NOTCH3 gene mutations in subjects clinically suspected of CADASIL

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic cerebrovascular disease.
• It is caused by mutations in the NOTCH3 gene, often involving cysteine residues.
• Accurate genetic diagnosis and counseling are crucial for affected families.

Purpose of the Study:

• To identify pathogenic mutations in the NOTCH3 gene in Italian patients with suspected CADASIL.
• To evaluate the diagnostic utility of screening the entire EGF-like domain region of the NOTCH3 gene.
• To provide genetic counseling and testing for at-risk relatives.

Main Methods:

• Direct sequencing of NOTCH3 exons 2-23 in 140 patients with clinical suspicion of CADASIL.
• Pre- and post-genetic counseling provided to all patients.
• Screening focused on EGF-like domains known to harbor mutations.

Main Results:

• Fourteen distinct causative mutations in the NOTCH3 gene were identified in 14 familial cases.
• Mutations were found across multiple exons (2, 3, 4, 5, 7, 10, 14, 19, 20, 22), with none in exons 6 and 8.
• Various genetic variations, including non-cysteine altering ones, were also detected.

Conclusions:

• Comprehensive screening of the NOTCH3 gene's EGF-like domains is essential for CADASIL molecular diagnosis in the Italian population.
• The study identified novel genetic variants beyond cysteine residue alterations.
• Genetic testing and counseling remain vital for managing CADASIL and its familial implications.