Chromatin regulators, phenotypic robustness, and autism risk

Frontiers in Genetics

Volumn 5, Issue APR, 2014, Pages

  Suliman, Reut ^a   Ben David, Eyal ^a   Shifman, Sagiv ^a  

^a HEBREW UNIVERSITY OF JERUSALEM   (Israel)

Author keywords

Autism spectrum disorder; Chromatin regulators; Common genetic variants; De novo mutation; Phenotypic robustness

Indexed keywords

CHROMATIN REGULATOR; REGULATOR PROTEIN; UNCLASSIFIED DRUG;

ALLELE; ARTICLE; AUTISM; CHROMATIN; CHROMOSOME ABERRATION; DNA DAMAGE; GENE EXPRESSION; GENE INTERACTION; GENE MUTATION; GENETIC HETEROGENEITY; GENETIC VARIABILITY; GENOMIC INSTABILITY; HUMAN; NEUROLOGIC DISEASE; NONHUMAN; PHENOTYPE; SCHIZOPHRENIA; SINGLE NUCLEOTIDE POLYMORPHISM; SYNAPTIC TRANSMISSION; TRANSCRIPTION REGULATION;

EID: 84898025894     PISSN: None     EISSN: 16648021     Source Type: Journal    
DOI: 10.3389/fgene.2014.00081     Document Type: Article

References (96)

