De novo mutations in epileptic encephalopathies

被引:1170
作者
Allen, Andrew S. [1 ,2 ]
Berkovic, Samuel F. [3 ]
Cossette, Patrick [4 ,5 ]
Delanty, Norman [6 ,7 ]
Dlugos, Dennis [8 ]
Eichler, Evan E. [9 ,10 ]
Epstein, Michael P. [11 ]
Glauser, Tracy [12 ]
Goldstein, David B. [13 ]
Han, Yujun [13 ]
Heinzen, Erin L. [13 ]
Hitomi, Yuki [13 ]
Howell, Katherine B. [14 ]
Johnson, Michael R. [15 ]
Kuzniecky, Ruben [16 ]
Lowenstein, Daniel H. [17 ]
Lu, Yi-Fan [13 ]
Madou, Maura R. Z. [17 ]
Marson, Anthony G. [18 ]
Mefford, Heather C. [19 ]
Nieh, Sahar Esmaeeli [20 ]
O'Brien, Terence J. [21 ,22 ]
Ottman, Ruth [23 ,24 ,25 ,26 ]
Petrovski, Slave [3 ,13 ,21 ,22 ]
Poduri, Annapurna [27 ]
Ruzzo, Elizabeth K. [13 ]
Scheffer, Ingrid E. [28 ,29 ,30 ]
Sherr, Elliott H. [31 ]
Yuskaitis, Christopher J. [32 ]
Abou-Khalil, Bassel [33 ]
Alldredge, Brian K. [34 ]
Bautista, Jocelyn F. [35 ]
Berkovic, Samuel F. [3 ]
Boro, Alex [36 ]
Cascino, Gregory D. [37 ]
Consalvo, Damian [38 ]
Crumrine, Patricia [39 ]
Devinsky, Orrin [40 ]
Dlugos, Dennis [8 ]
Epstein, Michael P. [11 ]
Fiol, Miguel [41 ]
Fountain, Nathan B. [42 ]
French, Jacqueline [16 ]
Friedman, Daniel [16 ]
Geller, Eric B. [43 ]
Glauser, Tracy [12 ]
Glynn, Simon [44 ]
Haut, Sheryl R. [45 ]
Hayward, Jean [46 ]
Helmers, Sandra L. [47 ]
机构
[1] Duke Univ, Med Ctr, Dept Biostat & Bioinformat, Duke Clin Res Inst, Durham, NC 27710 USA
[2] Duke Univ, Med Ctr, Ctr Human Genome Variat, Durham, NC 27710 USA
[3] Univ Melbourne Austin Hlth, Dept Med, Epilepsy Res Ctr, Heidelberg, Vic 3084, Australia
[4] Univ Montreal, CHUM Hop Notre Dame Montre, Montreal, PQ H2L 4M1, Canada
[5] CHUM Res Ctr, Montreal, PQ H2L 4M1, Canada
[6] Royal Coll Surg, Dublin 9, Ireland
[7] Beaumont Hosp, Dept Neurol, Dublin 9, Ireland
[8] Univ Penn, Perelman Sch Med, Childrens Hosp Philadelphia, Dept Neurol & Pediat, Philadelphia, PA 19104 USA
[9] Univ Washington, Sch Med, Dept Gen Sci, Seattle, WA 98195 USA
[10] Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA
[11] Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA 30322 USA
[12] Cincinnati Childrens Hosp Med Ctr, Div Neurol, Cincinnati, OH 45229 USA
[13] Duke Univ, Sch Med, Ctr Human Genome Variat, Durham, NC 27708 USA
[14] Royal Childrens Hosp Melbourne, Dept Neurol, Parkville, Vic 3052, Australia
[15] Ctr Clin Translat Div Brain Sci, London SW7 2AZ, England
[16] NYU, Sch Med, Dept Neurol, Comprehens Epilepsy Ctr, New York, NY 10016 USA
[17] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA
[18] Univ Liverpool, Ctr Clin Sci, Dept Mol & Clin Pharmacol, Liverpool L9 7LJ, Merseyside, England
[19] Univ Washington, Div Med Genet, Dept Pediat, Seattle, WA 98115 USA
[20] Univ Calif San Francisco, San Francisco, CA 94143 USA
[21] Royal Melbourne Hosp, Dept Med, Parkville, Vic 3146, Australia
[22] Royal Melbourne Hosp, Dept Neurol, Parkville, Vic 3146, Australia
[23] Columbia Univ, Dept Epidemiol, New York, NY 10027 USA
[24] Columbia Univ, Dept Neurol, New York, NY 10027 USA
[25] Columbia Univ, GH Sergievsky Ctr, New York, NY 10027 USA
[26] New York State Psychiat Inst & Hosp, Div Epidemiol, New York, NY 10032 USA
[27] Boston Childrens Hosp, Dept Neurol, Div Epilepsy & Clin Neurophysiol, Boston, MA 02115 USA
[28] Univ Melbourne Austin Hlth, Dept Med, Epilepsy Res Ctr, Heidelberg, Vic 3084, Australia
