A NOTCH3 p.Gly1105Cys variant in CADASIL: clinical characterization and an updated overview of exon 20 variants

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), an autosomal dominant cerebrovascular disorder caused by NOTCH3 variants. Although more than 400 NOTCH3 variants have been reported, exon 20 variants remain rare, and clinical characterization is limited. We report a 39-year-old Chinese male with recurrent lacunar infarctions involving the brainstem, basal ganglia, and corona radiata. He had right-sided hemiplegia and cognitive deficits, without dizziness, headache, dysphagia, or dysarthria. His mother and maternal uncle had a history of ischemic stroke. Genetic testing identified a heterozygous NOTCH3 c.3313G > T (p.Gly1105Cys) variant in exon 20 (NM_000435.3), classified as likely pathogenic according to the American College of Medical Genetics and Genomics (ACMG) criteria. Alongside adjusted medications for secondary stroke prevention, he received acupuncture and physical rehabilitation, followed by an improvement in mood and motor function. We also reviewed NOTCH3 exon 20 variants and found marked phenotypic heterogeneity across variants and populations. Migraine appears less frequent among Chinese carriers than in Western cohorts, whereas cognitive impairment may occur relatively early. Radiologically, temporal pole white matter hyperintensities were absent in our patient and other Chinese carriers of NOTCH3 variants in epidermal growth factor-like repeat (EGFr) domain 28, but reported in some with domain 27 variants. Although p.Gly1105Cys is located in a low-risk EGFr domain according to recent domain-based stratification models, our patient developed early-onset recurrent stroke, highlighting individual clinical variability. This case provides a detailed clinical and imaging description of CADASIL associated with NOTCH3 c.3313G > T (p.Gly1105Cys) and expands understanding of genotype-phenotype correlations among exon 20 variants.