Spectrum of mutations in biopsy-proven CADASIL - Implications for diagnostic strategies
Spectrum of mutations in biopsy-proven CADASIL - Implications for diagnostic strategies
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DOI：
10.1001/archneur.62.7.1091
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发表时间：
2005-07-01
影响因子：
--
通讯作者：
Dichgans, M
中科院分区：
文献类型：
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作者：
Peters, N;Opherk, C;Dichgans, M
背景资料：NOTCH 3基因突变是常染色体显性遗传性脑动脉病伴皮质下梗死和白质脑病（CADASIL）的原因，CADASIL是年轻人中风的重要原因。突变通常位于Notch 3受体细胞外部分的表皮生长因子样重复结构域内。突变的鉴定是关键的遗传咨询和测试的亲属在risk.Objectives：要确定光谱的NOTCH 3突变CADASIL和讨论的诊断strategies.Design的影响：筛查NOTCH 3突变进行了125个无关的德国CADASIL患者活检证实的疾病，通过直接测序的外显子编码表皮生长因子样重复序列。结果：在120例（96.0%）患者中检测到54个不同的突变（117个错义突变和3个框内缺失）。在突变中，58.3%位于外显子4，85.8%位于外显子2至6。5例（4.0%）未发现突变。结论：近90%的突变可在少数外显子（外显子2-6）内检测到。因此，基因检测最初应该集中在这些外显子上，根据正在进行的人群而有所不同。然而，CADASIL基因检测与假阴性结果的比例相关。如果基因检测结果为阴性，则应通过皮肤活检对临床高度怀疑的病例进行调查。
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.