Burden Analysis of Rare Microdeletions Suggests a Strong Impact of Neurodevelopmental Genes in Genetic Generalised Epilepsies

PLoS Genetics

Volumn 11, Issue 5, 2015, Pages

  Lal, Dennis ^a,b,c,d   Ruppert, Ann Kathrin ^a,d   Trucks, Holger ^a,d   Schulz, Herbert ^a,d   de Kovel, Carolien ^e   Kasteleijn Nolst Trenité, Dorothée ^d   Sonsma, Anja C M ^d,e   Koeleman, Bobby P C ^e   Lindhout, Dick ^d,e,f   Weber, Yvonne ^g   Lerche, Holger ^d,g   Kapser, Claudia ^d,h   Schankin, Christoph J ^d,h   Kunz, Wolfram S ^d,i   Surges, Rainer ^d,i   Elger, Christian E ^d,i   Gaus, Verena ^d,j   Schmitz, Bettina ^d,j,k   Helbig, Ingo ^d,l,ab   Muhle, Hiltrud ^d,l,ab   Stephani, Ulrich ^d,l,ab   Klein, Karl Martin ^m   Rosenow, Felix ^d,m,n   Neubauer, Bernd A ^c   Reinthaler, Eva M ^d,o   Zimprich, Fritz ^d,o,y   Feucht, Martha ^d,o,y   Møller, Rikke S ^d,p,q,z   Hjalgrim, Helle ^d,p,q   De Jonghe, Peter ^d,o,r,s   Suls, Arvid ^d,o,r,s   Lieb, Wolfgang ^t   Franke, Andre ^t   Strauch, Konstantin ^u,v   Gieger, Christian ^u   Schurmann, Claudia ^w   Schminke, Ulf ^x   Nürnberg, Peter ^a,b,d   Sander, Thomas ^a,d,j   Mörzinger, Martina ^y   Weckhuysen, Sarah ^o,r   Claes, Lieve ^o,r   Deprez, Liesbet ^o,r   Smets, Katrien ^o,r   Van Dyck, Tine ^o,r   Deconinck, Tine ^o,r   Klitten, Laura L ^p   Campus, Kiel ^aa   Ostertag, Philipp ^ab   von Spiczak, Sarah ^ab   Kleefuß Lie, Ailing A ⁱ   Janz, Dieter ^j   Reif, Philipp S ^m   Oertel, Wolfgang H ^m   Hamer, Hajo M ^m   Becker, Felicitas ^g   more..

^a UNIVERSITY OF COLOGNE   (Germany)

^b UNIVERSITY OF COLOGNE   (Germany)

^c UNIVERSITY HOSPITAL GIESSEN   (Germany)

^d EPICURE Consortium   (Germany)

^e UNIVERSITY MEDICAL CENTER UTRECHT   (Netherlands)

^f STICHTING EPILEPSIE INSTELLINGEN NEDERLAND SEIN   (Netherlands)

^g UNIVERSITY OF TÜBINGEN   (Germany)

^h LUDWIG MAXIMILIANS UNIVERSITY   (Germany)

ⁱ UNIVERSITY HOSPITAL BONN   (Germany)

^j CHARITÉ UNIVERSITÄTSMEDIZIN BERLIN   (Germany)

^k VIVANTES HOSPITAL   (Germany)

^l UNIVERSITY HOSPITAL SCHLESWIG HOLSTEIN   (Germany)

^m PHILIPPS UNIVERSITY MARBURG   (Germany)

ⁿ GOETHE UNIVERSITY   (Germany)

^o MEDICAL UNIVERSITY OF VIENNA   (Austria)

^p DANISH EPILEPSY CENTRE   (Denmark)

^q UNIVERSITY OF SOUTHERN DENMARK   (Denmark)

^r UNIVERSITY OF ANTWERP   (Belgium)

^s UNIVERSITY OF ANTWERP   (Belgium)

^t UNIVERSITY OF KIEL   (Germany)

^u INSTITUTE OF EPIDEMIOLOGY   (Germany)

^v UNIVERSITY OF MUNICH   (Germany)

^w UNIVERSITY OF GREIFSWALD   (Germany)

^x UNIVERSITY MEDICINE GREIFSWALD   (Germany)

^y Medical University of Vienna ^*  (Australia)

^z UNIVERSITY OF COPENHAGEN   (Denmark)

^aa UNIVERSITY HOSPITAL SCHLESWIG HOLSTEIN   (Germany)

^ab Humboldt University of Berlin ^*  (Germany)

more..

