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. Mu...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.展开更多
近日，国际肺癌研究协会举办的专业学术期刊《胸肿瘤学期刊》（Journal of Thoracic Oncology）在线发表了中科院生化与细胞所季红斌研究组与复旦大学肿瘤医院合作开展的最新研究成果，报道了中国肺腺癌人群中热点基因LKB1、EGFR和KRAS...近日，国际肺癌研究协会举办的专业学术期刊《胸肿瘤学期刊》（Journal of Thoracic Oncology）在线发表了中科院生化与细胞所季红斌研究组与复旦大学肿瘤医院合作开展的最新研究成果，报道了中国肺腺癌人群中热点基因LKB1、EGFR和KRAS的突变谱。展开更多
文摘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.
