Targeted exonic sequencing identifies novel variants in a cerebral small vessel disease cohort

Background and aims: Cerebral small vessel diseases (CSVDs) are a set of conditions that affect the small blood vessels in the brain and can cause severe neurological pathologies such as stroke and vascular dementia. The most common monogenic CSVD is cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) which is caused by mutations in NOTCH3. However, only 15-20% of CADASIL cases referred for genetic testing have pathogenic mutations in NOTCH3. We hypothesise that other monogenic causes of CSVD may be causing a CADASIL-like CSVD phenotype.

Methods: To test this, we performed whole exome sequencing for 50 individuals suspected of having CADASIL, but did not exhibit a disease-causing mutation in NOTCH3, and applied targeted analysis of all monogenic forms of CSVD.

Results: This analysis identified three mutations affecting the Collagen type IV genes in three individuals likely to be causative of CSVD.

Conclusions: This suggests that screening for all monogenic forms of CSVD when one monogenic form is clinically suspected may improve diagnosis in clinically suspected monogenic CSVD. However, despite these findings, the majority of NOTCH3 negative CSVD cases did not have candidate mutations in known CSVD genes, suggesting that additional genetic factors contributing to the disease are yet to be identified.