Diagnostic implications of genetic copy number variation in epilepsy plus

被引：69

作者：

Coppola, Antonietta ^{[1
,2
,3
]}

Cellini, Elena ^{[4
]}

Stamberger, Hannah ^{[5
,6
,7
]}

Saarentaus, Elmo ^{[8
,9
,10
]}

Cetica, Valentina ^{[4
]}

Lal, Dennis ^{[8
,9
,11
,12
,13
]}

Djemie, Tania ^{[5
,6
]}

Bartnik-Glaska, Magdalena ^{[14
]}

Ceulemans, Berten ^{[15
]}

Cross, J. Helen ^{[16
,17
,18
]}

Deconinck, Tine ^{[5
,6
]}

De Masi, Salvatore ^{[19
]}

Dorn, Thomas ^{[20
]}

Guerrini, Renzo ^{[4
]}

Hoffman-Zacharska, Dorotha ^{[14
]}

Kooy, Frank ^{[21
]}

Lagae, Lieven ^{[22
]}

Lench, Nicholas ^{[23
]}

Lemke, Johannes R. ^{[24
]}

Lucenteforte, Ersilia ^{[25
,26
]}

Madia, Francesca ^{[27
]}

Mefford, Heather C. ^{[28
]}

Morrogh, Deborah ^{[23
]}

Nuernberg, Peter ^{[13
]}

Palotie, Aarno ^{[8
,9
,10
]}

Schoonjans, An-Sofie ^{[15
]}

Striano, Pasquale ^{[29
]}

Szczepanik, Elzbieta ^{[30
]}

Tostevin, Anna ^{[1
,2
]}

Vermeesch, Joris R. ^{[31
]}

Van Esch, Hilde ^{[31
]}

Van Paesschen, Wim ^{[32
]}

Waters, Jonathan J. ^{[23
]}

Weckhuysen, Sarah ^{[5
,6
,7
]}

Zara, Federico ^{[27
]}

Jonghe, Peter De ^{[5
,6
,7
]}

Sisodiya, Sanjay M. ^{[1
,2
]}

Marini, Carla ^{[4
]}

Lehesjioki, Anna-Elina ^{[33
,34
]}

Craiu, Dana ^{[35
,36
,38
]}

Talvik, Tiina ^{[37
]}

Caglayan, Hande ^{[39
]}

Serratosa, Jose ^{[40
,41
]}

Sterbova, Katalin ^{[42
]}

Moller, Rikke S. ^{[43
,44
]}

Hjalgrim, Helle ^{[45
,46
]}

Lerche, Holger ^{[47
]}

Weber, Yvonne ^{[48
]}

Helbig, Ingo ^{[49
,50
]}

von Spiczak, Sarah ^{[51
]}

机构：

[1] UCL, Dept Clin & Expt Epilepsy, Inst Neurol, Queen Sq, London WC1N 3BG, England

[2] Chalfont Ctr Epilepsy, Chesham Lane, Gerrards Cross, Bucks, England

[3] Univ Naples Federico II, Dept Neurosci Reprod & Odontostomatol Sci, Epilepsy Ctr, Naples, Italy

[4] Univ Florence, Meyer Childrens Hosp, Neurosci Dept, Pediatr Neurol,Neurogenet & Neurobiol Unit & Labs, Florence, Italy

[5] VIB, Neurogenet Grp, Ctr Mol Neurol, B-2650 Antwerp, Belgium

[6] Univ Antwerp, Inst Born Bunge, Lab Neurogenet, Antwerp, Belgium

[7] Antwerp Univ Hosp, Dept Neurol, Antwerp, Belgium

[8] Harvard Med Sch, Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02115 USA

[9] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA

[10] Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland

[11] Cleveland Clin, Neurol Inst, Epilepsy Ctr, Cleveland, OH 44195 USA

[12] Lerner Res Inst Cleveland Clin, Genom Med Inst, Cleveland, OH 44195 USA

[13] Univ Cologne, Cologne Ctr Gen, Cologne, Germany

[14] Inst Mother & Child Hlth, Dept Med Genet, Warsaw, Poland

[15] Univ & Univ Hosp Antwerp, Dept Neurol Pediat Neurol, Antwerp, Belgium

[16] NHS Fdn Trust, Great Ormond St Hosp, Neurol Dept, London, England

[17] UCL, Clin Neurosci, London, England

[18] Young Epilepsy, Lingfield, England

[19] Meyer Childrens Hosp, Clin Trial Off, Florence, Italy

[20] Swiss Epilepsy Ctr, Bleulerstr 60, CH-8008 Zurich, Switzerland

[21] Univ Antwerp, Dept Med Genet, Antwerp, Belgium

[22] Katholieke Univ Leuven, Univ Hosp, Sect Pediat Neurol, Dept Dev & Regenerat, B-3000 Leuven, Belgium

[23] Great Ormond St Hosp Sick Children, NHS Fdn Trust, North East Thames Reg Genet Serv, London, England

[24] Univ Leipzig Hosp & Clin, Inst Human Genet, Leipzig, Germany

[25] Univ Pisa, Dept Clin & Expt Med, Pisa, Italy

[26] Meyer Childrens Hosp, Clin Trial Off, Florence, Italy

[27] Hospitalisat & Hlth Care IRCCS G Gaslini Inst, Sci Inst Res, Neurogenet Lab, Genoa, Italy

