Using Exome Sequencing to Reveal Mutations in TREM2 Presenting as a Frontotemporal Dementia-like Syndrome Without Bone Involvement

被引：270

作者：

Guerreiro, Rita Joao ^{[1
,2
,3
,4
]}

Lohmann, Ebba ^{[6
]}

Bras, Jose Miguel ^{[1
,2
,3
,4
]}

Gibbs, Jesse Raphael ^{[1
,3
,4
]}

Rohrer, Jonathan D. ^{[5
]}

Gurunlian, Nicole ^{[3
,4
]}

Dursun, Burcu ^{[7
]}

Bilgic, Basar ^{[6
]}

Hanagasi, Hasmet ^{[6
]}

Gurvit, Hakan ^{[6
]}

Emre, Murat ^{[6
]}

Singleton, Andrew ^{[1
]}

Hardy, John ^{[3
,4
]}

机构：

[1] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA

[2] Univ Coimbra, Ctr Neurosci & Cell Biol, Coimbra, Portugal

[3] Inst Neurol, Reta Lilla Weston Labs, London WC1N 3BG, England

[4] Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England

[5] UCL, UCL Inst Neurol, Dementia Res Ctr, Dept Neurodegenerat Dis, London, England

[6] Istanbul Univ, Behav Neurol & Movement Disorders Unit, Istanbul Fac Med, Dept Neurol, Istanbul, Turkey

[7] Istanbul Univ, Inst Expt Med, Istanbul, Turkey

来源：

JAMA NEUROLOGY | 2013年 / 70卷 / 01期

基金：

美国国家卫生研究院;

关键词：

NASU-HAKOLA-DISEASE; HEXANUCLEOTIDE REPEAT; COMPLEX; C9ORF72; VPS35; TAU;

D O I：

10.1001/jamaneurol.2013.579

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Objective: 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. Design: 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. Setting: Database of the Behavioral Neurology Outpatient-Clinic of the Department of Neurology, Istanbul Faculty of Medicine, Istanbul, Turkey. Patients: Forty-four Turkish patients with an FTD-like clinical diagnosis were included in the study. Relatives were screened when appropriate. Main Outcome Measure: Mutations in the triggering receptor expressed on myeloid cells 2 gene (TREM2). Results: 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. Conclusions: 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. JAMA Neurol. 2013;70(1):78-84. Published online October 8, 2012. doi:10.1001/jamaneurol.2013.579

引用

页码：78 / 84

页数：7

共 25 条

[21] Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia [J].

Rascovsky, Katya ;

Hodges, John R. ;

Knopman, David ;

Mendez, Mario F. ;

Kramer, Joel H. ;

Neuhaus, John ;

van Swieten, John C. ;

Seelaar, Harro ;

Dopper, Elise G. P. ;

Onyike, Chiadi U. ;

Hillis, Argye E. ;

Josephs, Keith A. ;

Boeve, Bradley F. ;

Kertesz, Andrew ;

Seeley, William W. ;

Rankin, Katherine P. ;

Johnson, Julene K. ;

Gorno-Tempini, Maria-Luisa ;

Rosen, Howard ;

Prioleau-Latham, Caroline E. ;

Lee, Albert ;

Kipps, Christopher M. ;

Lillo, Patricia ;

Piguet, Olivier ;

Rohrer, Jonathan D. ;

Rossor, Martin N. ;

Warren, Jason D. ;

Fox, Nick C. ;

Galasko, Douglas ;

Salmon, David P. ;

Black, Sandra E. ;

Mesulam, Marsel ;

Weintraub, Sandra ;

Dickerson, Brad C. ;

Diehl-Schmid, Janine ;

Pasquier, Florence ;

Deramecourt, Vincent ;

Lebert, Florence ;

Pijnenburg, Yolande ;

Chow, Tiffany W. ;

Manes, Facundo ;

Grafman, Jordan ;

Cappa, Stefano F. ;

Freedman, Morris ;

Grossman, Murray ;

Miller, Bruce L. .

BRAIN, 2011, 134 :2456-2477

[22] A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD [J].

