What's in a Domain? The Role of NOTCH3 EGFr Domains in CADASIL Disease Severity

Twenty-five years ago, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) was considered a rare, severe genetic small vessel disease leading to recurrent stroke and vascular dementia in midadulthood. Although it is now abundantly clear that CADASIL is at least as prevalent as more well-known genetic causes of dementia, such as Huntington disease and early-onset Alzheimer dementia, CADASIL remains stubbornly unknown, overlooked, and underrecognized. This may be partially attributable to the variable disease severity and presentation, as well as the clinical and neuroimaging overlap with sporadic causes of small vessel disease. In 2016, it was discovered that characteristic CADASIL-causing cysteine-altering NOTCH3 variants (NOTCH3^cys) are unexpectedly frequent in the general population (1:300).¹ This was a game changer in our understanding of CADASIL disease variability, leading to the identification of NOTCH3^cys variant position as the most important CADASIL disease modifier. NOTCH3^cys variants located in one of the first 6 EGFr domains of the NOTCH3 protein (EGFr 1–6) are frequent in CADASIL cohorts, rare in the population, and are associated with severe disease. Conversely, EGFr 7–34 variants are less frequent in CADASIL cohorts, highly frequent in the population, and are associated with a very broad disease spectrum ranging from “classical” severe CADASIL to a very mild small vessel disease and even nonpenetrance.^2-7