Author keywords

[No Author keywords available]

Indexed keywords

ARTICLE; AUTISM; CASE CONTROL STUDY; COHORT ANALYSIS; CONTROLLED STUDY; EPILEPTOGENESIS; EPM2A GENE; FEMALE; GENE; GENE DELETION; GENE REARRANGEMENT; GENERALIZED EPILEPSY; GENETIC ASSOCIATION; GENETIC DISORDER; GENETIC GENERALIZED EPILEPSY; GENETIC RISK; HUMAN; KCNA2 GENE; MAJOR CLINICAL STUDY; MALE; MICRODELETION; NRXN1 GENE; PCDH7 GENE; PLCB1 GENE; RBFOX1 GENE; RORB GENE; ADOLESCENT; ADULT; CHILD; COPY NUMBER VARIATION; GENETIC ASSOCIATION STUDY; GENETICS; HUMAN GENOME; MENTAL DISEASE; PROTEIN DOMAIN; SINGLE NUCLEOTIDE POLYMORPHISM; YOUNG ADULT;

ADOLESCENT; ADULT; CASE-CONTROL STUDIES; CHILD; COHORT STUDIES; DNA COPY NUMBER VARIATIONS; EPILEPSY, GENERALIZED; FEMALE; GENE REARRANGEMENT; GENETIC ASSOCIATION STUDIES; GENOME, HUMAN; HUMANS; MALE; NEURODEVELOPMENTAL DISORDERS; POLYMORPHISM, SINGLE NUCLEOTIDE; PROTEIN INTERACTION DOMAINS AND MOTIFS; SEQUENCE DELETION; YOUNG ADULT;

EID: 84975810789     PISSN: 15537390     EISSN: 15537404     Source Type: Journal    
DOI: 10.1371/journal.pgen.1005226     Document Type: Article

References (114)

1. Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W, et al. (2010) Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005–2009. Epilepsia 51: 676–685. doi: 10.1111/j.1528-1167.2010.02522.x 20196795
2. Hauser WA, Annegers JF, Kurland LT, (1993) Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota: 1935–1984. Epilepsia 34: 453–468. 8504780
3. Jallon P, Loiseau P, Loiseau J, (2001) Newly diagnosed unprovoked epileptic seizures: presentation at diagnosis in CAROLE study. Coordination Active du Reseau Observatoire Longitudinal de l' Epilepsie. Epilepsia 42: 464–475. 11440341
4. Commission on Classification and Terminology of the International League Against Epilepsy (1989) Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 30: 389–399. 2502382
5. Nordli DR, Jr. (2005) Idiopathic generalized epilepsies recognized by the International League Against Epilepsy. Epilepsia 46 Suppl 9: 48–56. 16302875
6. Berkovic SF, Howell RA, Hay DA, Hopper JL, (1998) Epilepsies in twins: genetics of the major epilepsy syndromes. Ann Neurol 43: 435–445. 9546323
7. Kjeldsen MJ, Kyvik KO, Christensen K, Friis ML, (2001) Genetic and environmental factors in epilepsy: a population-based study of 11900 Danish twin pairs. Epilepsy Res 44: 167–178. 11325572
8. Vadlamudi L, Milne RL, Lawrence K, Heron SE, Eckhaus J, Keay D, et al. (2014) Genetics of epilepsy: The testimony of twins in the molecular era. Neurology 83: 1042–1048. doi: 10.1212/WNL.0000000000000790 25107880
9. Peljto AL, Barker-Cummings C, Vasoli VM, Leibson CL, Hauser WA, Buchhalter JR, et al. (2014) Familial risk of epilepsy: a population-based study. Brain 137: 795–805. doi: 10.1093/brain/awt368 24468822
10. Dibbens LM, Heron SE, Mulley JC, (2007) A polygenic heterogeneity model for common epilepsies with complex genetics. Genes Brain Behav 6: 593–597. 17559416
11. Poduri A, Lowenstein D, (2011) Epilepsy genetics—past, present, and future. Curr Opin Genet Dev 21: 325–332. doi: 10.1016/j.gde.2011.01.005 21277190
12. Pandolfo M, (2013) Pediatric epilepsy genetics. Curr Opin Neurol 26: 137–145. doi: 10.1097/WCO.0b013e32835f19da 23449174
13. Scheffer IE, Mefford HC, (2014) Epilepsy: Beyond the single nucleotide variant in epilepsy genetics. Nat Rev Neurol 10: 490–491. doi: 10.1038/nrneurol.2014.146 25112510
14. de Kovel CG, Trucks H, Helbig I, Mefford HC, Baker C, Leu C, et al. (2010) Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies. Brain 133: 23–32. doi: 10.1093/brain/awp262 19843651
15. Heinzen EL, Radtke RA, Urban TJ, Cavalleri GL, Depondt C, Need AC, et al. (2010) Rare deletions at 16p13.11 predispose to a diverse spectrum of sporadic epilepsy syndromes. Am J Hum Genet 86: 707–718. doi: 10.1016/j.ajhg.2010.03.018 20398883
16. Mefford HC, Muhle H, Ostertag P, von Spiczak S, Buysse K, Baker C, et al. (2010) Genome-wide copy number variation in epilepsy: novel susceptibility loci in idiopathic generalized and focal epilepsies. PLoS Genet 6: e1000962. doi: 10.1371/journal.pgen.1000962 20502679
17. Mullen SA, Carvill GL, Bellows S, Bayly MA, Trucks H, Lal D, et al. (2013) Copy number variants are frequent in genetic generalized epilepsy with intellectual disability. Neurology 81: 1507–1514. doi: 10.1212/WNL.0b013e3182a95829 24068782
18. Striano P, Coppola A, Paravidino R, Malacarne M, Gimelli S, Robbiano A, et al. (2012) Clinical significance of rare copy number variations in epilepsy: a case-control survey using microarray-based comparative genomic hybridization. Arch Neurol 69: 322–330. doi: 10.1001/archneurol.2011.1999 22083797
19. Dimassi S, Labalme A, Lesca G, Rudolf G, Bruneau N, Hirsch E, et al. (2014) A subset of genomic alterations detected in rolandic epilepsies contains candidate or known epilepsy genes including GRIN2A and PRRT2. Epilepsia 55: 370–378. doi: 10.1111/epi.12502 24372385
20. Reinthaler EM, Lal D, Lebon S, Hildebrand MS, Dahl HH, Regan BM, et al. (2014) 16p11.2 600 kb Duplications confer risk for typical and atypical Rolandic epilepsy. Hum Mol Genet 23: 6069–6080. doi: 10.1093/hmg/ddu306 24939913
21. Itsara A, Cooper GM, Baker C, Girirajan S, Li J, Absher D, et al. (2009) Population analysis of large copy number variants and hotspots of human genetic disease. Am J Hum Genet 84: 148–161. doi: 10.1016/j.ajhg.2008.12.014 19166990