Renton, Alan E. ;

Majounie, Elisa ;

Waite, Adrian ;

Simon-Sanchez, Javier ;

Rollinson, Sara ;

Gibbs, J. Raphael ;

Schymick, Jennifer C. ;

Laaksovirta, Hannu ;

van Swieten, John C. ;

Myllykangas, Liisa ;

Kalimo, Hannu ;

Paetau, Anders ;

Abramzon, Yevgeniya ;

Remes, Anne M. ;

Kaganovich, Alice ;

Scholz, Sonja W. ;

Duckworth, Jamie ;

Ding, Jinhui ;

Harmer, Daniel W. ;

Hernandez, Dena G. ;

Johnson, Janel O. ;

Mok, Kin ;

Ryten, Mina ;

Trabzuni, Danyah ;

Guerreiro, Rita J. ;

Orrell, Richard W. ;

Neal, James ;

Murray, Alex ;

Pearson, Justin ;

Jansen, Iris E. ;

Sondervan, David ;

Seelaar, Harro ;

Blake, Derek ;

Young, Kate ;

Halliwell, Nicola ;

Callister, Janis Bennion ;

Toulson, Greg ;

Richardson, Anna ;

Gerhard, Alex ;

Snowden, Julie ;

Mann, David ;

Neary, David ;

Nalls, Michael A. ;

Peuralinna, Terhi ;

Jansson, Lilja ;

Isoviita, Veli-Matti ;

Kaivorinne, Anna-Lotta ;

Holtta-Vuori, Maarit ;

Ikonen, Elina ;

Sulkava, Raimo .

NEURON, 2011, 72 (02) :257-268

[23] Integrative genomics viewer [J].

Robinson, James T. ;

Thorvaldsdottir, Helga ;

Winckler, Wendy ;

Guttman, Mitchell ;

Lander, Eric S. ;

Getz, Gad ;

Mesirov, Jill P. .

NATURE BIOTECHNOLOGY, 2011, 29 (01) :24-26

[24] VPS35 Mutations in Parkinson Disease [J].

Vilarino-Gueell, Carles ;

Wider, Christian ;

Ross, Owen A. ;

Dachsel, Justus C. ;

Kachergus, Jennifer M. ;

Lincoln, Sarah J. ;

Soto-Ortolaza, Alexandra I. ;

Cobb, Stephanie A. ;

Wilhoite, Greggory J. ;

Bacon, Justin A. ;

Behrouz, Bahareh ;

Melrose, Heather L. ;

Hentati, Emna ;

Puschmann, Andreas ;

Evans, Daniel M. ;

Conibear, Elizabeth ;

Wasserman, Wyeth W. ;

Aasly, Jan O. ;

Burkhard, Pierre R. ;

Djaldetti, Ruth ;

Ghika, Joseph ;

Hentati, Faycal ;

Krygowska-Wajs, Anna ;

Lynch, Tim ;

Melamed, Eldad ;

Rajput, Alex ;

Rajput, Ali H. ;

Solida, Alessandra ;

Wu, Ruey-Meei ;

Uitti, Ryan J. ;

Wszolek, Zbigniew K. ;

Vingerhoets, Francois ;

Farrer, Matthew J. .

AMERICAN JOURNAL OF HUMAN GENETICS, 2011, 89 (01) :162-167

[25] A Mutation in VPS35, Encoding a Subunit of the Retromer Complex, Causes Late-Onset Parkinson Disease [J].

Zimprich, Alexander ;

Benet-Pages, Anna ;

Struhal, Walter ;

Graf, Elisabeth ;

Eck, Sebastian H. ;

Offman, Marc N. ;

Haubenberger, Dietrich ;

Spielberger, Sabine ;

Schulte, Eva C. ;

Lichtner, Peter ;

Rossle, Shaila C. ;

Klopp, Norman ;

Wolf, Elisabeth ;

Seppi, Klaus ;

Pirker, Walter ;

Presslauer, Stefan ;

Mollenhauer, Brit ;

Katzenschlager, Regina ;

Foki, Thomas ;

Hotzy, Christoph ;

Reinthaler, Eva ;

Harutyunyan, Ashot ;

Kralovics, Robert ;

Peters, Annette ;

Zimprich, Fritz ;

Bruecke, Thomas ;

Poewe, Werner ;

Auff, Eduard ;

Trenkwalder, Claudia ;

Rost, Burkhard ;

Ransmayr, Gerhard ;

Winkelmann, Juliane ;

Meitinger, Thomas ;

Strom, Tim M. .

AMERICAN JOURNAL OF HUMAN GENETICS, 2011, 89 (01) :168-175

← 1 2 3 →