分支位点的 SNP 和 3 个移码缺失。携带罕见 EGFr（表皮生长因子样重复）涉及的 变异的个体，其脑白质高信号体积较大，脑小血管病负担较重，而携带 EGFr 非涉及的 变异的个体则没有这种情况。痴呆或卒中患者携带罕见 EGFr 涉及的 变异的发生率明显高于无痴呆或卒中的患者（12.4%比 6.6%，=0.041）。磁共振成像提示 3.4%（5/145）罕见 EGFr 半胱氨酸保存 变异携带者存在 CADASIL 征象，但 2 例半胱氨酸改变的 变异携带者不存在。
在中国普通人群中，携带 EGFr 域涉及的罕见 变异的个体可能具有遗传易感性，易患年龄相关性脑小血管病。
