Pattern of Neuroimaging Markers Related to Cerebral Small Vessel Disease in Carriers of Rare Deleterious Variants
Chengqian Li1, Ming Yao1, Mengyao Wan1, Jingyi Liu1, Zi-Yue Liu1, Fei Han1, Lixin Zhou1, Jun Ni1, Yi-Cheng Zhu1
1Department of Neurology, Peking Union Medical College Hospital
Objective:
This study aimed to determine the associations of rare deleterious variants with imaging markers in a large multicenter CSVD cohort.
Background:
Previous studies reported that rare deleterious variants are associated with a heavy burden of cerebral small vessel disease (CSVD) in the general population while the patterns of imaging markers remain uncovered.
Design/Methods:
As part of a multicenter, prospective cohort, we included participants with complete brain magnetic resonance imaging (MRI) and whole-exome sequencing in analysis. 11 variants (NOTCH3, HTRA1, COL4A1, COL4A2, CTSA, GAL, TREX1, CTC1, APP, GSN, ADA2) with minor allele frequency <1% in all 4 public population databases were defined as rare deleterious variants. We used wilcoxon rank sum test to compare the patterns of imaging markers, including white matter hyperintensity (WMH), silent brain infarcts (SBIs), and cerebral microbleed (CMB), between rare deleterious variant carriers and noncarriers.
Results:
A total of 623 participants were included in analysis, among whom 232(37.24%) carried rare deleterious variants, with 111(17.82%) carrying rare NOTCH3 variants and 33(5.30%), 28(4.49%), 25(4.01%), 18(2.89%), 18(2.89%) carrying rare HTRA1, GSN, COL4A2, CTC1, APP variants, respectively. Compared with participants without any rare deleterious variant, rare NOTCH3 variants carriers had higher number of SBIs with a preferable distribution in basal ganglia and brainstem. In subgroup analysis, a higher number of SBIs was found in the epidermal growth factor-like repeats (EGFr)-involving rare NOTCH3 variants carriers, but not in carriers of EGFr-sparing rare NOTCH3 variants. Rare HTRA1 and GAL variants carriers presented a heavier burden of WMH involving both periventricular and subcortical area. Rare TREX1, COL4A1, COL4A2, CTSA, and CTC1 variants carriers were found to have a higher load of CMBs.
Conclusions:
Individuals with rare deleterious variants have a distinct pattern of MRI imaging markers related to CSVD. Carriers of rare deleterious variants may be genetically predisposed to age-related CSVD.
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