CADASIL is a cerebrovascular disease caused by mutations in the NOTCH3 gene. 
Most mutations result in a gain or loss of cysteine residue in one of the 34 
epidermal growth factor-like repeats in the extracellular domain of the Notch3 
protein, thus sparing the number of cysteine residues. To date, more than 130 
different mutations in the NOTCH3 gene have been reported in CADASIL patients, 
of which 95% are missense point mutations. Many polymorphisms have also been 
identified in the NOTCH3 coding sequence, some of them leading to amino acid 
substitutions. The aim of the present study was to analyze the NOTCH3 gene in a 
large group of patients affected by leukoencephalopathy and to investigate the 
presence of genetic variants. The molecular analysis revealed several nucleotide 
alterations. In particular, we identified 20 different mutations, 22 
polymorphisms, and 8 genetic variants of unknown pathological significance never 
reported previously. We hope that this NOTCH3 gene mutational analysis, 
performed in such a significant number of unrelated and related patients 
affected by leukoencephalopathy, will help in molecular screening for the NOTCH3 
gene, thus contributing to enlargement of the NOTCH3 gene variation database.