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Four Novel Disease-Causing Variants in the NOTCH3 Gene in Russian Patients with CADASIL
Fatima Bostanova1, Polina Tsygankova1, Ilya Nagornov1
1Research Centre for Medical Genetics, Moscow 115522, Russia.
Insights
This study identified four new NOTCH3 gene variants in five patients with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). These findings expand the known genetic causes of this inherited cerebrovascular disease.
Area of Science:
- Genetics
- Neurology
- Molecular Biology
Background:
- Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a rare inherited cerebrovascular disorder.
- It is characterized by recurrent strokes, dementia, mood disturbances, and migraines, primarily caused by NOTCH3 gene mutations.
Observation:
- Five patients from four families with clinical suspicion of CADASIL were analyzed.
- Genetic analysis revealed four novel pathogenic variants in the NOTCH3 gene: two missense and two splice-site variants.
- Patients presented with a spectrum of symptoms including headaches, transient ischemic attacks, memory impairment, and characteristic MRI findings.
Findings:
- Four previously undescribed pathogenic variants in the NOTCH3 gene were identified in five CADASIL patients.
- The identified variants include missense mutations (p.Gly70Cys, p.Cys379Tyr, p.Cys516Tyr) and a splice-site mutation (c.341-1G>C).
- The study details the clinical and genetic characteristics of these patients, linking novel mutations to the CADASIL phenotype.
Implications:
- These findings expand the known mutational spectrum of CADASIL, contributing to a better understanding of its genetic basis.
- Identification of novel variants aids in more accurate genetic diagnosis and counseling for families affected by CADASIL.
- Further research into these variants may elucidate specific pathomechanisms underlying NOTCH3-associated vasculopathy.
Background:
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited disease with unknown mechanisms and a broad phenotypic spectrum. It is caused by pathogenic variants in the NOTCH3 gene. The symptoms of the disease mainly include recurrent strokes with vascular risk factors, migraine with aura, dementia, and mood disturbances.
Case Presentation:
Peripheral blood samples were collected from five patients from four unrelated families to extract genomic DNA. In four patients, analysis of exons 2, 3, 4, 5, 6 and adjacent intronic regions of the NOTCH3 gene was made via Sanger sequencing. Two previously undescribed nucleotide variants were identified in two patients: missense variant c.208G>T, (p.Gly70Cys) in exon 1 and splice-site variant c.341-1G>C in intron 3. Further DNA of two other patients were analyzed using a next-generation sequencing-based custom AmpliSeq™ panel for 59 genes associated with leukodystrophies. Two novel missense variants in the NOTCH3 gene were identified, c.1136G>A, (p.Cys379Tyr) in exon 7 and c.1547G>A, (p.Cys516Tyr) in exon 10. The pathogenic variant c.1547G>A, (p.Cys516Tyr) was confirmed in the fifth patient (family case) by Sanger sequencing. All patients had a history of headaches, transient ischemic attacks, memory impairment, and characteristics of MRI results. Three patients had strokes and two patients had psychiatric symptoms.
Conclusion:
We found four previously undescribed pathogenic variants in the NOTCH3 gene in five patients with CADASIL and described their clinical and genetic characteristics. These results expand the mutational spectrum of CADASIL.
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