22. Helbig I, Mefford HC, Sharp AJ, Guipponi M, Fichera M, Franke A, et al. (2009) 15q13.3 microdeletions increase risk of idiopathic generalized epilepsy. Nat Genet 41: 160–162. doi: 10.1038/ng.292 19136953
23. Dibbens LM, Mullen S, Helbig I, Mefford HC, Bayly MA, Bellows S, et al. (2009) Familial and sporadic 15q13.3 microdeletions in idiopathic generalized epilepsy: precedent for disorders with complex inheritance. Hum Mol Genet 18: 3626–3631. doi: 10.1093/hmg/ddp311 19592580
24. Olson H, Shen Y, Avallone J, Sheidley BR, Pinsky R, Bergin AM, et al. (2014) Copy number variation plays an important role in clinical epilepsy. Ann Neurol 75: 943–958. doi: 10.1002/ana.24178 24811917
25. Dejanovic B, Lal D, Catarino CB, Arjune S, Belaidi AA, Trucks H, et al. (2014) Exonic microdeletions of the gephyrin gene impair GABAergic synaptic inhibition in patients with idiopathic generalized epilepsy. Neurobiol Dis 67: 88–96. doi: 10.1016/j.nbd.2014.02.001 24561070
26. Moller RS, Weber YG, Klitten LL, Trucks H, Muhle H, Kunz WS, et al. (2013) Exon-disrupting deletions of NRXN1 in idiopathic generalized epilepsy. Epilepsia 54: 256–264. doi: 10.1111/epi.12078 23294455
27. Lal D, Trucks H, Moller RS, Hjalgrim H, Koeleman BP, de Kovel CG, et al. (2013) Rare exonic deletions of the RBFOX1 gene increase risk of idiopathic generalized epilepsy. Epilepsia 54: 265–271. doi: 10.1111/epi.12084 23350840
28. Pinto D, Delaby E, Merico D, Barbosa M, Merikangas A, Klei L, et al. (2014) Convergence of genes and cellular pathways dysregulated in autism spectrum disorders. Am J Hum Genet 94: 677–694. doi: 10.1016/j.ajhg.2014.03.018 24768552
29. Carvill GL, Mefford HC, (2013) Microdeletion syndromes. Curr Opin Genet Dev 23: 232–239. doi: 10.1016/j.gde.2013.03.004 23664828
30. Krumm N, O'Roak BJ, Karakoc E, Mohajeri K, Nelson B, Vives L, et al. (2013) Transmission disequilibrium of small CNVs in simplex autism. Am J Hum Genet 93: 595–606. doi: 10.1016/j.ajhg.2013.07.024 24035194
31. Uddin M, Tammimies K, Pellecchia G, Alipanahi B, Hu P, Wang Z, et al. (2014) Brain-expressed exons under purifying selection are enriched for de novo mutations in autism spectrum disorder. Nat Genet 46: 742–747. doi: 10.1038/ng.2980 24859339
32. Xu B, Ionita-Laza I, Roos JL, Boone B, Woodrick S, Sun Y, et al. (2012) De novo gene mutations highlight patterns of genetic and neural complexity in schizophrenia. Nat Genet 44: 1365–1369. doi: 10.1038/ng.2446 23042115
33. Carter MT, Nikkel SM, Fernandez BA, Marshall CR, Noor A, Lionel AC, et al. (2011) Hemizygous deletions on chromosome 1p21.3 involving the DPYD gene in individuals with autism spectrum disorder. Clin Genet 80: 435–443. doi: 10.1111/j.1399-0004.2010.01578.x 21114665
34. Willemsen MH, Valles A, Kirkels LA, Mastebroek M, Olde Loohuis N, Kos A, et al. (2011) Chromosome 1p21.3 microdeletions comprising DPYD and MIR137 are associated with intellectual disability. J Med Genet 48: 810–818. doi: 10.1136/jmedgenet-2011-100294 22003227
35. Brew HM, Gittelman JX, Silverstein RS, Hanks TD, Demas VP, Robinson LC, et al. (2007) Seizures and reduced life span in mice lacking the potassium channel subunit Kv1.2, but hypoexcitability and enlarged Kv1 currents in auditory neurons. J Neurophysiol 98: 1501–1525. 17634333
36. Wimmer VC, Reid CA, So EY, Berkovic SF, Petrou S, (2010) Axon initial segment dysfunction in epilepsy. J Physiol 588: 1829–1840. doi: 10.1113/jphysiol.2010.188417 20375142
37. Robbins CA, Tempel BL, (2012) Kv1.1 and Kv1.2: similar channels, different seizure models. Epilepsia 53 Suppl 1: 134–141. doi: 10.1111/j.1528-1167.2012.03484.x 22612818
38. Pena SD, Coimbra RL, (2015) Ataxia and myoclonic epilepsy due to a heterozygous new mutation in KCNA2: proposal for a new channelopathy. Clin Genet 87: e1–3. doi: 10.1111/cge.12542 25477152
39. Syrbe S, Hedrich UB, Riesch E, Djemie T, Muller S, Moller RS, et al. (2015) De novo loss- or gain-of-function mutations in KCNA2 cause epileptic encephalopathy. Nat Genet, doi: 10.1038/ng.3239 [Epub ahead of print].
