Abstract Details

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

Topic Cerebrovascular Disease and Interventional Neurology

Presentation(s) S60 - Cerebrovascular Imaging and Biomarkers (2:12 PM-2:24 PM)

Poster/Presentation
Number 007

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.

Authors/Disclosures
PRESENTER	No disclosure on file
Yi Dai	No disclosure on file
Ding-Ding Zhang	Ding-Ding Zhang has nothing to disclose.
Fei Han	Fei Han has nothing to disclose.
Feifei Zhai	No disclosure on file
Lixin Zhou	Lixin Zhou has nothing to disclose.
Ming Yao	Ming Yao has nothing to disclose.
Jun Ni	Jun Ni has nothing to disclose.
Zheng-Yu Jin	No disclosure on file
Li-Ying Cui	No disclosure on file
Shu-Yang Zhang	No disclosure on file
Yi-Cheng Zhu, MD, PhD (Peking Union Medical College Hospital)	Dr. Zhu has nothing to disclose.

��ɫ��

��ɫ��