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Updated: Jul 11, 2025
Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
NOTCH3 Variants in Patients with Suspected CADASIL
Orhan Gorukmez1, Ozlem Gorukmez1, Ali Topak1
1Department of Medical Genetics, Bursa Yuksek Ihtisas Training and Research Hospital, Bursa, Turkey.
Insights
Genetic analysis of NOTCH3 mutations in 368 patients revealed that 12% had cerebral autosomal dominant arteriopathy with subcortical infarctions and leukoencephalopathy (CADASIL). This hereditary small vessel disease shows varied clinical and radiological features.
Area of Science:
- Neurology
- Genetics
- Vascular Medicine
Background:
- Cerebral autosomal dominant arteriopathy with subcortical infarctions and leukoencephalopathy (CADASIL) is the most prevalent hereditary cerebral small vessel disease.
- CADASIL is characterized by clinical, radiological, and genetic heterogeneity.
- The condition is primarily caused by mutations in the NOTCH3 gene.
Purpose of the Study:
- To investigate NOTCH3 mutations in patients with suspected CADASIL.
- To correlate genetic findings with clinical and radiological features.
- To identify novel NOTCH3 variants in a large patient cohort.
Main Methods:
- Next-generation sequencing was employed to analyze the NOTCH3 gene.
- 368 patients with suspected CADASIL were included in the study.
- Detected variants were analyzed alongside patient clinical and radiological data.
Main Results:
- Heterozygous NOTCH3 variants, predominantly missense mutations, were identified in approximately 12% (44 out of 368) of patients.
- A total of 30 distinct NOTCH3 variants were detected, with 17 being novel.
- No clear genotype-phenotype correlation was observed.
Conclusions:
- NOTCH3 mutations are confirmed as a cause of CADASIL.
- The study identified novel variants, expanding the known mutation spectrum.
- CADASIL presents a heterogeneous phenotype irrespective of the specific NOTCH3 variant, highlighting the complexity of the disease.
Background:
Cerebral autosomal dominant arteriopathy with subcortical infarctions and leukoencephalopathy (CADASIL) is the most common hereditary form of cerebral small vessel disease. It is clinically, radiologically, and genetically heterogeneous and is caused by NOTCH3 mutations.
Methods:
In this study, we analyzed NOTCH3 in 368 patients with suspected CADASIL using next-generation sequencing. The significant variants detected were reported along with the clinical and radiological features of the patients.
Results:
Heterozygous NOTCH3 changes, mostly missense mutations, were detected in 44 of the 368 patients (~12%).
Conclusions:
In this single-center study conducted on a large patient group, 30 different variants were detected, 17 of which were novel. CADASIL, which can result in mortality, has a heterogeneous phenotype among individuals in terms of clinical, demographic, and radiological findings regardless of the NOTCH3 variant.
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