40. Bena F, Bruno DL, Eriksson M, van Ravenswaaij-Arts C, Stark Z, Dijkhuizen T, et al. (2013) Molecular and clinical characterization of 25 individuals with exonic deletions of NRXN1 and comprehensive review of the literature. Am J Med Genet B Neuropsychiatr Genet 162B: 388–403. doi: 10.1002/ajmg.b.32148 23533028
41. Dabell MP, Rosenfeld JA, Bader P, Escobar LF, El-Khechen D, Vallee SE, et al. (2013) Investigation of NRXN1 deletions: clinical and molecular characterization. Am J Med Genet A 161A: 717–731. doi: 10.1002/ajmg.a.35780 23495017
42. Albayrak O, Putter C, Volckmar AL, Cichon S, Hoffmann P, Nothen MM, et al. (2013) Common obesity risk alleles in childhood attention-deficit/hyperactivity disorder. Am J Med Genet B Neuropsychiatr Genet 162B: 295–305. doi: 10.1002/ajmg.b.32144 23533005
43. Casey JP, Magalhaes T, Conroy JM, Regan R, Shah N, Anney R, et al. (2012) A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder. Hum Genet 131: 565–579. doi: 10.1007/s00439-011-1094-6 21996756
44. Lesch KP, Selch S, Renner TJ, Jacob C, Nguyen TT, Hahn T, et al. (2011) Genome-wide copy number variation analysis in attention-deficit/hyperactivity disorder: association with neuropeptide Y gene dosage in an extended pedigree. Mol Psychiatry 16: 491–503. doi: 10.1038/mp.2010.29 20308990
45. International League Against Epilepsy Consortium on Complex Epilepsies (2014) Genetic determinants of common epilepsies: a meta-analysis of genome-wide association studies. Lancet Neurol 13: 893–903. doi: 10.1016/S1474-4422(14)70171-1 25087078
46. Kim SY, Mo JW, Han S, Choi SY, Han SB, Moon BH, et al. (2010) The expression of non-clustered protocadherins in adult rat hippocampal formation and the connecting brain regions. Neuroscience 170: 189–199. doi: 10.1016/j.neuroscience.2010.05.027 20541594
47. Miyake K, Hirasawa T, Soutome M, Itoh M, Goto Y, Endoh K, et al. (2011) The protocadherins, PCDHB1 and PCDH7, are regulated by MeCP2 in neuronal cells and brain tissues: implication for pathogenesis of Rett syndrome. BMC Neurosci 12: 81. doi: 10.1186/1471-2202-12-81 21824415
48. Dibbens LM, Tarpey PS, Hynes K, Bayly MA, Scheffer IE, Smith R, et al. (2008) X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment. Nat Genet 40: 776–781. doi: 10.1038/ng.149 18469813
49. Lee Y, Ahn C, Han J, Choi H, Kim J, Yim J, et al. (2003) The nuclear RNase III Drosha initiates microRNA processing. Nature 425: 415–419. 14508493
50. Inoue YU, Asami J, Inoue T, (2008) Cadherin-6 gene regulatory patterns in the postnatal mouse brain. Mol Cell Neurosci 39: 95–104. doi: 10.1016/j.mcn.2008.05.020 18617008
51. Jimenez-Mateos EM, Henshall DC, (2013) Epilepsy and microRNA. Neuroscience 238: 218–229. doi: 10.1016/j.neuroscience.2013.02.027 23485811
52. Ayoub MA, Angelicheva D, Vile D, Chandler D, Morar B, Cavanaugh JA, et al. (2012) Deleterious GRM1 mutations in schizophrenia. PLoS One 7: e32849. doi: 10.1371/journal.pone.0032849 22448230
53. Minassian BA, Lee JR, Herbrick JA, Huizenga J, Soder S, Mungall AJ, et al. (1998) Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonus epilepsy. Nat Genet 20: 171–174. 9771710
54. Girirajan S, Dennis MY, Baker C, Malig M, Coe BP, Campbell CD, et al. (2013) Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder. Am J Hum Genet 92: 221–237. doi: 10.1016/j.ajhg.2012.12.016 23375656
55. Glessner JT, Wang K, Cai G, Korvatska O, Kim CE, Wood S, et al. (2009) Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature 459: 569–573. doi: 10.1038/nature07953 19404257
56. Gaier ED, Eipper BA, Mains RE, (2014) Pam heterozygous mice reveal essential role for Cu in amygdalar behavioral and synaptic function. Ann N Y Acad Sci 1314: 15–23. doi: 10.1111/nyas.12378 24593825
57. Scheuerle A, Wilson K, (2011) PARK2 copy number aberrations in two children presenting with autism spectrum disorder: further support of an association and possible evidence for a new microdeletion/microduplication syndrome. Am J Med Genet B Neuropsychiatr Genet 156B: 413–420. doi: 10.1002/ajmg.b.31176 21360662
58. La Cognata V, Iemmolo R, D'Agata V, Scuderi S, Drago F, Zappia M, et al. (2014) Increasing the Coding Potential of Genomes Through Alternative Splicing: The Case of PARK2 Gene. Curr Genomics 15: 203–216. doi: 10.2174/1389202915666140426003342 24955028
