Somatic variants in autosomal dominant genes are a rare cause of sporadic Alzheimer's disease

被引：47

作者：

Nicolas, Gael ^{[1
,2
,3
,4
]}

Acuna-Hidalgo, Rocio ^{[1
,4
,5
]}

Keogh, Michael J. ^{[6
,7
]}

Quenez, Olivier ^{[2
,3
]}

Steehouwer, Marloes ^{[1
]}

Lelieveld, Stefan ^{[1
]}

Rousseau, Stephane ^{[2
,3
]}

Richard, Anne-Claire ^{[2
,3
]}

Oud, Manon S. ^{[1
]}

Marguet, Florent ^{[2
,8
]}

Laquerriere, Annie ^{[2
,8
]}

Morris, Chris M. ^{[9
]}

Attems, Johannes ^{[9
]}

Smith, Colin ^{[10
]}

Ansorge, Olaf ^{[11
]}

Al Sarraj, Safa ^{[12
]}

Frebourg, Thierry ^{[2
,3
]}

Campion, Dominique ^{[2
,3
,13
]}

Hannequin, Didier ^{[2
,4
,14
]}

Wallon, David ^{[2
,4
,15
]}

Gilissen, Christian ^{[1
]}

Chinnery, Patrick F. ^{[6
,7
]}

Veltman, Joris A. ^{[1
,16
]}

Hoischen, Alexander ^{[1
,17
,18
]}

机构：

[1] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, Nijmegen, Netherlands

[2] Normandie Univ, UNIROUEN, INSERM, U1245, F-76000 Rouen, France

[3] Rouen Univ Hosp, Dept Genet, F-76000 Rouen, France

[4] CNR, MAJ, Normandy Ctr Genom & Personalized Med, F-76000 Rouen, France

[5] Max Planck Inst Mol Genet, RG Dev & Dis, Berlin, Germany

[6] Univ Cambridge, Dept Clin Neurosci, Cambridge Biomed Campus, Cambridge CB2 0QQ, England

[7] Univ Cambridge, MRC Mitochondrial Biol Unit, Cambridge CB2 0XY, England

[8] Rouen Univ Hosp, Dept Neuropathol, Normandy Ctr Genom & Personalized Med, F-76000 Rouen, France

[9] Newcastle Univ, Inst Neurosci, Newcastle Upon Tyne NE4 5PL, Tyne & Wear, England

[10] Univ Edinburgh, Western Gen Hosp, Natl CJD Res Surveillance Unit, Ctr Clin Brain Sci, Edinburgh EH4 2XU, Midlothian, Scotland

[11] John Radcliffe Hosp, Dept Neuropathol, Oxford OX3 9DU, England

[12] Kings Coll London, Inst Psychiat Psychol & Neurosci, Dept Basic & Clin Neurosci, London SE5 8AF, England

[13] Rouvray Psychiat Hosp, Dept Res, Sotteville Les Rouen, France

[14] Rouen Univ Hosp, Dept Genet, Dept Neurol, F-76000 Rouen, France

[15] Rouen Univ Hosp, Dept Neurol, F-76000 Rouen, France

[16] Newcastle Univ, Inst Genet Med, Int Ctr Life, Newcastle Upon Tyne, Tyne & Wear, England

[17] Radboud Univ Nijmegen, Med Ctr, Dept Internal Med, Nijmegen, Netherlands

[18] Radboud Univ Nijmegen, Med Ctr, Radboud Ctr Infect Dis RCI, Nijmegen, Netherlands

来源：

ALZHEIMERS & DEMENTIA | 2018年 / 14卷 / 12期

基金：

英国医学研究理事会;

关键词：

Mosaicism; Post-zygotic; Mutation; Alzheimer; Prion-like; MUTATIONS; FREQUENCY; PRESENILIN-1; ASSOCIATION; GUIDELINES; BRAINS;

D O I：

10.1016/j.jalz.2018.06.3056

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Introduction: A minority of patients with sporadic early-onset Alzheimer's disease (AD) exhibit de novo germ line mutations in the autosomal dominant genes such as APP, PSEN1, or PSEN2. We hypothesized that negatively screened patients may harbor somatic variants in these genes. Methods: We applied an ultrasensitive approach based on single-molecule molecular inversion probes followed by deep next generation sequencing of 11 genes to 100 brain and 355 blood samples from 445 sporadic patients with AD (>80% exhibited an early onset, <66 years). Results: We identified and confirmed nine somatic variants (allele fractions: 0.2%-10.8%): two APP, five SORL1, one NCSTN, and one MARK4 variants by independent amplicon-based deep sequencing. Discussion: Two of the SORL1 variant might have contributed to the disease, the two APP variants were interpreted as likely benign and the other variants remained of unknown significance. Somatic variants in the autosomal dominant AD genes may not be a common cause of sporadic AD, including early onset cases. (C) 2018 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer's Association.

引用

页码：1632 / 1639

页数：8

共 24 条

[1] Ultra-sensitive Sequencing Identifies High Prevalence of Clonal Hematopoiesis-Associated Mutations throughout Adult Life [J].

Acuna-Hidalgo, Rocio ;

Sengul, Hilal ;

Steehouwer, Marloes ;

van de Vorst, Maartje ;

Vermeulen, Sita H. ;

Kiemeney, Lambertus A. L. M. ;

Veltman, Joris A. ;

Gilissen, Christian ;

Hoischen, Alexander .

AMERICAN JOURNAL OF HUMAN GENETICS, 2017, 101 (01) :50-64

[2] New insights into the generation and role of de novo mutations in health and disease [J].

