Rare NOTCH3 Variants in a Chinese Population-Based Cohort and Its Relationship With Cerebral Small Vessel Disease

BACKGROUND AND PURPOSE: Researches on rare variants of NOTCH3 in the general Chinese population are lacking. This study aims to describe the spectrum of rare NOTCH3 variants by whole-exome sequencing in a Chinese community-based cohort and to investigate the association between rare NOTCH3 variants and age-related cerebral small vessel disease.
METHODS: The cross-sectional study comprised 1065 participants who underwent whole-exome sequencing and brain magnetic resonance imaging. NOTCH3 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 NOTCH3 variants and volume of white matter hyperintensities and cerebral small vessel disease burden. Clinical and imaging characteristics of rare NOTCH3 variant carriers were summarized.
RESULTS: Sixty-five rare NOTCH3 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 NOTCH3 EGFr (epidermal growth factor-like repeats)-involving variants, but not in carriers of EGFr-sparing variants. The carrying rate of rare EGFr-involving NOTCH3 variants in participants with dementia or stroke was significantly higher than those without dementia or stroke (12.4% versus 6.6%, P=0.041). Magnetic resonance imaging signs suggestive of CADASIL were found in 3.4% (5/145) rare EGFr cysteine-sparing NOTCH3 variant carriers but not in 2 cysteine-altering NOTCH3 variant carriers.
CONCLUSIONS: Carriers of rare NOTCH3 variants involving the EGFr domain may be genetically predisposed to age-related cerebral small vessel disease in the general Chinese population.
GRAPHIC ABSTRACT: An online graphic abstract is available for this article.

研究背景与目的：目前针对中国普通人群中NOTCH3基因罕见变异的相关研究仍较为匮乏。本研究旨在基于中国社区人群队列，通过全外显子组测序（whole-exome sequencing）明确NOTCH3基因罕见变异的频谱特征，并探讨NOTCH3基因罕见变异与年龄相关性脑小血管病之间的关联。

研究方法：本项横断面研究共纳入1065名受试者，所有受试者均接受了全外显子组测序与脑部磁共振成像（brain magnetic resonance imaging）检查。以在全部4个公共人群数据库（千人基因组计划（1000 Genomes）、ESP6500siv2_ALL、基因组聚合数据库全人群版（GnomAD_ALL）及东亚人群版（GnomAD_EAS））中次要等位基因频率（minor allele frequency）<1%的变异定义为罕见变异。采用多变量线性回归与逻辑回归分析，探究NOTCH3基因罕见变异与脑白质高信号（white matter hyperintensities）体积及脑小血管病负荷（cerebral small vessel disease burden）之间的关联。同时总结了NOTCH3基因罕见变异携带者的临床与影像学特征。

研究结果：本研究共在1065名受试者中的147名（13.8%）体内鉴定出65种NOTCH3基因罕见变异，其中包括57种错义单核苷酸多态性（single nucleotide polymorphisms，SNPs）、5个位于剪接分支位点的SNPs以及3种移码缺失（frameshift deletions）。携带涉及表皮生长因子样重复序列（epidermal growth factor-like repeats，EGFr）的NOTCH3罕见变异的受试者，其脑白质高信号体积显著更高，脑小血管病负荷也更重；而未涉及EGFr的变异携带者则未观察到此类关联。合并痴呆或卒中的受试者中，涉及EGFr的NOTCH3罕见变异携带率显著高于无痴呆或卒中的受试者（12.4% vs 6.6%，P=0.041）。在145名携带EGFr半胱氨酸保守型NOTCH3罕见变异的受试者中，有3.4%（5/145）出现了提示伴皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病（Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy，CADASIL）的磁共振成像征象，而在2名携带半胱氨酸改变型NOTCH3变异的受试者中未发现此类征象。

研究结论：在中国普通人群中，携带涉及EGFr结构域的NOTCH3基因罕见变异的个体，可能在遗传上易患年龄相关性脑小血管病。

图文摘要：本文附带在线图文摘要。