The disorder is inherited in an autosomal dominant way. In 1996, mutations in the transmembrane receptor gene Notch3 have been recognized as a cause of CADASIL¹⁾. This gene encodes a 2321 amino acid protein and is divided over 33 exons on more than 45.5 kB of chromosome 19q13.1. Most pathogenic mutations, often involving the loss or gain of a cystein residue, have been detected within the 34 epidermal growth factor-like repeats in the extracellular domain of the Notch3 protein. The mutations in only two exons of the gene (exon 3 and 4), cover 70% of the CADASIL cases^{2, 3, 4)}.

The screening of the Notch3 gene for mutations supports the clinical diagnosis of CADASIL and enables detection of clinically unaffected carriers of mutant alleles among family members of CADASIL patients.

When suspecting CADASIL, we routinely amplify and sequence the target exons 3 and 4 from the genomic DNA of the patient. When these exons are free of mutations, it is possible to screen more protein-coding exons of the Notch3 gene (e.g. exons 2, 5, 6, 8, 11, 18, 19)^{3, 4)}. The screening order depends on the ethnic background of the patient and the mutation frequency. We usually provide results of the screening of the exons 3 and 4 and their flanking intron sequences within 2 days after receipt of the sample.

When mutations are found, we recommend analyzing the Notch3 genes of the patient's relatives as a secondary confirmation and to detect carrier of the gene defect.

¹⁾ Joutel, A. et al. (1996) Nature 383:707-710. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia.
²⁾ Joutel, A. (2000) Ann. Neurol. 47:388-39. De novo mutation in the Notch3 gene causing CADASIL.
³⁾Joutel, A. et al.(1997) Lancet 350:1511-1515. Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients.
⁴⁾ Peters, N. et al. (2005) Arch. Neurol. 62:1091-1094. Spectrum of Mutations in Biopsy-Proven CADASIL