1. Abrahams, B. S., and Geschwind, D. H. (2008). Advances in autism genetics: on the threshold of a new neurobiology. Nat. Rev. Genet. 9, 341-355. doi: 10.1038/nrg2346
2. Amir, R. E., Van Den Veyver, I. B., Wan, M., Tran, C. Q., Francke, U., and Zoghbi, H. Y. (1999). Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat. Genet. 23, 185-188. doi: 10.1038/13810
3. Anney, R., Klei, L., Pinto, D., Regan, R., Conroy, J., Magalhaes, T. R., 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
4. Baron-Cohen, S., Knickmeyer, R. C., and Belmonte, M. K. (2005). Sex differences in the brain: implications for explaining autism. Science 310, 819-823. doi: 10.1126/science.1115455
5. Ben-David, E., and Shifman, S. (2012). Networks of neuronal genes affected by common and rare variants in autism spectrum disorders. PLoS Genet. 8:e1002556. doi: 10.1371/journal.pgen.1002556
6. Ben-David, E., and Shifman, S. (2013). Combined analysis of exome sequencing points toward a major role for transcription regulation during brain development in autism. Mol. Psychiatry 18, 1054-1056. doi: 10.1038/mp.2012.148
7. Ben-Shachar, S., Lanpher, B., German, J. R., Qasaymeh, M., Potocki, L., Nagamani, S. C., et al. (2009). Microdeletion 15q13.3: a locus with incomplete penetrance for autism, mental retardation, and psychiatric disorders. J. Med. Genet. 46, 382-388. doi: 10.1136/jmg.2008.064378
8. Berenbaum, S. A., and Beltz, A. M. (2011). Sexual differentiation of human behavior: effects of prenatal and pubertal organizational hormones. Front. Neuroendocrinol. 32, 183-200. doi: 10.1016/j.yfrne.2011.03.001
9. Bernier, R., Gerdts, J., Munson, J., Dawson, G., and Estes, A. (2012). Evidence for broader autism phenotype characteristics in parents from multiple-incidence autism families. Autism Res. 5, 13-20. doi: 10.1002/aur.226
10. Betancur, C. (2011). Etiological heterogeneity in autism spectrum disorders: more than 100 genetic and genomic disorders and still counting. Brain Res. 1380, 42-77. doi: 10.1016/j.brainres.2010.11.078
11. Beunders, G., Van De Kamp, J. M., Veenhoven, R. H., Van Hagen, J. M., Nieuwint, A. W., and Sistermans, E. A. (2010). A triplication of the Williams-Beuren syndrome region in a patient with mental retardation, a severe expressive language delay, behavioural problems and dysmorphisms. J. Med. Genet. 47, 271-275. doi: 10.1136/jmg.2009.070490
12. Borkenau, P., McCrae, R. R., and Terracciano, A. (2013). Do Men Vary more than women in personality? A study in 51 cultures. J. Res. Pers. 47, 135-144. doi: 10.1016/j.jrp.2012.12.001
13. Burga, A., Casanueva, M. O., and Lehner, B. (2011). Predicting mutation outcome from early stochastic variation in genetic interaction partners. Nature 480, 250-253. doi: 10.1038/nature10665
14. Cook, E. H. Jr., Lindgren, V., Leventhal, B. L., Courchesne, R., Lincoln, A., Shulman, C., et al. (1997). Autism or atypical autism in maternally but not paternally derived proximal 15q duplication. Am. J. Hum. Genet. 60, 928-934.
15. Cross-Disorder Group of the Psychiatric Genomics Consortium. (2013). Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet 381, 1371-1379. doi: 10.1016/S0140-6736(12)62129-1
16. Devlin, B., and Scherer, S. W. (2012). Genetic architecture in autism spectrum disorder. Curr. Opin. Genet. Dev. 22, 229-237. doi: 10.1016/j.gde.2012.03.002
17. Gai, X., Xie, H. M., Perin, J. C., Takahashi, N., Murphy, K., Wenocur, A. S., et al. (2011). Rare structural variation of synapse and neurotransmission genes in autism. Mol. Psychiatry 17, 402-411. doi: 10.1038/mp.2011.10
18. Gibson, G. (2009). Decanalization and the origin of complex disease. Nat. Rev. Genet. 10, 134-140. doi: 10.1038/nrg2502
19. Gibson, G., and Dworkin, I. (2004). Uncovering cryptic genetic variation. Nat. Rev. Genet. 5, 681-690. doi: 10.1038/nrg1426
20. Gibson, G., and Wagner, G. (2000). Canalization in evolutionary genetics: a stabilizing theory? Bioessays 22, 372-380. doi: 10.1002/(SICI)1521-1878(200004)22:4%3C372::AID-BIES7%3E3.3.CO;2-A
21. Gilman, S. R., Iossifov, I., Levy, D., Ronemus, M., Wigler, M., and Vitkup, D. (2011). Rare de novo variants associated with autism implicate a large functional network of genes involved in formation and function of synapses. Neuron 70, 898-907. doi: 10.1016/j.neuron.2011.05.021
