BACKGROUND: Mutations in the TREX1 and NOTCH3 genes cause retinal vasculopathy 
with cerebral leukodystrophy (RVCL) and cerebral autosomal dominant arteriopathy 
with subcortical infarcts and leukoencephalopathy (CADASIL), respectively. Both 
are hereditary small vessel diseases of the brain (HSVDB).
METHODS: We performed mutational analyses of TREX1 in genomic DNA from 39 
unrelated patients who were NOTCH3-negative in genetic testing, selected out of 
72 unrelated consecutive patients with HSVDB.
RESULTS: Only one patient had a TREX1 sequence variation, a heterozygous TREX1 
c.294dupA, putatively resulting in a truncated protein, p.C99MfsX3. The medical 
history of the patient's family was scrutinized, which revealed that 
heterozygous TREX1 p.C99MfsX3 was not segregating with the HSVDB. Re-examination 
of the NOTCH3 sequence data of the proband led to the identification of a 
homozygous NOTCH3 c.1630C>T (p.R544C) mutation, which segregated with the HSVDB 
in the family. The proband had a slightly more severe phenotype in comparison 
with her heterozygous p.R544C sister.
CONCLUSION: TREX1 mutation is not a common cause of HSVDB. TREX1 p.C99MfsX3 is 
not a dominant mutation. Homozygosity of the NOTCH3 p.R544C has a modestly 
deleterious effect on the CADASIL phenotype. The NOTCH3 mutation may cause 
CADASIL through a gain-of-toxic function effect, which can be modified by other 
genetic or environmental factors and results in the phenotypic variation of 
CADASIL.