The Association Between Notch3 Mutations and Cerebral Small Vessel Disease Burden in a Chinese Population-based Sample

Objective: Via whole-exome sequencing (WES), we aimed to investigate whether presence of rare and predicted harmful mutations in NOTCH3 is associated with higher burden of CSVD seen on brain MRI in general population. Background: Research on rare variants in NOTCH3 coding region and its correlation with cerebral small vessel disease (CSVD) burden in the general population are lacking. Design/Methods: A total of 1229 participants (61.99±9.43 years) from the ongoing population based Shunyi Study who underwent WES and brain magnetic resonance imaging were included. NOTCH3 variants satisfying the following conditions were defined as rare and predicted harmful mutation: (1) Located in exon regions or splicing sites and (2) Frequencies less than 1% in all 3 databases (1000 Genomes Project, GnomAD, ESP 6500), and (3) Considered harmful in more than 2 of the 4 prediction tools (SIFT, Polyphen, MutationTaster, CADD). WMH were automatically segmented. Lacunes and cerebral microbleeds were visually rated. Multivariable logistic and linear regressions were used to investigate the associations between presence of NOTCH3 mutations and CSVD burden. Results: Among 1229 participants, 134 (10.9%) had rare and harmful mutation in NOTCH3 coding region, 67 (4.2%) of which affected the extracellular epidermal growth factor-like repeats (EGFr) domain. Only 2 cases had typical cysteine residue substitution. NOTCH3 mutations located in EGFr domain were associated with higher CSVD burden, especially larger WMH volume (β=0.501, CI: 0.031~0.047, p=0.031). The association remained when adjusted for age, gender, whole-brain volume, and cardiovascular risk factors. In the 2 participants with cysteine residue involvement, had mild WMH. Conclusions: Rare and predicted harmful mutations of NOTCH3 genes involving the EGFr domain, even if not involving cysteine residue, increase the risk of CSVD burden in the general population. Additional investigations are required to explore the biological mechanisms underlying the observed association. Disclosure: Dr. Liu has nothing to disclose. Dr. Dai has nothing to disclose. Dr. Zhang has nothing to disclose. Dr. Han has nothing to disclose. Dr. Zhai has nothing to disclose. Dr. Zhou has nothing to disclose. Dr. Yao has nothing to disclose. Dr. Ni has nothing to disclose. Dr. Jin has nothing to disclose. Dr. Cui has nothing to disclose. Dr. Zhang has nothing to disclose. Dr. Zhu has nothing to disclose.