22. Gulsuner, S., Walsh, T., Watts, A. C., Lee, M. K., Thornton, A. M., Casadei, S., et al. (2013). Spatial and temporal mapping of de novo mutations in schizophrenia to a fetal prefrontal cortical network. Cell 154, 518-529. doi: 10.1016/j.cell.2013.06.049
23. Halgren, C., Kjaergaard, S., Bak, M., Hansen, C., El-Schich, Z., Anderson, C. M., et al. (2011). Corpus callosum abnormalities, intellectual disability, speech impairment, and autism in patients with haploinsufficiency of ARID1B. Clin. Genet. 82, 248-255. doi: 10.1111/j.1399-0004.2011.01755.x
24. Hedges, L. V., and Nowell, A. (1995). Sex differences in mental test scores, variability, and numbers of high-scoring individuals. Science 269, 41-45. doi: 10.1126/science.7604277
25. Hodge, J. C., Mitchell, E., Pillalamarri, V., Toler, T. L., Bartel, F., Kearney, H. M., et al. (2013). Disruption of MBD5 contributes to a spectrum of psychopathology and neurodevelopmental abnormalities. Mol. Psychiatry 19, 368-379. doi: 10.1038/mp.2013.42
26. Huguet, G., Ey, E., and Bourgeron, T. (2013). The genetic landscapes of autism spectrum disorders. Annu. Rev. Genomics Hum. Genet. 14, 191-213. doi: 10.1146/annurev-genom-091212-153431
27. Iossifov, I., Ronemus, M., Levy, D., Wang, Z., Hakker, I., Rosenbaum, J., et al. (2012). De novo gene disruptions in children on the autistic spectrum. Neuron 74, 285-299. doi: 10.1016/j.neuron.2012.04.009
28. Jaillard, S., Dubourg, C., Gerard-Blanluet, M., Delahaye, A., Pasquier, L., Dupont, C., et al. (2009). 2q23.1 microdeletion identified by array comparative genomic hybridisation: an emerging phenotype with Angelman-like features? J. Med. Genet. 46, 847-855. doi: 10.1136/jmg.2008.058156
29. Kadesjo, B., and Gillberg, C. (2000). Tourette's disorder: epidemiology and comorbidity in primary school children. J. Am. Acad. Child Adolesc. Psychiatry 39, 548-555. doi: 10.1097/00004583-200005000-00007
30. King, I. F., Yandava, C. N., Mabb, A. M., Hsiao, J. S., Huang, H. S., Pearson, B. L., et al. (2013). Topoisomerases facilitate transcription of long genes linked to autism. Nature 501, 58-62. doi: 10.1038/nature12504
31. Kirov, G., Rees, E., Walters, J. T., Escott-Price, V., Georgieva, L., Richards, A. L., et al. (2013). The penetrance of copy number variations for schizophrenia and developmental delay. Biol. Psychiatry 75, 378-385. doi: 10.1016/j.biopsych.2013.07.022
32. Klei, L., Sanders, S. J., Murtha, M. T., Hus, V., Lowe, J. K., Willsey, A. J., et al. (2012). Common genetic variants, acting additively, are a major source of risk for autism. Mol. Autism 3, 9. doi: 10.1186/2040-2392-3-9
33. Krumm, N., O'roak, B. J., Shendure, J., and Eichler, E. E. (2014). A de novo convergence of autism genetics and molecular neuroscience. Trends Neurosci. 37, 95-105. doi: 10.1016/j.tins.2013.11.005
34. Kurotaki, N., Imaizumi, K., Harada, N., Masuno, M., Kondoh, T., Nagai, T., et al. (2002). Haploinsufficiency of NSD1 causes Sotos syndrome. Nat. Genet. 30, 365-366. doi: 10.1038/ng863
35. Leblond, C. S., Heinrich, J., Delorme, R., Proepper, C., Betancur, C., Huguet, G., et al. (2012). Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders. PLoS Genet. 8:e1002521. doi: 10.1371/journal.pgen.1002521
36. Lee, S. H., Ripke, S., Neale, B. M., Faraone, S. V., Purcell, S. M., Perlis, R. H., et al. (2013). Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nat. Genet. 45, 984-994. doi: 10.1038/ng.2711
37. Lehner, B. (2008). Selection to minimise noise in living systems and its implications for the evolution of gene expression. Mol. Syst. Biol. 4, 170. doi: 10.1038/msb.2008.11
38. Lehner, B., Crombie, C., Tischler, J., Fortunato, A., and Fraser, A. G. (2006). Systematic mapping of genetic interactions in Caenorhabditis elegans identifies common modifiers of diverse signaling pathways. Nat. Genet. 38, 896-903. doi: 10.1038/ng1844
39. Levy, D., Ronemus, M., Yamrom, B., Lee, Y.-H., Leotta, A., Kendall, J., et al. (2011). Rare de novo and transmitted copy-number variation in autistic spectrum disorders. Neuron 70, 886-897. doi: 10.1016/j.neuron.2011.05.015