59. Elia J, Glessner JT, Wang K, Takahashi N, Shtir CJ, Hadley D, et al. (2012) Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder. Nat Genet 44: 78–84. doi: 10.1093/jncimonographs/lgs016 22623599
60. Prasad A, Merico D, Thiruvahindrapuram B, Wei J, Lionel AC, Sato D, et al. (2012) A discovery resource of rare copy number variations in individuals with autism spectrum disorder. G3 (Bethesda) 2: 1665–1685. doi: 10.1534/g3.112.004689 23275889
61. Asadollahi R, Oneda B, Joset P, Azzarello-Burri S, Bartholdi D, Steindl K, et al. (2014) The clinical significance of small copy number variants in neurodevelopmental disorders. J Med Genet 2: 1665–1685.
62. Sleiman P, Wang D, Glessner J, Hadley D, Gur RE, Cohen N, et al. (2013) GWAS meta analysis identifies TSNARE1 as a novel Schizophrenia / Bipolar susceptibility locus. Sci Rep 3: 3075. doi: 10.1038/srep03075 24166486
63. Boudry-Labis E, Demeer B, Le Caignec C, Isidor B, Mathieu-Dramard M, Plessis G, et al. (2013) A novel microdeletion syndrome at 9q21.13 characterised by mental retardation, speech delay, epilepsy and characteristic facial features. Eur J Med Genet 56: 163–170. doi: 10.1016/j.ejmg.2012.12.006 23279911
64. McGrath CL, Glatt SJ, Sklar P, Le-Niculescu H, Kuczenski R, Doyle AE, et al. (2009) Evidence for genetic association of RORB with bipolar disorder. BMC Psychiatry 9: 70. doi: 10.1186/1471-244X-9-70 19909500
65. Ersland KM, Christoforou A, Stansberg C, Espeseth T, Mattheisen M, Mattingsdal M, et al. (2012) Gene-based analysis of regionally enriched cortical genes in GWAS data sets of cognitive traits and psychiatric disorders. PLoS One 7: e31687. doi: 10.1371/journal.pone.0031687 22384057
66. Mroczkowski HJ, Arnold G, Schneck FX, Rajkovic A, Yatsenko SA, (2014) Interstitial 10p11.23-p12.1 microdeletions associated with developmental delay, craniofacial abnormalities, and cryptorchidism. Am J Med Genet A 164A: 2623–2626. doi: 10.1002/ajmg.a.36627 25073539
67. Cichon S, Winge I, Mattheisen M, Georgi A, Karpushova A, Freudenberg J, et al. (2008) Brain-specific tryptophan hydroxylase 2 (TPH2): a functional Pro206Ser substitution and variation in the 5'-region are associated with bipolar affective disorder. Hum Mol Genet 17: 87–97. 17905754
68. Mosienko V, Beis D, Pasqualetti M, Waider J, Matthes S, Qadri F, et al. (2014) Life without brain serotonin: Reevaluation of serotonin function with mice deficient in brain serotonin synthesis. Behav Brain Res 227C: 78–88.
69. Mosienko V, Matthes S, Hirth N, Beis D, Flinders M, Bader M, et al. (2014) Adaptive changes in serotonin metabolism preserve normal behavior in mice with reduced TPH2 activity. Neuropharmacology 85: 73–80. doi: 10.1016/j.neuropharm.2014.05.015 24863038
70. Colin E, Huynh Cong E, Mollet G, Guichet A, Gribouval O, Arrondel C, et al. (2014) Loss-of-Function Mutations in WDR73 Are Responsible for Microcephaly and Steroid-Resistant Nephrotic Syndrome: Galloway-Mowat Syndrome. Am J Hum Genet 95: 637–648. doi: 10.1016/j.ajhg.2014.10.011 25466283
71. Gehman LT, Stoilov P, Maguire J, Damianov A, Lin CH, Shiue L, et al. (2011) The splicing regulator Rbfox1 (A2BP1) controls neuronal excitation in the mammalian brain. Nat Genet 43: 706–711. doi: 10.1038/ng.841 21623373
72. Zhao WW, (2013) Intragenic deletion of RBFOX1 associated with neurodevelopmental/neuropsychiatric disorders and possibly other clinical presentations. Mol Cytogenet 6: 26. doi: 10.1186/1755-8166-6-26 23822903
73. Fogel BL, Wexler E, Wahnich A, Friedrich T, Vijayendran C, Gao F, et al. (2012) RBFOX1 regulates both splicing and transcriptional networks in human neuronal development. Hum Mol Genet 21: 4171–4186. doi: 10.1093/hmg/dds240 22730494
74. Kurian MA, Meyer E, Vassallo G, Morgan NV, Prakash N, Pasha S, et al. (2010) Phospholipase C beta 1 deficiency is associated with early-onset epileptic encephalopathy. Brain 133: 2964–2970. doi: 10.1093/brain/awq238 20833646
75. Ngoh A, McTague A, Wentzensen IM, Meyer E, Applegate C, Kossoff EH, et al. (2014) Severe infantile epileptic encephalopathy due to mutations in PLCB1: expansion of the genotypic and phenotypic disease spectrum. Dev Med Child Neurol 56: 1124–1128. doi: 10.1111/dmcn.12450 24684524
