A homozygous NOTCH3 mutation p.R544C and a heterozygous TREX1 variant p.C99MfsX3 in a family with hereditary small vessel disease of the brain.

[cadasil]

Mutations in the TREX 1 and NOTCH 3 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 ).We performed mutational analyses of TREX 1 in genomic DNA from 39 unrelated patients who were NOTCH 3 -negative in genetic testing , selected out of 72 unrelated consecutive patients with HSVDB .Only one patient had a TREX 1 sequence variation , a heterozygous TREX 1 c .294 dupA , putatively resulting in a truncated protein , p .C 9 9 MfsX 3 . The medical history of the patient 's family was scrutinized , which revealed that heterozygous TREX 1 p .C 9 9 MfsX 3 was not segregating with the HSVDB . Re-examination of the NOTCH 3 sequence data of the proband led to the identification of a homozygous NOTCH 3 c .1630 C >T (p .R 544 C ) mutation , which segregated with the HSVDB in the family . The proband had a slightly more severe phenotype in comparison with her heterozygous p .R 544 C sister .TREX 1 mutation is not a common cause of HSVDB . TREX 1 p .C 9 9 MfsX 3 is not a dominant mutation . Homozygosity of the NOTCH 3 p .R 544 C has a modestly deleterious effect on the CADASIL phenotype . The NOTCH 3 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 .