40. Levy, S. F., and Siegal, M. L. (2008). Network hubs buffer environmental variation in Saccharomyces cerevisiae. PLoS Biol. 6:e264. doi: 10.1371/journal.pbio.0060264
41. Ma, D., Salyakina, D., Jaworski, J. M., Konidari, I., Whitehead, P. L., Andersen, A. N., et al. (2009). A genome-wide association study of autism reveals a common novel risk locus at 5p14.1. Ann. Hum. Genet. 73, 263-273. doi: 10.1111/j.1469-1809.2009.00523.x
42. Manning, M. A., Cassidy, S. B., Clericuzio, C., Cherry, A. M., Schwartz, S., Hudgins, L., et al. (2004). Terminal 22q deletion syndrome: a newly recognized cause of speech and language disability in the autism spectrum. Pediatrics 114, 451-457. doi: 10.1542/peds.114.2.451
43. Marshall, C. R., Noor, A., Vincent, J. B., Lionel, A. C., Feuk, L., Skaug, J., et al. (2008). Structural variation of chromosomes in autism spectrum disorder. Am. J. Hum. Genet. 82, 477-488. doi: 10.1016/j.ajhg.2007.12.009
44. McAdams, H. H., and Arkin, A. (1997). Stochastic mechanisms in gene expression. Proc. Natl. Acad. Sci. U.S.A. 94, 814-819. doi: 10.1073/pnas.94.3.814
45. McGrath, J. J., Hannan, A. J., and Gibson, G. (2011). Decanalization, brain development and risk of schizophrenia. Transl. Psychiatry 1, e14. doi: 10.1038/tp.2011.16
46. Memari, A., Ziaee, V., Mirfazeli, F., and Kordi, R. (2012). Investigation of autism comorbidities and associations in a school-based community sample. J. Child Adolesc. Psychiatr. Nurs. 25, 84-90. doi: 10.1111/j.1744-6171.2012.00325.x
47. Najmabadi, H., Hu, H., Garshasbi, M., Zemojtel, T., Abedini, S. S., Chen, W., et al. (2011). Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature 478, 57-63. doi: 10.1038/nature10423
48. Neale, B. M., Kou, Y., Liu, L., Ma'ayan, A., Samocha, K. E., Sabo, A., et al. (2012). Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 485, 242-245. doi: 10.1038/nature11011
49. Nord, A. S., Roeb, W., Dickel, D. E., Walsh, T., Kusenda, M., O'Connor, K. L., et al. (2011). Reduced transcript expression of genes affected by inherited and de novo CNVs in autism. Eur. J. Hum. Genet. 19, 727-731. doi: 10.1038/ejhg.2011.24
50. O'Roak, B. J., Vives, L., Fu, W., Egertson, J. D., Stanaway, I. B., Phelps, I. G., et al. (2012a). Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science 338, 1619-1622. doi: 10.1126/science.1227764
51. O'Roak, B. J., Vives, L., Girirajan, S., Karakoc, E., Krumm, N., Coe, B. P., et al. (2012b). Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485, 246-250. doi: 10.1038/nature10989
52. Ozonoff, S., Young, G. S., Carter, A., Messinger, D., Yirmiya, N., Zwaigenbaum, L., et al. (2011). Recurrence risk for autism spectrum disorders: a baby siblings research consortium study. Pediatrics 128, e488-495. doi: 10.1542/peds.2010-2825
53. Petrij, F., Giles, R. H., Dauwerse, H. G., Saris, J. J., Hennekam, R. C., Masuno, M., et al. (1995). Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP. Nature 376, 348-351. doi: 10.1038/376348a0
54. Pinto, D., Pagnamenta, A. T., Klei, L., Anney, R., Merico, D., Regan, R., et al. (2010). Functional impact of global rare copy number variation in autism spectrum disorders. Nature 466, 368-372. doi: 10.1038/nature09146
55. Queitsch, C., Carlson, K. D., and Girirajan, S. (2012). Lessons from model organisms: phenotypic robustness and missing heritability in complex disease. PLoS Genet. 8:e1003041. doi: 10.1371/journal.pgen.1003041
56. Raj, A., Rifkin, S. A., Andersen, E., and Van Oudenaarden, A. (2010). Variability in gene expression underlies incomplete penetrance. Nature 463, 913-918. doi: 10.1038/nature08781
57. Raychaudhuri, S., Korn, J. M., McCarroll, S. A., Altshuler, D., Sklar, P., Purcell, S., et al. (2010). Accurately assessing the risk of schizophrenia conferred by rare copy-number variation affecting genes with brain function. PLoS Genet. 6:e1001097. doi: 10.1371/journal.pgen.1001097
58. Risch, N., and Merikangas, K. (1996). The future of genetic studies of complex human diseases. Science 273, 1516-1517. doi: 10.1126/science.273.5281.1516
59. Risch, N., Spiker, D., Lotspeich, L., Nouri, N., Hinds, D., Hallmayer, J., et al. (1999). A genomic screen of autism: evidence for a multilocus etiology. Am. J. Hum. Genet. 65, 493-507. doi: 10.1086/302497
