Homozygous NOTCH3 c.3373G > A (p.(Glu1125Lys)) in a consanguineous Chinese family presenting with vestibular migraine and epilepsy: Expanding the genotype-phenotype spectrum
Abstract
Pathogenic variants in NOTCH3 are the main genetic cause of CADASIL, classically through disruption of cysteine residues within epidermal growth factor-like repeat (EGFr) domains. We report a consanguineous Han Chinese family in which two siblings carried a rare homozygous cysteine-sparing NOTCH3 variant (NM_000435.3: c.3373G > A; p.(Glu1125Lys)) presenting with vestibular migraine and epilepsy and severe cerebral small-vessel disease on neuroimaging. Both patients underwent detailed clinical assessment, including neurological examination and modified NINDS-CADASIL scoring. Brain magnetic resonance imaging (MRI) was obtained, and total cerebral microbleeds (CMBs) were quantified as counts/cm³ by two blinded neuroradiologists. Both siblings harbored the variant in a homozygous state within EGFr19 of NOTCH3. MRI showed confluent periventricular and temporal pole white matter hyperintensities (Fazekas grade 3) and numerous deep CMBs, particularly in the basal ganglia and cerebellum. Quantitatively, total CMB density was higher compared with controls (mean 2.15 counts/cm³ vs. 0.4 ± 0.2 counts/cm³; p = 0.008). This report expands the allelic and phenotypic spectrum of NOTCH3-related cerebral small-vessel disease and suggests that biallelic cysteine-sparing variants in EGFr19 may be associated with early-onset vestibular migraine, epilepsy, and a high CMB burden in the setting of consanguinity.Clinical trial registration: Not applicable.
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