**4. Diagnosis**

The pathology should be suspected in all cases with unexplained white matter hyperintensities and a family history of stroke and/or vascular dementia, consistent with an autosomal dominant inheritance. However, because affected family members may have been misdiagnosed [80] and de novo cases have been described [69, 81], the lack of an apparent family history of CADASIL does not preclude the diagnosis. Several groups of clinicians [13, 14, 82] proposed suitable diagnostic strategies to be used in the clinical setting for the selection of patients to be subjected to NOTCH3 gene analysis. In fact, in order to establish a correct diagnosis, clinical signs, neuroimaging findings, and family history need to be evaluated. Molecular screening is the gold standard for the diagnosis and is based on the identification in a proband of a pathogenic variation in the NOTCH3 coding sequence [36, 83]. With a suggestive diagnosis of CADASIL, a single-gene testing or a multigene panel could be applied; if NOTCH3 screening is unavailable or gives a negative result in a patient with convincing clinical and MRI findings highly suggestive of CADASIL, a skin biopsy analysis using both Notch3 immunostaining and electron microscopy should be recommended to confirm or reject the diagnosis [21, 84]. If CADASIL phenotype overlaps with other inherited cerebrovascular diseases, a comprehensive genomic testing, such as exome sequencing, should be recommended in evaluating different genes involved.
