Spectrum of NOTCH3 mutations in Korean patients with clinically suspicious cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy
Spectrum of NOTCH3 mutations in Korean patients with clinically suspicious cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy
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DOI：
10.1016/j.neurobiolaging.2013.09.004
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发表时间：
2014-03-01
影响因子：
4.2
通讯作者：
Na, Duk L.
中科院分区：
文献类型：
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作者：
Kim, Young-Eun;Yoon, Cindy W.;Na, Duk L.
伴有皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病（CADASIL）是由19号染色体上的NOTCH 3基因突变引起的。先前的研究表明，NOTCH 3包含突变热点，这些突变热点在不同种族背景的个体中可能会有所不同。在这项研究中，我们调查了韩国CADASIL患者的NOTCH 3突变谱。我们回顾性分析了156例接受NOTCH 3基因检测的CADASIL分子诊断患者，采用分层方法进行桑格测序。首先，我们筛选了先前报道的突变热点（外显子2-6、8、11、18、19和22）。如果没有检测到突变，并且样本可用，我们将分析扩展到其他外显子（7，9，10，14，15，20，21，23和25）。在156例患者中的45例（28.8%）中，确定了29个突变和16个未知意义的新变体（VUS）。NOTCH 3第11号外显子中的p.R544C突变是最常见的突变（n = 8），其次是第3号外显子中的p.R75P（n = 7）、第6号外显子中的p.R332C（n = 3）、第2号外显子中的p.R54C（n = 2）和第3号外显子中的p.R90C（n = 2）。在VUS中，外显子22的p.R1175W、外显子8的p.S414C和外显子22的p.N1207S分别在5、3和2例患者中发现。在各1例患者中观察到其他突变和VUS。虽然这不是一项前瞻性的全国性队列研究，但上述结果表明，韩国人的NOTCH 3突变谱可能与高加索人不同。因此，可能需要对韩国CADASIL患者进行进一步分析，以实施韩国特异性突变筛查模式。(C)2014爱思唯尔公司All rights reserved.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by mutations in the NOTCH3 gene on chromosome 19. Previous studies showed that NOTCH3 contains mutational hotspots that can vary among individuals of different ethnic backgrounds. In this study, we investigated the spectrum of NOTCH3 mutations in Korean patients with CADASIL. We retrospectively analyzed 156 patients who underwent NOTCH3 gene testing for molecular diagnosis of CADASIL using Sanger sequencing with a tiered approach. First, we screened previously reported mutational hotspots (exons 2-6, 8, 11, 18, 19, and 22). If no mutation was detected and samples were available, we extended our analysis to additional exons (7, 9,10,14,15, 20, 21, 23, and 25). In 45 of 156 patients (28.8%), 29 mutations and 16 novel variants of unknown significance (VUS) were identified. The p.R544C mutation in exon 11 of NOTCH3 was the most frequently observed mutation (n = 8), followed by p.R75P in exon 3 (n = 7), p.R332C in exon 6 (n = 3), p.R54C in exon 2 (n = 2), and p.R90C in exon 3 (n = 2). Among the VUS, p.R1175W in exon 22, p.S414C in exon 8, and p.N1207S in exon 22 were found in 5, 3, and 2 patients, respectively. Other mutations and VUS were observed in 1 patient each. Although this was not a prospective, nationwide cohort study, the results above suggested that the spectrum of NOTCH3 mutations might be different in Koreans than in individuals of Caucasian ethnicity. Therefore, further analysis of Koreans with CADASIL might be necessary to implement a Korean-specific mutation screening paradigm. (C) 2014 Elsevier Inc. All rights reserved.