Acuna-Hidalgo, Rocio ;

Veltman, Joris A. ;

Hoischen, Alexander .

GENOME BIOLOGY, 2016, 17

[3] Somatic and germline mosaicism in sporadic early-onset Alzheimer's disease [J].

Beck, JA ;

Poulter, M ;

Campbell, TA ;

Uphill, JB ;

Adamson, G ;

Geddes, JF ;

Revesz, T ;

Davis, MB ;

Wood, NW ;

Collinge, J ;

Tabrizi, SJ .

HUMAN MOLECULAR GENETICS, 2004, 13 (12) :1219-1224

[4] Contribution to Alzheimer's disease risk of rare variants in TREM2, SORL1, and ABCA7 in 1779 cases and 1273 controls [J].

Bellenguez, Celine ;

Charbonnier, Camille ;

Grenier-Boley, Benjamin ;

Quenez, Olivier ;

Le Guennec, Kilan ;

Nicolas, Gael ;

Chauhan, Ganesh ;

Wallon, David ;

Rousseau, Stephane ;

Richard, Anne Claire ;

Boland, Anne ;

Bourque, Guillaume ;

Munter, Hans Markus ;

Olaso, Robert ;

Meyer, Vincent ;

Rollin-Sillaire, Adeline ;

Pasquier, Florence ;

Letenneur, Luc ;

Redon, Richard ;

Dartigues, Jean-Francois ;

Tzourio, Christophe ;

Frebourg, Thierry ;

Lathrop, Mark ;

Deleuze, Jean-Francois ;

Hannequin, Didier ;

Genin, Emmanuelle ;

Amouyel, Philippe ;

Debette, Stephanie ;

Lambert, Jean-Charles ;

Campion, Dominique .

NEUROBIOLOGY OF AGING, 2017, 59 :220.e1-220.e9

[5] Spreading of pathology in neurodegenerative diseases: a focus on human studies [J].

Brettschneider, Johannes ;

Del Tredici, Kelly ;

Lee, Virginia M. -Y ;

Trojanowski, John Q. .

NATURE REVIEWS NEUROSCIENCE, 2015, 16 (02) :109-120

[6] Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population based study of presenile Alzheimer disease [J].

Cruts, M ;

van Duijn, CM ;

Backhovens, H ;

Van den Broeck, M ;

Wehnert, A ;

Serneels, S ;

Sherrington, R ;

Hutton, M ;

Hardy, J ;

St George-Hyslop, PH ;

Hofman, A ;

Van Broeckhoven, C .

HUMAN MOLECULAR GENETICS, 1998, 7 (01) :43-51

[7] On the identification of low allele frequency mosaic mutations in the brains of Alzheimer's disease patients [J].

Frigerio, Carlo Sala ;

Lau, Pierre ;

Troakes, Claire ;

Deramecourt, Vincent ;

Gele, Patrick ;

Van Loo, Peter ;

Voet, Thierry ;

De Strooper, Bart .

ALZHEIMERS & DEMENTIA, 2015, 11 (11) :1265-1276

[8] Single molecule molecular inversion probes for targeted, high-accuracy detection of low-frequency variation [J].

Hiatt, Joseph B. ;

Pritchard, Colin C. ;

Salipante, Stephen J. ;

O'Roak, Brian J. ;

Shendure, Jay .

GENOME RESEARCH, 2013, 23 (05) :843-854

[9] Genetic compendium of 1511 human brains available through the UK Medical Research Council Brain Banks Network Resource [J].

Keogh, Michael J. ;

Wei, Wei ;

Wilson, Ian ;

Coxhead, Jon ;

Ryan, Sarah ;

Rollinson, Sara ;

Griffin, Helen ;

Kurzawa-Akanbi, Marzena ;

Santibariez-Koref, Mauro ;

Talbot, Kevin ;

Turner, Martin R. ;

McKenzie, Chris Anne ;

Troakes, Claire ;

Attems, Johannes ;

Smith, Colin ;

Al Sarraj, Safa ;

Morris, Chris M. ;

Ansorge, Olaf ;

Pickering-Brown, Stuart ;

Ironside, James W. ;

Chinnery, Patrick F. .

GENOME RESEARCH, 2017, 27 (01) :165-173

[10] APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases [J].

Lanoiselee, Helene-Marie ;

Nicolas, Gael ;

Wallon, David ;

Rovelet-Lecrux, Anne ;

Lacour, Morgane ;

Rousseau, Stephane ;

Richard, Anne -Claire ;

Pasquier, Florence ;

Rollin-Sillaire, Adeline ;

Martinaudl, Olivier ;

Quillard-Muraine, Muriel ;

de la Sayette, Vincent ;

Boutoleau-Bretonniere, Claire ;

Etcharry-Bouyx, Frederique ;

Chauvire, Valerie ;

Sarazin, Marie ;

le Berl, Isabelle ;

Epelbaum, Stephane ;

Jonveaux, Therese ;

Rouaud, Olivier ;

Ceccaldi, Mathieu ;

Felician, Olivier ;

Godefroy, Olivier ;

Formaglio, Maite ;

Croisile, Bernard ;

Auriacombe, Sophie ;

Chamard, Ludivine ;

Vincent, Jean-Louis ;

Sauvee, Mathilde ;

Marelli-Tosi, Cecilia ;

Gabelle, Audrey ;

Ozsancak, Canan ;

Pariente, Jeremie ;

Paquet, Claire ;

Hannequin, Didier ;

Campion, Dominique .

PLOS MEDICINE, 2017, 14 (03)

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