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Interpretation of NOTCH3 mutations in the diagnosis of CADASIL
Julie W Rutten1, Joost Haan, Gisela M Terwindt
1Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Insights
Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is linked to NOTCH3 gene mutations. This study provides guidance on interpreting these NOTCH3 mutations for accurate CADASIL diagnosis.
Area of Science:
- Genetics
- Neurology
- Molecular Biology
Background:
- Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is an inherited cerebrovascular disorder.
- It presents in mid-adulthood with dementia and stroke-like symptoms.
- CADASIL is caused by mutations in the NOTCH3 gene.
Purpose of the Study:
- To clarify the role of NOTCH3 gene mutations in CADASIL.
- To provide recommendations for interpreting NOTCH3 mutations in CADASIL diagnosis.
Main Methods:
- Review of existing literature on NOTCH3 mutations and CADASIL.
- Analysis of mutation types associated with CADASIL.
- Discussion of diagnostic criteria.
Main Results:
- Pathogenic NOTCH3 mutations typically alter cysteine residues in EGFr domains.
- While most mutations are missense, deletions, insertions, and splice-site mutations also occur.
- The pathogenicity of some NOTCH3 mutation types remains debated.
Conclusions:
- Accurate interpretation of NOTCH3 mutations is crucial for CADASIL diagnosis.
- Recommendations are provided to aid clinicians and researchers in this interpretation.
Abstract:
CADASIL is an autosomal dominant inherited disease, characterized by mid-adult onset of cerebrovascular disease and dementia. CADASIL is caused by mutations in the NOTCH3 gene, which encodes the NOTCH3 protein. Pathogenic mutations in CADASIL are highly distinctive in the sense that they lead to the loss or gain of a cysteine residue in 1 of the 34 EGFr domains of the NOTCH3 protein. The majority are missense mutations, but small deletions, insertions and splice-site mutations have been reported, which typically also lead to a numerical cysteine alteration. Whether numerical cysteine-altering mutations are a rule in CADASIL remains subject of debate, as there are reports suggesting pathogenicity of other types of mutations. However, for most of these the association with CADASIL was later revoked or is questionable. Here, we discuss and provide recommendations for the interpretation of NOTCH3 mutations in the diagnosis of CADASIL.