76. McOmish CE, Burrows EL, Howard M, Hannan AJ, (2008) PLC-beta1 knockout mice as a model of disrupted cortical development and plasticity: behavioral endophenotypes and dysregulation of RGS4 gene expression. Hippocampus 18: 824–834. doi: 10.1002/hipo.20443 18493969
77. Lo Vasco VR, Cardinale G, Polonia P, (2012) Deletion of PLCB1 gene in schizophrenia-affected patients. J Cell Mol Med 16: 844–851. doi: 10.1111/j.1582-4934.2011.01363.x 22507702
78. Anney R, Klei L, Pinto D, Regan R, Conroy J, Magalhaes TR, et al. (2010) A genome-wide scan for common alleles affecting risk for autism. Hum Mol Genet 19: 4072–4082. doi: 10.1093/hmg/ddq307 20663923
79. Lionel AC, Crosbie J, Barbosa N, Goodale T, Thiruvahindrapuram B, Rickaby J, et al. (2011) Rare copy number variation discovery and cross-disorder comparisons identify risk genes for ADHD. Sci Transl Med 3: 95ra75.
80. Kohannim O, Hibar DP, Stein JL, Jahanshad N, Hua X, Rajagopalan P, et al. (2012) Discovery and Replication of Gene Influences on Brain Structure Using LASSO Regression. Front Neurosci 6: 115. doi: 10.3389/fnins.2012.00115 22888310
81. Bradley WE, Raelson JV, Dubois DY, Godin E, Fournier H, Prive C, et al. (2010) Hotspots of large rare deletions in the human genome. PLoS One 5: e9401. doi: 10.1371/journal.pone.0009401 20195527
82. Jones RM, Cadby G, Blangero J, Abraham LJ, Whitehouse AJ, Moses EK, (2014) MACROD2 gene associated with autistic-like traits in a general population sample. Psychiatr Genet 24: 241–248. doi: 10.1097/YPG.0000000000000052 25360606
83. Higuchi M, Maas S, Single FN, Hartner J, Rozov A, Burnashev N, et al. (2000) Point mutation in an AMPA receptor gene rescues lethality in mice deficient in the RNA-editing enzyme ADAR2. Nature 406: 78–81. 10894545
84. Vesely C, Tauber S, Sedlazeck FJ, Tajaddod M, Haeseler A, Jantsch MF, (2014) ADAR2 induces reproducible changes in sequence and abundance of mature microRNAs in the mouse brain. Nucleic Acids Res 42: 12155–12168. doi: 10.1093/nar/gku844 25260591
85. Rossin EJ, Lage K, Raychaudhuri S, Xavier RJ, Tatar D, Benita Y, et al. (2011) Proteins encoded in genomic regions associated with immune-mediated disease physically interact and suggest underlying biology. PLoS Genet 7: e1001273. doi: 10.1371/journal.pgen.1001273 21249183
86. Chen EY, Tan CM, Kou Y, Duan Q, Wang Z, Meirelles GV, et al. (2013) Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinformatics 14: 128. doi: 10.1186/1471-2105-14-128 23586463
87. Pinto D, Darvishi K, Shi X, Rajan D, Rigler D, Fitzgerald T, et al. (2011) Comprehensive assessment of array-based platforms and calling algorithms for detection of copy number variants. Nat Biotechnol 29: 512–520. doi: 10.1038/nbt.1852 21552272
88. Watson CT, Marques-Bonet T, Sharp AJ, Mefford HC, (2014) The genetics of microdeletion and microduplication syndromes: an update. Annu Rev Genomics Hum Genet 15: 215–244. doi: 10.1146/annurev-genom-091212-153408 24773319
89. Cooper GM, Coe BP, Girirajan S, Rosenfeld JA, Vu TH, Baker C, et al. (2011) A copy number variation morbidity map of developmental delay. Nat Genet 43: 838–846. doi: 10.1038/ng.909 21841781
90. Cooper NJ, Shtir CJ, Smyth DJ, Guo H, Swafford AD, Zanda M, et al. (2015) Detection and correction of artefacts in estimation of rare copy number variants and analysis of rare deletions in type 1 diabetes. Hum Mol Genet 24: 1774–1790. doi: 10.1093/hmg/ddu581 25424174
91. Grayton HM, Fernandes C, Rujescu D, Collier DA, (2012) Copy number variations in neurodevelopmental disorders. Prog Neurobiol 99: 81–91. doi: 10.1016/j.pneurobio.2012.07.005 22813947
92. McLysaght A, Makino T, Grayton HM, Tropeano M, Mitchell KJ, Vassos E, et al. (2014) Ohnologs are overrepresented in pathogenic copy number mutations. Proc Natl Acad Sci U S A 111: 361–366. doi: 10.1073/pnas.1309324111 24368850
93. Mefford HC, Mulley JC, (2010) Genetically complex epilepsies, copy number variants and syndrome constellations. Genome Med 2: 71. doi: 10.1186/gm192 20923578
94. Helbig I, Swinkels ME, Aten E, Caliebe A, van 't Slot R, Boor R, et al. (2014) Structural genomic variation in childhood epilepsies with complex phenotypes. Eur J Hum Genet 22: 896–901. doi: 10.1038/ejhg.2013.262 24281369