60. Robinson, E. B., Lichtenstein, P., Anckarsater, H., Happe, F., and Ronald, A. (2013). Examining and interpreting the female protective effect against autistic behavior. Proc. Natl. Acad. Sci. U.S.A. 110, 5258-5262. doi: 10.1073/pnas.1211070110
61. Rutherford, S. L., and Lindquist, S. (1998). Hsp90 as a capacitor for morphological evolution. Nature 396, 336-342. doi: 10.1038/24550
62. Rutter, M., Caspi, A., and Moffitt, T. E. (2003). Using sex differences in psychopathology to study causal mechanisms: unifying issues and research strategies. J. Child Psychol. Psychiatry 44, 1092-1115. doi: 10.1111/1469-7610.00194
63. Sakai, Y., Shaw, C. A., Dawson, B. C., Dugas, D. V., Al-Mohtaseb, Z., Hill, D. E., et al. (2011). Protein interactome reveals converging molecular pathways among autism disorders. Sci. Transl. Med. 3, 86-86. doi: 10.1126/scitranslmed.3002166
64. Sanders, S. J., Ercan-Sencicek, A. G., Hus, V., Luo, R., Murtha, M. T., Moreno-De-Luca, D., et al. (2011). Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron 70, 863-885. doi: 10.1016/j.neuron.2011.05.002
65. Sanders, S. J., Murtha, M. T., Gupta, A. R., Murdoch, J. D., Raubeson, M. J., Willsey, A. J., et al. (2012). De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485, 237-241. doi: 10.1038/nature10945
66. Schaaf, C. P., Sabo, A., Sakai, Y., Crosby, J., Muzny, D., Hawes, A., et al. (2011). Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders. Hum. Mol. Genet. 20, 3366-3375. doi: 10.1093/hmg/ddr243
67. Sebat, J., Lakshmi, B., Malhotra, D., Troge, J., Lese-Martin, C., Walsh, T., et al. (2007). Strong association of de novo copy number mutations with autism. Science 316, 445-449. doi: 10.1126/science.1138659
68. Shaywitz, S. E., Shaywitz, B. A., Fletcher, J. M., and Escobar, M. D. (1990). Prevalence of reading disability in boys and girls. Results of the connecticut longitudinal study. JAMA 264, 998-1002. doi: 10.1001/jama.1990.03450080084036
69. Shen, Y., Dies, K. A., Holm, I. A., Bridgemohan, C., Sobeih, M. M., Caronna, E. B., et al. (2010). Clinical genetic testing for patients with autism spectrum disorders. Pediatrics 125, e727-e735. doi: 10.1542/peds.2009-1684
70. Simon, V., Czobor, P., Balint, S., Meszaros, A., and Bitter, I. (2009). Prevalence and correlates of adult attention-deficit hyperactivity disorder: meta-analysis. Br. J. Psychiatry 194, 204-211. doi: 10.1192/bjp.bp.107.048827
71. Simonoff, E., Pickles, A., Charman, T., Chandler, S., Loucas, T., and Baird, G. (2008). Psychiatric disorders in children with autism spectrum disorders: prevalence, comorbidity, and associated factors in a population-derived sample. J. Am. Acad. Child Adolesc. Psychiatry 47, 921-929. doi: 10.1097/CHI.0b013e318179964f
72. Skuse, D. H. (2000). Imprinting, the X-chromosome, and the male brain: explaining sex differences in the liability to autism. Pediatr. Res. 47, 9-16. doi: 10.1203/00006450-200001000-00006
73. Specchia, V., Piacentini, L., Tritto, P., Fanti, L., D'alessandro, R., Palumbo, G., et al. (2010). Hsp90 prevents phenotypic variation by suppressing the mutagenic activity of transposons. Nature 463, 662-665. doi: 10.1038/nature08739
74. Spencer, C. M., Alekseyenko, O., Hamilton, S. M., Thomas, A. M., Serysheva, E., Yuva-Paylor, L. A., et al. (2011). Modifying behavioral phenotypes in Fmr1KO mice: genetic background differences reveal autistic-like responses. Autism Res. 4, 40-56. doi: 10.1002/aur.168
75. Splawski, I., Timothy, K. W., Sharpe, L. M., Decher, N., Kumar, P., Bloise, R., et al. (2004). Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell 119, 19-31. doi: 10.1016/j.cell.2004.09.011
76. Stefansson, H., Meyer-Lindenberg, A., Steinberg, S., Magnusdottir, B., Morgen, K., Arnarsdottir, S., et al. (2014). CNVs conferring risk of autism or schizophrenia affect cognition in controls. Nature 505, 361-366. doi: 10.1038/nature12818
77. Stoll, G., Pietilainen, O. P., Linder, B., Suvisaari, J., Brosi, C., Hennah, W., et al. (2013). Deletion of TOP3beta, a component of FMRP-containing mRNPs, contributes to neurodevelopmental disorders. Nat. Neurosci. 16, 1228-1237. doi: 10.1038/nn.3484
