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

Abstract

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.

Pattern of Brain Parenchymal Damage Related to Cerebral Small Vessel Disease in Carriers of Rare NOTCH3 Variants

“…Our findings of heavier global WMH burden associated with rare NOTCH3 variants are consistent with our previous work 5 and the earlier report of Schmidt 6 in a population-based cohort and the report of Ramirez 28 in patients with Parkinson disease. In addition, this association appeared more prominent in EGFr-involving variants.…”

“…1 Accumulating evidence revealed that pathogenic variants known to cause Mendelian forms of CSVD are frequent among the general population, such as the characteristic cysteine-altering variation in the NOTCH3 gene. [2][3][4] In addition, our previous study 5 and the study by Schmidt 6 reported the susceptibility to heavy CSVD burden in rare NOTCH3 variant carriers. As carriers of rare NOTCH3 variants have been identified in more than 10% of the general population, 5 their patterns of brain parenchymal injury deserve in-depth investigation to uncover the important genetic predisposition in age-related CSVD in the general population.…”

“…[2][3][4] In addition, our previous study 5 and the study by Schmidt 6 reported the susceptibility to heavy CSVD burden in rare NOTCH3 variant carriers. As carriers of rare NOTCH3 variants have been identified in more than 10% of the general population, 5 their patterns of brain parenchymal injury deserve in-depth investigation to uncover the important genetic predisposition in age-related CSVD in the general population.…”

“…The protocol used for WES data assessment and quality control was provided in our previous publication. 5 In brief, NOTCH3 variants with minor allele frequency <1% in all 4 public population databases were defined as rare variants, including 57 missense SNPs, of which 31 were located in epidermal growth factor-like repeats (EGFr).…”

Leukoaraiosis: Epidemiology, Imaging, Risk Factors, and Management of Age-Related Cerebral White Matter Hyperintensities

“…[265][266][267] Many LA susceptibility genes have been identified in the past decades through genetic studies with different study designs on different ethnic cohorts. 251,[268][269][270][271][272][273][274][275][276][277][278][279][280][281][282][283][284][285][286] Of these, candidate gene association studies have identified up to 52 susceptibility genes significantly associated with LA (Figure 4A). 67,251,[268][269][270][271][272][273][274][275][277][278][279][280][281][282][283][284] Two recent exome-wide association studies on individuals of European and African descent and UK Biobank subjects revealed that 10 single nucleotide polymorphisms in eight genes (TRIM65, ACOX1, CARF, FBF1, MRPL38, NBEAL1, WDR12, and GBE1) are significantly associated with the risk of LA (Figure 4A).…”