[28] Univ Washington, Div Med Genet, Dept Pediat, Seattle, WA 98195 USA

[29] Univ Genoa G Gaslini Inst, Dept Neurosci Rehabil Ophthalmol Genet Maternal &, DINOGMI, Pediat Neurol & Muscular Dis Unit, Genoa, Italy

[30] Inst Mother & Child Hlth, Clin Neurol Children & Adolescents, Warsaw, Poland

[31] Univ Hosp Leuven, Ctr Human Genet, Herestr 49, B-3000 Leuven, Belgium

[32] Univ Hosp Leuven, Dept Neurol, Herestr 49, B-3000 Leuven, Belgium

[33] Univ Helsinki, Folkhalsan Inst, Genet Neurosci Ctr, Helsinki, Finland

[34] Univ Helsinki, Res Programs Unit Mol Neurol, Helsinki, Finland

[35] Carol Davila Univ Med Bucharest, Bucharest, Romania

[36] Alexandru Obregia Hosp, Pediat Neurol Clin, Dept Clin Neurosci 6, Bucharest, Romania

[37] Tartu Univ Hosp, Childrens Clin, Tartu, Estonia

[38] Univ Tartu, Dept Pediat, Tartu, Estonia

[39] Bogazici Univ, Dept Mol Biol & Genet, Istanbul, Turkey

[40] Autonomous Univ Madrid, Jimenez Diaz Fdn, Dept Neurol, Healthcare Investigat Inst, Madrid, Spain

[41] Jimenez Diaz Fdn, Healthcare Investigat Inst, Madrid, Spain

[42] Charles Univ Prague, Motol Hosp, Dept Child Neurol, Fac Med 2, Prague, Czech Republic

[43] Danish Epilepsy Ctr, Dianalund, Denmark

[44] Univ Southern Denmark, Inst Reg Hlth Serv, Odense, Denmark

[45] Danish Epilepsy Ctr, Dianalund, Denmark

[46] Danish Epilepsy Ctr, Dianalund, Denmark

[47] Univ Tubingen, Hertie Inst Clin Brain Res, Dept Neurol & Epileptol, Tubingen, Germany

[48] Univ Tubingen, Hertie Inst Clin Brain Res, Dept Neurol & Epileptol, Tubingen, Germany

[49] Childrens Hosp Philadelphia, Div Neurol, Philadelphia, PA 19104 USA

[50] Univ Med Ctr Schleswig Holstein, Dept Neuropediat, Kiel, Germany

来源：

EPILEPSIA | 2019年 / 60卷 / 04期

基金：

瑞士国家科学基金会; 英国惠康基金;

关键词：

array CGH; copy number variants; epilepsy genes; SNP array; DE-NOVO MUTATIONS; MOLECULAR CHARACTERIZATION; CHROMOSOMAL MICROARRAY; ILAE COMMISSION; ONSET EPILEPSY; RORB GENE; PATIENT; ENCEPHALOPATHY; DISABILITIES; PHENOTYPE;

D O I：

10.1111/epi.14683

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

100204 [神经病学];

摘要：

Objective Copy number variations (CNVs) represent a significant genetic risk for several neurodevelopmental disorders including epilepsy. As knowledge increases, reanalysis of existing data is essential. Reliable estimates of the contribution of CNVs to epilepsies from sizeable populations are not available. Methods We assembled a cohort of 1255 patients with preexisting array comparative genomic hybridization or single nucleotide polymorphism array based CNV data. All patients had "epilepsy plus," defined as epilepsy with comorbid features, including intellectual disability, psychiatric symptoms, and other neurological and nonneurological features. CNV classification was conducted using a systematic filtering workflow adapted to epilepsy. Results Of 1097 patients remaining after genetic data quality control, 120 individuals (10.9%) carried at least one autosomal CNV classified as pathogenic; 19 individuals (1.7%) carried at least one autosomal CNV classified as possibly pathogenic. Eleven patients (1%) carried more than one (possibly) pathogenic CNV. We identified CNVs covering recently reported (HNRNPU) or emerging (RORB) epilepsy genes, and further delineated the phenotype associated with mutations of these genes. Additional novel epilepsy candidate genes emerge from our study. Comparing phenotypic features of pathogenic CNV carriers to those of noncarriers of pathogenic CNVs, we show that patients with nonneurological comorbidities, especially dysmorphism, were more likely to carry pathogenic CNVs (odds ratio = 4.09, confidence interval = 2.51-6.68; P = 2.34 x 10(-9)). Meta-analysis including data from published control groups showed that the presence or absence of epilepsy did not affect the detected frequency of CNVs. Significance The use of a specifically adapted workflow enabled identification of pathogenic autosomal CNVs in 10.9% of patients with epilepsy plus, which rose to 12.7% when we also considered possibly pathogenic CNVs. Our data indicate that epilepsy with comorbid features should be considered an indication for patients to be selected for a diagnostic algorithm including CNV detection. Collaborative large-scale CNV reanalysis leads to novel declaration of pathogenicity in unexplained cases and can promote discovery of promising candidate epilepsy genes.

引用

页码：689 / 706

页数：18

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