Xiangyu Chen1, Sheng Deng1,2, Hongbo Xu1, Deren Hou3, Pengzhi Hu4, Yan Yang3, Jie Wen1, Hao Deng1,3, Lamei Yuan5. 1. Center for Experimental Medicine, the Third Xiangya Hospital, Central South University, Changsha, China. 2. Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, China. 3. Department of Neurology, the Third Xiangya Hospital, Central South University, Changsha, China. 4. Department of Radiology, the Third Xiangya Hospital, Central South University, Changsha, China. 5. Center for Experimental Medicine, the Third Xiangya Hospital, Central South University, Changsha, China, yuanlamei229@163.com.
Abstract
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.
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.