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Novel and Recurring NOTCH3 Mutations in Two Chinese Patients with CADASIL
Xiangyu Chen1, Sheng Deng1,2, Hongbo Xu1
1Center for Experimental Medicine, the Third Xiangya Hospital, Central South University, Changsha, China.
Insights
This study identified two NOTCH3 gene mutations in Han-Chinese patients with Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). These findings expand the known genetic causes for this inherited vascular disorder.
Area of Science:
- Genetics
- Neurology
- Vascular Biology
Background:
- Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is an inherited vascular disorder affecting small arteries.
- It manifests as migraine, stroke, cognitive decline, and dementia.
- Mutations in NOTCH3 and HTRA1 genes are known causes, with NOTCH3 being the most common.
Purpose of the Study:
- To investigate the genetic basis of CADASIL in two unrelated Han-Chinese patients.
- To identify specific gene mutations responsible for the clinical presentation.
Main Methods:
- Whole exome sequencing was employed for genetic analysis in both patients.
- Potential pathogenic mutations were confirmed using Sanger sequencing.
Main Results:
- Two NOTCH3 gene mutations were identified as the cause of CADASIL in the Han-Chinese patients.
- A known mutation (c.268C>T / p.Arg90Cys) and a novel mutation (c.331G>T / p.Gly111Cys) were detected.
- Bioinformatic analyses predicted both mutations to be deleterious.
Conclusions:
- NOTCH3 mutations are confirmed as the genetic cause of CADASIL in these cases.
- The study expands the spectrum of NOTCH3 mutations associated with CADASIL.
- Integrated clinical and molecular genetic analysis is crucial for CADASIL diagnosis, counseling, and treatment development.
Background:
Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal-dominant, inherited, systemic, vascular disorder primarily involving the small arteries. It is characterized by migraine, recurrent ischemic strokes, cognitive decline, and dementia. Mutations in the Notch receptor 3 gene (NOTCH3) and the HtrA serine peptidase 1 gene (HTRA1) are 2 genetic causes for CADASIL. The NOTCH3 gene, located on chromosome 19p13.12, is the most common disease-causing gene in CADASIL.
Objective:
To investigate genetic causes in 2 unrelated Han-Chinese patients with presentations strongly suggestive of CADASIL.
Methods:
Exome sequencing was performed on both patients and potential pathogenic mutations were validated by Sanger sequencing.
Results:
This study reports on 2 unrelated Han-Chinese patients with presentations strongly suggestive of CADASIL, identifying that NOTCH3 mutations were the genetic cause. A common mutation, c.268C>T (p.Arg90Cys), and a novel mutation, c.331G>T (p.Gly111Cys) in the NOTCH3 gene, were detected and confirmed in the patients, respectively, and were predicted to be deleterious based on bioinformation analyses.
Conclusions:
We identified 2 NOTCH3 mutations as likely genetic causes for CADASIL in these 2 patients. Our findings broaden the mutational spectrum of the NOTCH3 gene accountable for CADASIL. Clinical manifestations supplemented with molecular genetic analyses are critical for accurate diagnosis, the provision of genetic counseling, and the development of therapies for CADASIL.
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