A novel homozygous loss-of-function NOTCH3 variant in a Moroccan patient: expanding the spectrum beyond CADASIL

NOTCH3, a key regulator of vascular smooth muscle cell function within the Notch signaling pathway, is essential for maintaining small artery integrity, especially in cerebral microvasculature. Pathogenic heterozygous missense variants in NOTCH3 cause CADASIL, an autosomal dominant small-vessel disease marked by extracellular domain aggregation, granular osmiophilic material deposition, and vascular smooth muscle cell dysfunction, leading to early-onset ischemic strokes, migraine with aura, and progressive cognitive decline. We report a 12-year-old Moroccan girl, born to first-degree consanguineous parents, presenting with global developmental delay, spastic tetraparesis, epilepsy, and bilateral periventricular white matter abnormalities. Whole-exome sequencing identified a novel homozygous frameshift variant in NOTCH3 (NM_000435.3:c.2985_2991del; NP_000426.2:p.(Gln996ArgfsTer274)), confirmed by Sanger sequencing, with heterozygous carrier parents. Emerging evidence shows that biallelic loss-of-function variants, unlike the gain-of-function variants underlying CADASIL, define a distinct autosomal recessive leukodystrophy characterized by early-onset pyramidal signs, epilepsy, and white matter abnormalities, thereby expanding the phenotypic and molecular spectrum of NOTCH3-related disorders. This work highlights the functional divergence between dominant and recessive NOTCH3 variants and supports the inclusion of NOTCH3 in gene panels for early-onset leukodystrophies, especially in consanguineous populations.