95. Fung WL, Butcher NJ, Costain G, Andrade DM, Boot E, Chow EW, et al. (2015) Practical guidelines for managing adults with 22q11.2 deletion syndrome. Genet Med, doi: 10.1038/gim.2014.175 [Epub ahead of print].
96. Steffens M, Leu C, Ruppert AK, Zara F, EPICURE Consortium, EMINet Consortium, et al. (2012) Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1, 2q22.3 and 17q21.32. Hum Mol Genet 21: 5359–5372. doi: 10.1093/hmg/dds373 22949513
97. Pathania M, Davenport EC, Muir J, Sheehan DF, Lopez-Domenech G, Kittler JT, (2014) The autism and schizophrenia associated gene CYFIP1 is critical for the maintenance of dendritic complexity and the stabilization of mature spines. Transl Psychiatry 4: e423.
98. Schaaf CP, (2014) Nicotinic acetylcholine receptors in human genetic disease. Genet Med 16: 649–656. doi: 10.1038/gim.2014.9 24556925
99. Paciorkowski AR, Keppler-Noreuil K, Robinson L, Sullivan C, Sajan S, Christian SL, et al. (2013) Deletion 16p13.11 uncovers NDE1 mutations on the non-deleted homolog and extends the spectrum of severe microcephaly to include fetal brain disruption. Am J Med Genet A 161A: 1523–1530. doi: 10.1002/ajmg.a.35969 23704059
100. Djemie T, Weckhuysen S, Holmgren P, Hardies K, Van Dyck T, Hendrickx R, et al. (2014) PRRT2 mutations: exploring the phenotypical boundaries. J Neurol Neurosurg Psychiatry 85: 462–465. doi: 10.1136/jnnp-2013-305122 24101679
101. Hoischen A, Krumm N, Eichler EE, (2014) Prioritization of neurodevelopmental disease genes by discovery of new mutations. Nat Neurosci 17: 764–772. doi: 10.1038/nn.3703 24866042
102. Coe BP, Witherspoon K, Rosenfeld JA, van Bon BW, Vulto-van Silfhout AT, Bosco P, et al. (2014) Refining analyses of copy number variation identifies specific genes associated with developmental delay. Nat Genet 46: 1063–1071. doi: 10.1038/ng.3092 25217958
103. Bill BR, Lowe JK, Dybuncio CT, Fogel BL, (2013) Orchestration of neurodevelopmental programs by RBFOX1: implications for autism spectrum disorder. Int Rev Neurobiol 113: 251–267. doi: 10.1016/B978-0-12-418700-9.00008-3 24290388
104. Smith JJ, Sumiyama K, Amemiya CT, (2012) A living fossil in the genome of a living fossil: Harbinger transposons in the coelacanth genome. Mol Biol Evol 29: 985–993. doi: 10.1093/molbev/msr267 22045999
105. Coe BP, Girirajan S, Eichler EE, (2012) A genetic model for neurodevelopmental disease. Curr Opin Neurobiol 22: 829–836. doi: 10.1016/j.conb.2012.04.007 22560351
106. Wichmann HE, Gieger C, Illig T, Group MKS (2005) KORA-gen—resource for population genetics, controls and a broad spectrum of disease phenotypes. Gesundheitswesen 67 Suppl 1: S26–30. 16032514
107. Krawczak M, Nikolaus S, von Eberstein H, Croucher PJ, El Mokhtari NE, Schreiber S, (2006) PopGen: population-based recruitment of patients and controls for the analysis of complex genotype-phenotype relationships. Community Genet 9: 55–61. 16490960
108. Volzke H, Alte D, Schmidt CO, Radke D, Lorbeer R, Friedrich N, et al. (2011) Cohort profile: the study of health in Pomerania. Int J Epidemiol 40: 294–307. doi: 10.1093/ije/dyp394 20167617
109. Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D, (2006) Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 38: 904–909. 16862161
110. Zhang D, Qian Y, Akula N, Alliey-Rodriguez N, Tang J, Bipolar Genome S, et al. (2011) Accuracy of CNV Detection from GWAS Data. PLoS One 6: e14511. doi: 10.1371/journal.pone.0014511 21249187
111. Jacquemont S, Coe BP, Hersch M, Duyzend MH, Krumm N, Bergmann S, et al. (2014) A higher mutational burden in females supports a "female protective model" in neurodevelopmental disorders. Am J Hum Genet 94: 415–425. doi: 10.1016/j.ajhg.2014.02.001 24581740
112. Berger SI, Posner JM, Ma'ayan A, (2007) Genes2Networks: connecting lists of gene symbols using mammalian protein interactions databases. BMC Bioinformatics 8: 372. 17916244
113. Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, et al. (2000) Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet 25: 25–29. 10802651
114. Smith CM, Finger JH, Hayamizu TF, McCright IJ, Eppig JT, Kadin JA, et al. (2007) The mouse Gene Expression Database (GXD): 2007 update. Nucleic Acids Res 35: D618–623. 17130151