Whole Exome Sequencing of Suspected Monogenic Cerebral Small Vessel Disease Patients reveals Novel Gene Associations

Cerebral small vessel diseases (CSVDs) are a group of disorders affecting the small arteries, veins, and capillaries supplying the white matter and deep grey matter structures. They are the most common form of cerebrovascular disease, accounting for almost half of vascular dementia cases worldwide and approximately 20% of stroke incidence. Whilst genetic testing is a routine diagnostic tool for monogenic CSVDs, less than 20% of patients have a causal variant in known CSVD genes. We performed whole exome sequencing on 117 patients suspected of monogenic CSVD that had previously tested negative for pathogenic variants in seven well-characterised CSVD genes (NOTCH3, HTRA1, COL4A1, COL4A2, TREX1, GLA, and FOXC1). Targeted analysis was conducted on known and associated CSVD genes as well as candidate genes causative of conditions with symptomatic overlap to CSVD. Burden analysis focusing on rare, functional variants was used to identify novel associations when compared against a cohort of 1035 non-neurological control samples. We identified 18 candidate disease-causing variants across nine CSVD-associated genes and a significant burden of rare and rare, likely disease-causing heterozygous variants in ABCC6. Two genes identified from stroke and neurodegenerative disease gene panels, MYH11 (adjusted P=1x10-2) and NOTCH1 (adjusted P=1x10-2), also had a significant burden of candidate disease-causing variants. Additionally, we identified novel associations for seven genes (COL7A1, HMCN1, LAMA1, MMP9, TENM4, TNC, TTN) with monogenic CSVD. Our findings implicate several genes as potentially causal of monogenic CSVD, highlighting the need for more extensive genetic screening in suspected CSVD cases and also functional characterisation of novel implicated variants to determine their mechanistic role in CSVD pathogenesis.