An in trans NOTCH3 loss-of-function variant modifies disease severity in CADASIL: A family-based study

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic disorder caused by NOTCH3 gene variants.
• Disease severity in CADASIL shows significant variation, and the effect of reduced NOTCH3 gene dosage is not fully understood.

Purpose of the Study:

• To investigate the impact of reduced NOTCH3 gene dosage on CADASIL severity.
• To analyze a family with diverse NOTCH3 variants and intrafamilial phenotypic heterogeneity.

Main Methods:

• Clinical assessment, brain MRI, and genetic analysis were performed on four related individuals.
• NOTCH3 complementary DNA (cDNA) sequencing and skin biopsy were utilized to assess gene expression and protein presence.

Main Results:

• A proband with compound heterozygous NOTCH3 variants (cysteine-altering and loss-of-function) presented with severe CADASIL symptoms and extensive brain imaging abnormalities.
• Individuals carrying a single NOTCH3 variant (either cysteine-altering or loss-of-function) exhibited milder clinical and imaging phenotypes.
• Reduced loss-of-function allele expression was observed in skin tissue, and NOTCH3 extracellular domain immunoreactivity was present only in carriers of the cysteine-altering variant.

Conclusions:

• Reduced NOTCH3 gene dosage appears to be a modifying factor in CADASIL disease severity.
• Intrafamilial phenotypic heterogeneity in CADASIL can be influenced by the specific combination and dosage of NOTCH3 variants.