Approved Research

The full phenotypic spectrum of hereditary small vessel diseases and its modifiers

Lay summary

Small vessel diseases are an important cause of dementia, and can have various underlying causes. Some forms of small vessel disease are heritable, caused by variants in a specific gene. The most frequent cause of hereditary small vessel disease is Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), caused by variants in the Neurogenic locus notch homolog protein 3 (NOTCH3) gene.

Until recently, it was thought that all individuals with a CADASIL-associated NOTCH3 variant develop CADASIL, with recurrent ischemic strokes and vascular dementia. However, our recent studies show that CADASIL- causing NOTCH3 variants are found in 1 in 300 individuals in the general population, and that many individuals with these variants do not have small vessel disease. This project will investigate why certain individuals with a NOTCH3 variant develop a severe small vessel disease and others do not. A second objective is to better interpret newly identified genetic variants which may be associated with hereditary small vessel disease.

To answer our research questions, we will identify individuals with a CADASIL- associated NOTCH3 variant in the UK Biobank exomes. These individuals mostly have a mild, late onset small vessel disease or even no small vessel disease at all, and are thus much milder than CADASIL patients. We will analyze the neuroimaging small vessel disease markers and clinical symptoms in individuals with a NOTCH3 variant in UK Biobank, and compare this to a group of CADASIL patients with severe disease, diagnosed in our outpatient clinic. Also, we will compare the genetic code of the individuals with a NOTCH3 variant in UK Biobank to those who are diagnosed in our clinic, to identify genetic factors that may influence disease severity. In addition to NOTCH3 variants and CADASIL, we will also study the clinical symptoms and neuroimaging of individuals with other, more rare hereditary small vessel diseases. Finally, we will use the genetic data in UK Biobank to interpret new genetic variants that are detected in families with an hitherto unexplained small vessel disease. This will help us to determine whether these variants are disease- causing or not.

This research will lead to a better disease prediction for (family members of)  individuals in whom a NOTCH3 or other hereditary small vessel disease variant is found, for example as an incidental finding during genetic testing for a congenital disorder.  

This project will be performed over the course of three years.