We aim to investigate how rare NOTCH3 variants relate to cerebral small vessel disease (CSVD) phenotypes including white matter hyperintensity (WMH), brain atrophy, dementia and stroke outcomes in the diverse population of UK Biobank (UKB).

NOTCH3 variants are linked to a broad spectrum neurological conditions, including cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), dementia, and stroke. Previous studies in the Chinese Shunyi Cohort identified rare NOTCH3 variants associated with increased WMH, but limited to a small study population.

Whole exome sequencing (WES) data and clinical information were extracted from UKB. Rare variants were defined as those with minor allele frequency <1% using gnomAD v4.1 and determined to be protein-disrupting. Cystein-altering variants located in epidermal growth factor–like repeat (EGFr) domains or with R75P, D80G, R61W, R213K were defined as CADASIL-causing. Pathogenicity was determined using refGene, Dbnsfp42a, and ClinVar, CADD and REVEL score. We applied linear regression model to analyze log-transformed WMH, brain atrophy measures. Dementia and stroke prevalence and age of onset were analyzed using logistic regression and linear regression.

Among 42,306 participants, 2,351 participants carried rare protein-disrupting variants; 1,402 carried pathogenic variants, among which 113 carried CADASIL-causing variants. Higher total WMH were found in carriers of any rare variants (β[95%CI] = 0.064[0.029,0.110], p<0.001), EGFr-involving variants (β[95%CI] = 0.064[0.025,0.104],p=0.002), and pathogenic rare variants (β[95%CI] = 0.119[0.074,0.164], p<0.001). Carriers of pathogenic rare variants had increased stroke prevalence (OR[95%CI] = 1.419[1.046,1.881], p=0.019). After excluding CADASIL-causing variants, the effects of carrying any pathogenic variants remained significant in total WMH, deep WMH, and periventricular WMH (p=0.003, p=0.004, p=0.005 respectively), but disappeared in stroke. 

Carriers of rare NOTCH3 variants, including those are not CADASIL-causing, have higher CSVD burden represented by white matter lesions.