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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease caused by mutations in the  NOTCH3  gene. Archetypal disease-causing mutations are cysteine-affecting variants within the 34 epidermal growth factor-like repeat (EGFr) region of the Notch3 extracellular subunit. Cysteine-sparing variants and variants outside the EGFr coding region associated with CADASIL phenotype have been reported. However, the linkage between untypical variants and CADASIL is unclear. In this study, we investigated the spectrum of  NOTCH3  variants in a cohort of 38 probands from unrelated families diagnosed as CADASIL. All coding exons of the  NOTCH3  gene were analyzed, and clinical data were retrospectively studied. We identified 23 different  NOTCH3  variants including 14 cysteine-affecting pathogenic variants, five cysteine-sparing pathogenic variants, two reported cysteine-sparing variants of unknown significance (VUS), and two novel VUS outside EGFr region. In retrospective studies of clinical data, we found that patients carrying cysteine-sparing pathogenic variants showed later symptom onset (51.36 ± 7.06 vs. 44.96 ± 8.82,  p  = 0.023) and milder temporal lobe involvement (1.50 ± 1.74 vs. 3.11 ± 2.32,  p  = 0.027) than patients carrying cysteine-affecting pathogenic variants. Our findings suggested that untypical variants comprise a significant part of  NOTCH3  variants and may be associated with a distinctive phenotype.

NOTCH3 Variants and Genotype-Phenotype Features in Chinese CADASIL Patients