Unravelling the Genetics of Cerebral Small Vessel Disease

Cerebral small vessel disease (CSVD) is a major cause of stroke and vascular dementia. While CSVD is mostly sporadic (caused by a complex mix of environmental and genetic risk factors), its rare monogenic forms have been increasingly identified. The most common of these, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by NOTCH3 variants, and the second most frequent, CADASIL type 2, by autosomal dominant HTRA1 variants. COL4A1/2 variants can cause small vessel stroke and intracerebral haemorrhage. This thesis investigates the genetics of CSVD in the context of monogenic conditions using data from three cohorts. Firstly, I correlate NOTCH3 mutations with disease severity in a cohort of 485 patients with CADASIL. Secondly, I investigate factors that may influence the penetrance of NOTCH3, HTRA1 and COL4A1/2 variants in 454,756 UK Biobank participants. Thirdly, I perform a case-control comparison of genomes in 13,310 participants of the National Institute for Health Research BioResource Rare Disease (NBR-RD) study to identify likely causative variants for familial CSVD in known and novel genes. I demonstrate that variant position and cardiovascular risk factors are likely to influence the disease severity of patients with CADASIL and UK Biobank subjects with familial CSVD variants. I also identify novel rare variants in several genes that may contribute to the development of CSVD in the NBR-RD study, although their exact relationship to CSVD requires further investigation. My study highlights the need for better-quality data and more robust analytical and experimental methods to identify other as-yet-unidentified genes and factors underlying CSVD.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2023

Author dc:creator

• Cho, Pok Him

Advisor dc:contributor.advisor

• Markus, Hugh

• Genetics
• Stroke

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/87e680d7-8bd4-46ec-a749-b0612853af36/download
• https://creativecommons.org/licenses/by/4.0/

Language dc:language

eng

Author Identifier

0000-0002-5034-3234

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/358364