Rare <i>NOTCH3</i> Variants in a Chinese Population-Based Cohort and Its Relationship With Cerebral Small Vessel Disease.

Abstract

Researches on rare variants of <i>NOTCH3</i> in the general Chinese population are lacking. This study aims to describe the spectrum of rare <i>NOTCH3</i> variants by whole-exome sequencing in a Chinese community-based cohort and to investigate the association between rare <i>NOTCH3</i> 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. <i>NOTCH3</i> 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 <i>NOTCH3</i> variants and volume of white matter hyperintensities and cerebral small vessel disease burden. Clinical and imaging characteristics of rare <i>NOTCH3</i> variant carriers were summarized. Sixty-five rare <i>NOTCH3</i> 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 <i>NOTCH3</i> EGFr (epidermal growth factor-like repeats)-involving variants, but not in carriers of EGFr-sparing variants. The carrying rate of rare EGFr-involving <i>NOTCH3</i> variants in participants with dementia or stroke was significantly higher than those without dementia or stroke (12.4% versus 6.6%, <i>P</i>=0.041). Magnetic resonance imaging signs suggestive of CADASIL were found in 3.4% (5/145) rare EGFr cysteine-sparing <i>NOTCH3</i> variant carriers but not in 2 cysteine-altering <i>NOTCH3</i> variant carriers. Carriers of rare <i>NOTCH3</i> variants involving the EGFr domain may be genetically predisposed to age-related cerebral small vessel disease in the general Chinese population.