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Updated: Aug 17, 2026
Comparative Lesions Analysis Through a Targeted Sequencing Approach
Published on: November 5, 2019
Spectrum of mutations in biopsy-proven CADASIL: implications for diagnostic strategies
Nils Peters1, Christian Opherk, Tanja Bergmann
1Department of Neurology, Neurogenetics Laboratory, Klinikum Grosshadern, Ludwig-Maximilians University, Munich, Germany.
Insights
Identifying NOTCH3 gene mutations is key for diagnosing cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Most mutations occur in exons 2-6, guiding genetic testing strategies.
Area of Science:
- Genetics
- Neurology
- Molecular Biology
Background:
- Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by NOTCH3 gene mutations.
- These mutations are typically found in the extracellular epidermal growth factor-like repeat domains of the Notch3 receptor.
- Accurate mutation identification is crucial for genetic counseling and risk assessment in affected families.
Purpose of the Study:
- To determine the range of NOTCH3 mutations in CADASIL patients.
- To evaluate the effectiveness of current diagnostic strategies for CADASIL.
- To provide insights for improved genetic testing protocols.
Main Methods:
- Direct sequencing of NOTCH3 exons encoding epidermal growth factor-like repeats was performed.
- The study included 125 unrelated German patients with biopsy-proven CADASIL.
- Results were compared with existing published data.
Main Results:
- 54 distinct NOTCH3 mutations (117 missense, 3 in-frame deletions) were identified in 120 out of 125 patients (96.0%).
- The majority of mutations (58.3%) were located in exon 4, and 85.8% were found in exons 2 through 6.
- No mutation was detected in 5 patients (4.0%).
Conclusions:
- Approximately 90% of NOTCH3 mutations are concentrated in exons 2-6, suggesting these as primary targets for genetic testing.
- Genetic testing for CADASIL may yield false-negative results, necessitating alternative diagnostic approaches.
- Skin biopsy should be considered for patients with high clinical suspicion of CADASIL if genetic testing is negative.
Background:
Mutations in the NOTCH3 gene are the cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which is an important cause of stroke in young adults. Mutations are typically located within epidermal growth factor-like repeat domains in the extracellular part of the Notch3 receptor. Identification of the mutation is critical for genetic counseling and testing of relatives at risk.
Objectives:
To identify the spectrum of NOTCH3 mutations in CADASIL and to discuss the implications for diagnostic strategies.
Design:
Screening for NOTCH3 mutations was performed in 125 unrelated German CADASIL patients with biopsy-proven disease by direct sequencing of exons coding for epidermal growth factor-like repeats. Results were compared with those of previously published studies.
Results:
We detected 54 distinct mutations (117 missense mutations and 3 in-frame deletions) in 120 (96.0%) of the 125 patients. Of the mutations, 58.3% were located in exon 4 and 85.8% in exons 2 through 6. In 5 patients (4.0%), no mutation was identified.
Conclusions:
Almost 90% of mutations could be detected within a few exons (exons 2-6). Thus, genetic testing should initially be focused on these exons, with some variation depending on the population in whom it is being performed. Yet, genetic testing for CADASIL is associated with a nameable proportion of false-negative results. Cases with a high index of clinical suspicion should be investigated by skin biopsy if genetic testing is negative.