78. Talkowski, M. E., Mullegama, S. V., Rosenfeld, J. A., Van Bon, B. W., Shen, Y., Repnikova, E. A., et al. (2011). Assessment of 2q23.1 microdeletion syndrome implicates MBD5 as a single causal locus of intellectual disability, epilepsy, and autism spectrum disorder. Am. J. Hum. Genet. 89, 551-563. doi: 10.1016/j.ajhg.2011.09.011
79. Talkowski, M. E., Rosenfeld, J. A., Blumenthal, I., Pillalamarri, V., Chiang, C., Heilbut, A., et al. (2012). Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries. Cell 149, 525-537. doi: 10.1016/j.cell.2012.03.028
80. Tirosh, I., Reikhav, S., Sigal, N., Assia, Y., and Barkai, N. (2010). Chromatin regulators as capacitors of interspecies variations in gene expression. Mol. Syst. Biol. 6, 435. doi: 10.1038/msb.2010.84
81. Tokuriki, N., and Tawfik, D. S. (2009). Chaperonin overexpression promotes genetic variation and enzyme evolution. Nature 459, 668-673. doi: 10.1038/nature08009
82. Van Bon, B. W., Koolen, D. A., Brueton, L., McMullan, D., Lichtenbelt, K. D., Ades, L. C., et al. (2010). The 2q23.1 microdeletion syndrome: clinical and behavioural phenotype. Eur. J. Hum. Genet. 18, 163-170. doi: 10.1038/ejhg.2009.152
83. Vissers, L. E., Van Ravenswaaij, C. M., Admiraal, R., Hurst, J. A., De Vries, B. B., Janssen, I. M., et al. (2004). Mutations in a new member of the chromodomain gene family cause CHARGE syndrome. Nat. Genet. 36, 955-957. doi: 10.1038/ng1407
84. Voineagu, I., Wang, X., Johnston, P., Lowe, J. K., Tian, Y., Horvath, S., et al. (2011). Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature 474, 380-384. doi: 10.1038/nature10110
85. Wagenstaller, J., Spranger, S., Lorenz-Depiereux, B., Kazmierczak, B., Nathrath, M., Wahl, D., et al. (2007). Copy-number variations measured by single-nucleotide-polymorphism oligonucleotide arrays in patients with mental retardation. Am. J. Hum. Genet. 81, 768-779. doi: 10.1086/521274
86. Wang, K., Zhang, H., Ma, D., Bucan, M., Glessner, J. T., Abrahams, B. S., et al. (2009). Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature 459, 528-533. doi: 10.1038/nature07999
87. Weiss, L. A., Arking, D. E., Daly, M. J., and Chakravarti, A. (2009). A genome-wide linkage and association scan reveals novel loci for autism. Nature 461, 802-808. doi: 10.1038/nature08490
88. Werling, D. M., and Geschwind, D. H. (2013). Sex differences in autism spectrum disorders. Curr. Opin. Neurol. 26, 146-153. doi: 10.1097/WCO.0b013e32835ee548
89. Williams, S. R., Aldred, M. A., Der Kaloustian, V. M., Halal, F., Gowans, G., McLeod, D. R., et al. (2010a). Haploinsufficiency of HDAC4 causes brachydactyly mental retardation syndrome, with brachydactyly type E, developmental delays, and behavioral problems. Am. J. Hum. Genet. 87, 219-228. doi: 10.1016/j.ajhg.2010.07.011
90. Williams, S. R., Mullegama, S. V., Rosenfeld, J. A., Dagli, A. I., Hatchwell, E., Allen, W. P., et al. (2010b). Haploinsufficiency of MBD5 associated with a syndrome involving microcephaly, intellectual disabilities, severe speech impairment, and seizures. Eur. J. Hum. Genet. 18, 436-441. doi: 10.1038/ejhg.2009.199
91. Wing, L. (1981). Sex ratios in early childhood autism and related conditions. Psychiatry Res. 5, 129-137. doi: 10.1016/0165-1781(81)90043-3
92. Woolf, C. M. (1997). Does the genotype for schizophrenia often remain unexpressed because of canalization and stochastic events during development? Psychol. Med. 27, 659-668.
93. Xu, D., Shen, W., Guo, R., Xue, Y., Peng, W., Sima, J., et al. (2013). Top3beta is an RNA topoisomerase that works with fragile X syndrome protein to promote synapse formation. Nat. Neurosci. 16, 1238-1247. doi: 10.1038/nn.3479
94. Zaidi, S., Choi, M., Wakimoto, H., Ma, L., Jiang, J., Overton, J. D., et al. (2013). De novo mutations in histone-modifying genes in congenital heart disease. Nature 498, 220-223. doi: 10.1038/nature12141
95. Zhao, X., Leotta, A., Kustanovich, V., Lajonchere, C., Geschwind, D. H., Law, K., et al. (2007). A unified genetic theory for sporadic and inherited autism. Proc. Natl. Acad. Sci. U.S.A. 104, 12831-12836. doi: 10.1073/pnas.0705803104
96. Zoghbi, H. Y. (2003). Postnatal neurodevelopmental disorders: meeting at the synapse? Science 302, 826-830. doi: 10.1126/science.1089071