Copy Number Variation Plays an Important Role in Clinical Epilepsy

被引：132

作者：

Olson, Heather ^{[1
,2
,3
]}

Shen, Yiping ^{[4
,5
,6
]}

Avallone, Jennifer ^{[3
,7
]}

Sheidley, Beth R. ^{[1
,2
,3
]}

Pinsky, Rebecca ^{[1
,2
,3
]}

Bergin, Ann M. ^{[3
,7
]}

Berry, Gerard T. ^{[3
,8
]}

Duffy, Frank H. ^{[3
,7
]}

Eksioglu, Yaman ^{[3
,7
]}

Harris, David J. ^{[3
,8
]}

Hisama, Fuki M. ^{[3
,8
,9
]}

Ho, Eugenia ^{[3
,10
,11
]}

Irons, Mira ^{[3
,8
]}

Jacobsen, Christina M. ^{[3
,8
,12
]}

James, Philip ^{[3
,8
]}

Kothare, Sanjeev ^{[3
,13
]}

Khwaja, Omar ^{[3
,10
]}

Lipton, Jonathan ^{[3
,10
]}

Loddenkemper, Tobias ^{[3
,7
]}

Markowitz, Jennifer ^{[3
,10
]}

Maski, Kiran ^{[3
,10
]}

Megerian, J. Thomas ^{[3
,10
]}

Neilan, Edward ^{[3
,8
]}

Raffalli, Peter C. ^{[3
,10
]}

Robbins, Michael ^{[3
,10
]}

Roberts, Amy ^{[3
,8
,14
]}

Roe, Eugene ^{[3
,10
]}

Rollins, Caitlin ^{[3
,10
]}

Sahin, Mustafa ^{[3
,10
]}

Sarco, Dean ^{[3
,7
]}

Schonwald, Alison ^{[15
,16
]}

Smith, Sharon E. ^{[3
,8
]}

Soul, Janet ^{[3
,10
]}

Stoler, Joan M. ^{[3
,8
]}

Takeoka, Masanori ^{[3
,7
]}

Tan, Wen-Han ^{[3
,8
]}

Torres, Alcy R. ^{[3
,10
,15
,16
]}

Tsai, Peter ^{[3
,10
]}

Urion, David K. ^{[3
,10
]}

Weissman, Laura ^{[3
,17
]}

Wolff, Robert ^{[3
,10
]}

Wu, Bai-Lin ^{[4
,5
,6
]}

Miller, David T. ^{[3
,6
,8
]}

Poduri, Annapurna ^{[1
,2
,3
]}

机构：

[1] Boston Childrens Hosp, Dept Neurol, Epilepsy Genet Program, Div Epilepsy & Clin Neurophysiol, Boston, MA 02115 USA

[2] Boston Childrens Hosp, Dept Neurol, Neurogenet Program, Boston, MA 02115 USA

[3] Harvard Univ, Sch Med, Boston, MA USA

[4] Boston Childrens Hosp, Dept Lab Med, Boston, MA 02115 USA

[5] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA

[6] Claritas Genom Inc, Cambridge, MA USA

[7] Boston Childrens Hosp, Div Epilepsy & Clin Neurophysiol, Dept Neurol, Boston, MA 02115 USA

[8] Boston Childrens Hosp, Div Genet & Genom, Boston, MA 02115 USA

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

[10] Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA

[11] Univ So Calif, Keck Sch Med, Childrens Hosp Los Angeles, Dept Neurol, Los Angeles, CA 90033 USA

