Department of Neurology and Stroke Medicine, Yokohama City University, Yokohama, Japan.
Department of Neurology, Yokohama City University Medical Center, Yokohama, Japan.
Clin Genet. 2018 Aug;94(2):232-238. doi: 10.1111/cge.13371. Epub 2018 Jun 8.
Leukoencephalopathies encompass all clinical syndromes that predominantly affect brain white matter. Genetic diagnosis informs clinical management of these patients, but a large part of the genetic contribution to adult leukoencephalopathy remains unresolved. To examine this genetic contribution, we analyzed genomic DNA from 60 Japanese patients with adult leukoencephalopathy of unknown cause by next generation sequencing using a custom-designed gene panel. We selected 55 leukoencephalopathy-related genes for the gene panel. We identified pathogenic mutations in 8 of the 60 adult leukoencephalopathy patients (13.3%): NOTCH3 mutations were detected in 5 patients, and EIF2B2, CSF1R, and POLR3A mutations were found independently in 1 patient each. These results indicate that cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) caused by NOTCH3 mutations is the most frequent adult leukoencephalopathy in our cohort. Moreover, brain imaging analysis indicates that CADASIL patients who do not present typical phenotypes may be underdiagnosed if not examined genetically.
脑白质病涵盖所有主要影响脑白质的临床综合征。基因诊断为这些患者的临床管理提供了信息，但成人脑白质病的遗传贡献很大一部分仍未得到解决。为了研究这种遗传贡献，我们通过使用定制设计的基因面板对 60 名日本成人不明原因脑白质病患者的基因组 DNA 进行了下一代测序分析。我们选择了 55 个与脑白质病相关的基因用于基因面板。我们在 60 名成人脑白质病患者中的 8 名（13.3%）中发现了致病性突变：5 名患者检测到 NOTCH3 突变，1 名患者分别独立发现 EIF2B2、CSF1R 和 POLR3A 突变。这些结果表明，NOTCH3 突变引起的脑常染色体显性动脉病伴皮质下梗死和脑白质病（CADASIL）是我们队列中最常见的成人脑白质病。此外，脑影像学分析表明，如果不进行基因检测，不表现出典型表型的 CADASIL 患者可能会被漏诊。
