Using exome sequencing to reveal mutations in TREM2 presenting as a frontotemporal dementia-like syndrome without bone involvement.
Using exome sequencing to reveal mutations in TREM2 presenting as a frontotemporal dementia-like syndrome without bone involvement.
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DOI：
10.1001/jamaneurol.2013.579
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发表时间：
2013-01
期刊：
影响因子：
29
通讯作者：
Hardy, John
中科院分区：
文献类型：
--
作者：
Guerreiro, Rita Joao;Lohmann, Ebba;Bras, Jose Miguel;Gibbs, Jesse Raphael;Rohrer, Jonathan D.;Gurunlian, Nicole;Dursun, Burcu;Bilgic, Basar;Hanagasi, Hasmet;Gurvit, Hakan;Emre, Murat;Singleton, Andrew;Hardy, John
识别与额颞性痴呆(FTD)相关的新基因和危险因素。一些基因和基因座与不同形式的FTD有关，但大量痴呆症患者家族中没有这些基因的突变。所有患者均进行全外显子组测序和全基因组基因分型。将全外显子组测序获得的遗传变异与全基因组基因分型获得的数据进行整合。伊斯坦布尔医学院神经内科行为神经科门诊数据库，土耳其伊斯坦布尔。这项研究包括44名临床诊断为FTD的土耳其患者。在适当的时候对亲属进行筛查。髓系细胞2基因(TREM2)表达的触发受体突变。在3个患有FTD样病的先证者中，我们发现了不同的TREM2纯合子突变，这些突变以前与多囊脂肪膜性骨发育不良伴硬化性白质脑病(PLOSL)相关。这3名患者都没有典型的PLOSL临床表现：他们有行为改变和随后的认知障碍和运动特征，但没有任何骨囊肿或骨相关表型。影像显示3例患者均有脑白质异常和额叶萎缩。我们的结果显示，在我们的队列中，TREM2导致了出人意料的大量痴呆症病例，这表明当排除其他痴呆症基因的突变时，应该考虑到这个基因。即使对于像痴呆症这样的复杂综合征，外显子组测序也已被证明是一种快速且具有成本效益的工具来识别基因突变，允许将临床表型与意想不到的分子基础联系起来。
To identify new genes and risk factors associated with frontotemporal dementia (FTD). Several genes and loci have been associated with different forms of FTD, but a large number of families with dementia do not harbor mutations in these genes. Whole-exome sequencing and whole-genome genotyping were performed in all patients. Genetic variants obtained from whole-exome sequencing were integrated with the data obtained from whole-genome genotyping. Database of the Behavioral Neurology Outpatient Clinic of the Department of Neurology, Istanbul Faculty of Medicine, Istanbul, Turkey. Forty-four Turkish patients with an FTD-like clinical diagnosis were included in the study. Relatives were screened when appropriate. Mutations in the triggering receptor expressed on myeloid cells 2 gene (TREM2). In 3 probands with FTD-like disease, we identified different homozygous mutations in TREM2 that had previously been associated with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL). None of these 3 patients had a typical clinical presentation of PLOSL: they presented with behavioral change and subsequent cognitive impairment and motor features but without any bone cysts or bone-associated phenotypes. Imaging showed white matter abnormalities as well as frontal atrophy in all 3 patients. Our results show that TREM2 is responsible for an unexpectedly high number of dementia cases in our cohort, suggesting that this gene should be taken into account when mutations in other dementia genes are excluded. Even for complex syndromes such as dementia, exome sequencing has proven to be a rapid and cost-effective tool to identify genetic mutations, allowing for the association of clinical phenotypes with unexpected molecular underpinnings.
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影响因子：
64.8
作者：
Cruts, Marc;Gijselinck, Ilse;Van Broeckhoven, Christine
通讯作者：
Van Broeckhoven, Christine
使用下一代 DNA 测序数据进行变异发现和基因分型的框架。
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
9.8
作者：
Zimprich, Alexander;Benet-Pages, Anna;Strom, Tim M.
通讯作者：
Strom, Tim M.
影响因子：
64.8
作者：
Baker, Matt;Mackenzie, Ian R.;Hutton, Mike
通讯作者：
Hutton, Mike
影响因子：
4
作者：
Bianchin, MM;Capella, HM;Sakamoto, AC
通讯作者：
Sakamoto, AC