[12] Boston Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA

[13] NYU, Dept Neurol, New York, NY 10016 USA

[14] Boston Childrens Hosp, Dept Cardiol, Boston, MA 02115 USA

[15] Boston Univ, Boston Med Ctr, Dept Pediat, Boston, MA 02215 USA

[16] Boston Univ, Boston Med Ctr, Dept Neurol, Boston, MA 02215 USA

[17] Boston Childrens Hosp, Div Dev Med, Boston, MA 02115 USA

来源：

ANNALS OF NEUROLOGY | 2014年 / 75卷 / 06期

关键词：

IDIOPATHIC GENERALIZED EPILEPSY; CONTIGUOUS-GENE-SYNDROME; COMPARATIVE-GENOMIC-HYBRIDIZATION; FAMILIAL NEONATAL SEIZURES; AUTISM SPECTRUM DISORDERS; SEVERE MYOCLONIC EPILEPSY; INTELLECTUAL DISABILITY; CHROMOSOMAL MICROARRAY; 15Q13.3; MICRODELETIONS; MOLECULAR CHARACTERIZATION;

D O I：

10.1002/ana.24178

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Objective: To evaluate the role of copy number abnormalities detectable using chromosomal microarray (CMA) testing in patients with epilepsy at a tertiary care center. Methods: We identified patients with International Classification of Diseases, ninth revision (ICD-9) codes for epilepsy or seizures and clinical CMA testing performed between October 2006 and February 2011 at Boston Children's Hospital. We reviewed medical records and included patients who met criteria for epilepsy. We phenotypically characterized patients with epilepsy-associated abnormalities on CMA. Results: Of 973 patients who had CMA and ICD-9 codes for epilepsy or seizures, 805 patients satisfied criteria for epilepsy. We observed 437 copy number variants (CNVs) in 323 patients (1-4 per patient), including 185 (42%) deletions and 252 (58%) duplications. Forty (9%) were confirmed de novo, 186 (43%) were inherited, and parental data were unavailable for 211 (48%). Excluding full chromosome trisomies, CNV size ranged from 18kb to 142Mb, and 34% were >500kb. In at least 40 cases (5%), the epilepsy phenotype was explained by a CNV, including 29 patients with epilepsy-associated syndromes and 11 with likely disease-associated CNVs involving epilepsy genes or "hotspots." We observed numerous recurrent CNVs including 10 involving loss or gain of Xp22.31, a region described in patients with and without epilepsy. Interpretation: Copy number abnormalities play an important role in patients with epilepsy. Because the diagnostic yield of CMA for epilepsy patients is similar to the yield in autism spectrum disorders and in prenatal diagnosis, for which published guidelines recommend testing with CMA, we recommend the implementation of CMA in the evaluation of unexplained epilepsy.

引用

页码：943 / 958

页数：16

共 57 条

[1] MOLECULAR CHARACTERIZATION OF HUMAN X/Y TRANSLOCATIONS SUGGESTS THEIR ETIOLOGY THROUGH ABERRANT EXCHANGE BETWEEN HOMOLOGOUS SEQUENCES ON XP AND YQ [J].

BALLABIO, A ;

CARROZZO, R ;

GIL, A ;

GILLARD, B ;

AFFARA, N ;

FERGUSONSMITH, MA ;

FRASER, N ;

CRAIG, I ;

ROCCHI, M ;

ROMEO, G ;

ANDRIA, G .

ANNALS OF HUMAN GENETICS, 1989, 53 :9-14

[2] Application of array comparative genomic hybridization in 102 patients with epilepsy and additional neurodevelopmental disorders [J].

Bartnik, Magdalena ;

Szczepanik, Elzbieta ;

Derwinska, Katarzyna ;

Wisniowiecka-Kowalnik, Barbara ;

Gambin, Tomasz ;

Sykulski, Maciej ;

Ziemkiewicz, Kamila ;

Kedzior, Marta ;

Gos, Monika ;

Hoffman-Zacharska, Dorota ;

Mazurczak, Tomasz ;

Jeziorek, Anetta ;

Antczak-Marach, Dorota ;

Rudzka-Dybala, Mariola ;

Mazurkiewicz, Hanna ;

Goszczanska-Ciuchta, Alicja ;

Zalewska-Miszkurka, Zofia ;

Terczynska, Iwona ;

Sobierajewicz, Malgorzata ;

Shaw, Chad A. ;

Gambin, Anna ;

Mierzewska, Hanna ;

Mazurczak, Tadeusz ;

Obersztyn, Ewa ;

Bocian, Ewa ;

Stankiewicz, Pawel .

AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS, 2012, 159B (07) :760-771

[3] An Emerging 1q21.1 Deletion-Associated Neurodevelopmental Phenotype [J].

Basel-Vanagaite, Lina ;

Goldberg-Stern, Hadassa ;

Mimouni-Bloch, Aviva ;

Shkalim, Vered ;

Boehm, Detlef ;

Kohlhase, Juergen .

JOURNAL OF CHILD NEUROLOGY, 2011, 26 (01) :113-116

[4] Confirmation of chromosomal microarray as a firsttier clinical diagnostic test for individuals with developmental delay, intellectual disability, autism spectrum disorders and dysmorphic features. [J].

Battaglia, Agatino ;

Doccini, Viola ;

Bernardini, Laura ;

Novelli, Antonio ;

Loddo, Sara ;

Capalbo, Anna ;

Filippi, Tiziana ;

Carey, John C. .

EUROPEAN JOURNAL OF PAEDIATRIC NEUROLOGY, 2013, 17 (06) :589-599

[5] PRRT2-related disorders: further PKD and ICCA cases and review of the literature [J].

Becker, Felicitas ;

Schubert, Julian ;

Striano, Pasquale ;

Anttonen, Anna-Kaisa ;

Liukkonen, Elina ;

Gaily, Eija ;

Gerloff, Christian ;

Mueller, Stephan ;

Heussinger, Nicole ;

Kellinghaus, Christoph ;

Robbiano, Angela ;

Polvi, Anne ;

Zittel, Simone ;

von Oertzen, Tim J. ;

Rostasy, Kevin ;

Schoels, Ludger ;

Warner, Tom ;

Muenchau, Alexander ;

Lehesjoki, Anna-Elina ;

Zara, Federico ;

Lerche, Holger ;

Weber, Yvonne G. .

JOURNAL OF NEUROLOGY, 2013, 260 (05) :1234-1244

[6] Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities [J].

Brunetti-Pierri, Nicola ;

Berg, Jonathan S. ;

Scaglia, Fernando ;

Belmont, John ;

Bacino, Carlos A. ;

Sahoo, Trilochan ;

Lalani, Seema R. ;

Graham, Brett ;

Lee, Brendan ;

Shinawi, Marwan ;

Shen, Joseph ;

Kang, Sung-Hae L. ;

Pursley, Amber ;

Lotze, Timothy ;

Kennedy, Gail ;

Lansky-Shafer, Susan ;

Weaver, Christine ;

Roeder, Elizabeth R. ;

Grebe, Theresa A. ;

Arnold, Georgianne L. ;

Hutchison, Terry ;

Reimschisel, Tyler ;

Amato, Stephen ;

Geragthy, Michael T. ;

Innis, Jeffrey W. ;

Obersztyn, Ewa ;

Nowakowska, Beata ;

Rosengren, Sally S. ;

Bader, Patricia I. ;

Grange, Dorothy K. ;

Naqvi, Sayed ;

Garnica, Adolfo D. ;

Bernes, Saunder M. ;

Fong, Chin-To ;

Summers, Anne ;

Walters, W. David ;

Lupski, James R. ;

Stankiewicz, Pawel ;

Cheung, Sau Wai ;

Patel, Ankita .

NATURE GENETICS, 2008, 40 (12) :1466-1471

[7] Deletions of NRXN1 (Neurexin-1) Predispose to a Wide Spectrum of Developmental Disorders [J].

