Novel heterozygous NOTCH3 pathogenic variant found in two Chinese patients with CADASIL

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a hereditary cerebrovascular disease.
• NOTCH3 gene mutations are the primary known cause of CADASIL.

Observation:

• Two patients from a Chinese family presented with clinical symptoms consistent with CADASIL.
• Whole genome sequencing was employed to investigate the genetic basis of the disease in these patients.

Findings:

• A novel heterozygous variant, c.128G>C (p.Cys43Ser), in the NOTCH3 gene was identified in both patients.
• This variant, leading to a cysteine-to-serine substitution at codon 43, was classified as pathogenic according to ACMG guidelines.
• Other identified variants in HTRA1, COL4A1, and COL4A2 were deemed benign.

Implications:

• This discovery expands the spectrum of known NOTCH3 mutations associated with CADASIL.
• The findings contribute to the genetic diagnosis and understanding of CADASIL in the Chinese population.
• Further research may explore the functional impact of this specific NOTCH3 variant on vascular health.