Whole-exome sequencing identifies matrisomal gene associations in monogenic cerebral small vessel disease

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 approximately half of vascular dementia cases and 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 who 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 which cause conditions with overlapping symptomology to CSVD. Burden analysis focussing on rare, functional variants was used to identify novel associations when compared against a cohort of 1035 non-neurological controls. We identified 18 suspected disease-causing variants across nine CSVD-associated genes and a significant burden of both rare and rare, likely disease-causing heterozygous variants in ABCC6. Two genes from stroke and neurodegenerative disease gene panels also possessed a significant burden of rare, likely disease-causing variants, MYH11 (adjusted P = 1 × 10^-2) and NOTCH1 (adjusted P = 1 × 10^-2). We further identified novel associations for seven genes (COL7A1, HMCN1, LAMA1, MMP9, TENM4, TNC, TTN) with monogenic CSVD in this cohort. Our findings implicate several genes as potentially causal of monogenic CSVD, highlighting the need for more extensive genetic screening in suspected CSVD cases, and functional characterisation of implicated variants to determine their mechanistic role in CSVD pathogenesis.