Ching, Michael S. L. ;

Shen, Yiping ;

Tan, Wen-Hann ;

Jeste, Shafali S. ;

Morrow, Eric M. ;

Chen, Xiaoli ;

Mukaddes, Nahit M. ;

Yoo, Seung-Yun ;

Hanson, Ellen ;

Hundley, Rachel ;

Austin, Christina ;

Becker, Ronald E. ;

Berry, Gerard T. ;

Driscoll, Katherine ;

Engle, Elizabeth C. ;

Friedman, Sandra ;

Gusella, James F. ;

Hisama, Fuki M. ;

Irons, Mira B. ;

Lafiosca, Tina ;

LeClair, Elaine ;

Miller, David T. ;

Neessen, Michael ;

Picker, Jonathan D. ;

Rappaport, Leonard ;

Rooney, Cynthia M. ;

Sarco, Dean P. ;

Stoler, Joan M. ;

Walsh, Christopher A. ;

Wolff, Robert R. ;

Zhang, Ting ;

Nasir, Ramzi H. ;

Wu, Bai-Lin .

AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS, 2010, 153B (04) :937-947

[8] Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy [J].

Cossette, P ;

Liu, LD ;

Brisebois, K ;

Dong, HH ;

Lortie, A ;

Vanasse, M ;

Saint-Hilaire, JM ;

Carmant, L ;

Verner, A ;

Lu, WY ;

Wang, YT ;

Rouleau, GA .

NATURE GENETICS, 2002, 31 (02) :184-189

[9] Investigation of NRXN1 deletions: Clinical and molecular characterization [J].

Dabell, Mindy Preston ;

Rosenfeld, Jill A. ;

Bader, Patricia ;

Escobar, Luis F. ;

El-Khechen, Dima ;

Vallee, Stephanie E. ;

Dinulos, Mary Beth Palko ;

Curry, Cynthia ;

Fisher, Jamie ;

Tervo, Raymond ;

Hannibal, Mark C. ;

Siefkas, Kiana ;

Wyatt, Philip R. ;

Hughes, Lauren ;

Smith, Rosemarie ;

Ellingwood, Sara ;

Lacassie, Yves ;

Stroud, Tracy ;

Farrell, Sandra A. ;

Sanchez-Lara, Pedro A. ;

Randolph, Linda M. ;

Niyazov, Dmitriy ;

Stevens, Cathy A. ;

Schoonveld, Cheri ;

Skidmore, David ;

MacKay, Sara ;

Miles, Judith H. ;

Moodley, Manikum ;

Huillet, Adam ;

Neill, Nicholas J. ;

Ellison, Jay W. ;

Ballif, Blake C. ;

Shaffer, Lisa G. .

AMERICAN JOURNAL OF MEDICAL GENETICS PART A, 2013, 161A (04) :717-731

[10] Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies [J].

de Kovel, Carolien G. F. ;

Trucks, Holger ;

Helbig, Ingo ;

Mefford, Heather C. ;

Baker, Carl ;

Leu, Costin ;

Kluck, Christian ;

Muhle, Hiltrud ;

von Spiczak, Sarah ;

Ostertag, Philipp ;

Obermeier, Tanja ;

Kleefuss-Lie, Ailing A. ;

Hallmann, Kerstin ;

Steffens, Michael ;

Gaus, Verena ;

Klein, Karl M. ;

Hamer, Hajo M. ;

Rosenow, Felix ;

Brilstra, Eva H. ;

Trenite, Dorothee Kasteleijn-Nolst ;

Swinkels, Marielle E. M. ;

Weber, Yvonne G. ;

Unterberger, Iris ;

Zimprich, Fritz ;

Urak, Lydia ;

Feucht, Martha ;

Fuchs, Karoline ;

Moller, Rikke S. ;

Hjalgrim, Helle ;

De Jonghe, Peter ;

Suls, Arvid ;

Rueckert, Ina-Maria ;

Wichmann, Heinz-Erich ;

Franke, Andre ;

Schreiber, Stefan ;

Nuernberg, Peter ;

Elger, Christian E. ;

Lerche, Holger ;

Stephani, Ulrich ;

Koeleman, Bobby P. C. ;

Lindhout, Dick ;

Eichler, Evan E. ;

Sander, Thomas .

BRAIN, 2010, 133 :23-32

← 1 2 3 4 5 6 →