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

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.