[29] Univ Melbourne, Florey Inst, Parkville, Vic 3052, Australia
[30] Univ Melbourne, Dept Pediat, Royal Childrens Hosp, Parkville, Vic 3052, Australia
[31] Univ Calif San Francisco, Pediat & Inst Human Genet, Dept Neurol, San Francisco, CA 94158 USA
[32] Harvard Univ, Sch Med, Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA
[33] Vanderbilt Univ, Med Ctr, Dept Neurol, Nashville, TN 37232 USA
[34] Univ Calif San Francisco, Sch Med, UCSF Sch Pharm, Dept Clin Pharm,Dept Neurol, San Francisco, CA 94143 USA
[35] Cleveland Clin Neurol Inst, Cleveland Clin Lerner Coll Med & Epilepsy Ctr, Dept Neurol, Cleveland, OH 44195 USA
[36] Albert Einstein Coll Med, Montefiore Med Ctr, Dept Neurol, Bronx, NY 10467 USA
[37] Mayo Clin, Div Epilepsy, Rochester, MN 55905 USA
[38] Ramos Meji Hosp, Div Neurol, Epilepsy Ctr, RA-1221 Buenos Aires, DF, Argentina
[39] Univ Pittsburgh, UPMC, Med Epilepsy Program & EEG & Child Neurol, Childrens Hosp Pittsburgh,Sch Med, Pittsburgh, PA 15224 USA
[40] NYU, Sch Med, St Barnabas Epilepsy Ctr, New York, NY 10016 USA
[41] Univ Minnesota, Sch Med, Epilepsy Care Ctr, Dept Neurol, Minneapolis, MN 55414 USA
[42] Univ Virginia, FE Dreifuss Comprehens Epilepsy Program, Charlottesville, VA 22908 USA
[43] St Barnabas Hosp, Div Neurol, Livingston, NJ 07039 USA
[44] Univ Michigan Hlth Syst, Dept Neurol, Comprehens Epilepsy Program, Ann Arbor, MI 48109 USA
[45] Montefiore Med Ctr, Comprehens Epilepsy Ctr, Bronx, NY 10467 USA
[46] Kaiser Permanente Grp, Oakland, CA 94618 USA
[47] Emory Univ, Sch Med, Atlanta, GA 30322 USA
[48] Univ Michigan, Ann Arbor, MI 48109 USA
[49] Rush Univ, Med Ctr, Rush Epilepsy Ctr, Dept Neurol Sci, Chicago, IL 60612 USA
[50] Univ Calif San Francisco, Dept Radiol, San Francisco, CA 94143 USA
基金
美国国家卫生研究院;
关键词
EPILEPSIES; DISEASE;
D O I
10.1038/nature12439
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Epileptic encephalopathies are a devastating group of severe childhood epilepsy disorders for which the cause is often unknown(1). Here we report a screen for de novo mutations in patients with two classical epileptic encephalopathies: infantile spasms (n = 149) and Lennox-Gastaut syndrome (n = 115). We sequenced the exomes of 264 probands, and their parents, and confirmed 329 de novo mutations. A likelihood analysis showed a significant excess of de novo mutations in the similar to 4,000 genes that are the most intolerant to functional genetic variation in the human population (P = 2.9 x 10(-3)). Among these are GABRB3, with de novo mutations in four patients, and ALG13, with the same de novo mutation in two patients; both genes show clear statistical evidence of association with epileptic encephalopathy. Given the relevant site-specific mutation rates, the probabilities of these outcomes occurring by chance are P = 4.1 x 10(-10) and P = 7.8 x 10(-12), respectively. Other genes with de novo mutations in this cohort include CACNA1A, CHD2, FLNA, GABRA1, GRIN1, GRIN2B, HNRNPU, IQSEC2, MTOR and NEDD4L. Finally, we show that the de novo mutations observed are enriched in specific gene sets including genes regulated by the fragile X protein (P < 10(-8)), as has been reported previously for autism spectrum disorders(2).
引用
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页码:217 / +
页数:7
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