1932

Abstract

Autism is a common and complex neurologic disorder whose scientific underpinnings have begun to be established in the past decade. The essence of this breakthrough has been a focus on families, where genetic analyses are strongest, versus large-scale, case-control studies. Autism genetics has progressed in parallel with technology, from analyses of copy number variation to whole-exome sequencing (WES) and whole-genome sequencing (WGS). Gene mutations causing complete loss of function account for perhaps one-third of cases, largely detected through WES. This limitation has increased interest in understanding the regulatory variants of genes that contribute in more subtle ways to the disorder. Strategies combining biochemical analysis of gene regulation, WGS analysis of the noncoding genome, and machine learning have begun to succeed. The emerging picture is that careful control of the amounts of transcription, mRNA, and proteins made by key brain genes—stoichiometry—plays a critical role in defining the clinical features of autism.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-neuro-100119-024851
2020-07-08
2024-12-14
Loading full text...

Full text loading...

/deliver/fulltext/neuro/43/1/annurev-neuro-100119-024851.html?itemId=/content/journals/10.1146/annurev-neuro-100119-024851&mimeType=html&fmt=ahah

Literature Cited

  1. Abraham WC, Williams JM. 2003. Properties and mechanisms of LTP maintenance. Neuroscientist 9:6463–74
    [Google Scholar]
  2. Akins MR, Berk-Rauch HE, Kwan KY, Mitchell ME, Shepard KA et al. 2017. Axonal ribosomes and mRNAs associate with fragile X granules in adult rodent and human brains. Hum. Mol. Genet. 26:1192–209
    [Google Scholar]
  3. Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY 1999. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat. Genet. 23:2185–88
    [Google Scholar]
  4. An J-Y, Lin K, Zhu L, Werling DM, Dong S et al. 2018. Genome-wide de novo risk score implicates promoter variation in autism spectrum disorder. Science 362:6420eaat6576
    [Google Scholar]
  5. Autism Spectr. Disord. Work. Group Psychiatr. Genom. Consort 2017. Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia. Mol. Autism 8:21
    [Google Scholar]
  6. Bai D, Yip BHK, Windham GC, Sourander A, Francis R et al. 2019. Association of genetic and environmental factors with autism in a 5-country cohort. JAMA Psychiatry 76:101035–43
    [Google Scholar]
  7. Baker P, Piven J, Schwartz S, Patil S 1994. Brief report: duplication of chromosome 15q11-13 in two individuals with autistic disorder. J. Autism Dev. Disord. 24:4529–35
    [Google Scholar]
  8. Bassell GJ, Warren ST. 2008. Fragile X syndrome: loss of local mRNA regulation alters synaptic development and function. Neuron 60:2201–14
    [Google Scholar]
  9. Bean Jaworski JL, Flynn T, Burnham N, Chittams JL et al. 2017. Rates of autism and potential risk factors in children with congenital heart defects. Congenit. Heart Dis. 12:4421–29
    [Google Scholar]
  10. Bear MF, Huber KM, Warren ST 2004. The mGluR theory of fragile X mental retardation. Trends Neurosci 27:7370–77
    [Google Scholar]
  11. Bhalla K, Phillips HA, Crawford J, McKenzie OK et al. 2004. The de novo chromosome 16 translocations of two patients with abnormal phenotypes (mental retardation and epilepsy) disrupt the A2BP1 gene. J. Hum. Genet. 49:308–311
    [Google Scholar]
  12. Buckanovich RJ, Posner JB, Darnell RB 1993. Nova, the paraneoplastic Ri antigen, is homologous to an RNA-binding protein and is specifically expressed in the developing motor system. Neuron 11:4657–72
    [Google Scholar]
  13. Bundey S, Hardy C, Vickers S, Kilpatrick MW, Corbett JA 1994. Duplication of the 15q11-13 region in a patient with autism, epilepsy and ataxia. Dev. Med. Child Neurol. 36:8736–42
    [Google Scholar]
  14. Carmona-Mora P, Walz K. 2010. Retinoic acid induced 1, RAI1: a dosage sensitive gene related to neurobehavioral alterations including autistic behavior. Curr. Genom. 11:8607–17
    [Google Scholar]
  15. Ceman S, O'Donnell WT, Reed M, Patton S, Pohl J, Warren ST 2003. Phosphorylation influences the translation state of FMRP-associated polyribosomes. Hum. Mol. Genet. 12:243295–305
    [Google Scholar]
  16. [Google Scholar]
  17. Christie SB, Akins MR, Schwob JE, Fallon JR 2009. The FXG: a presynaptic fragile X granule expressed in a subset of developing brain circuits. J. Neurosci. 29:51514–24
    [Google Scholar]
  18. Cirulli ET, Lasseigne BN, Petrovski S, Sapp PC, Dio PA et al. 2015. Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. Science 347:62291436–41
    [Google Scholar]
  19. Conrad B, Antonarakis SE. 2007. Gene duplication: a drive for phenotypic diversity and cause of human disease. Annu. Rev. Genom. Hum. Genet. 8:17–35
    [Google Scholar]
  20. Cook EH Jr., Courchesne RY, Cox NJ, Lord C, Gonen D et al. 1998. Linkage-disequilibrium mapping of autistic disorder, with 15q11-13 markers. Am. J. Hum. Genet. 62:51077–83
    [Google Scholar]
  21. Cummings BB, Marshall JL, Tukiainen T et al. 2017. Improving genetic diagnosis in Mendelian disease with transcriptome sequencing. Sci. Transl. Med. 9:386eaaI5209
    [Google Scholar]
  22. Darnell JC, Fraser CE, Mostovetsky O, Stefani G, Jones TA et al. 2005. Kissing complex RNAs mediate interaction between the fragile-X mental retardation protein KH2 domain and brain polyribosomes. Genes Dev 19:8903–18
    [Google Scholar]
  23. Darnell JC, Jensen KB, Jin P, Brown V, Warren ST, Darnell RB 2001. Fragile X mental retardation protein targets G quartet mRNAs important for neuronal function. Cell 107:4489–99
    [Google Scholar]
  24. Darnell JC, Van Driesche SJ, Zhang C, Hung KYS, Mele A et al. 2011. FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell 146:2247–61
    [Google Scholar]
  25. Darnell RB. 2013. RNA protein interactions in neurons. Annu. Rev. Neurosci. 36:243–70
    [Google Scholar]
  26. Das Sharma S, Metz JB, Li H, Hobson BD, Hornstein N et al. 2019. Widespread alterations in translation elongation in the brain of juvenile Fmr1 knockout mice. Cell Rep 26:123313–22.e5
    [Google Scholar]
  27. De Rubeis S, He X, Goldberg AP, Poultney CS, Samocha K et al. 2014. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature 515:7526209–15
    [Google Scholar]
  28. Dhindsa RS, Goldstein DB. 2015. Genetic discoveries drive molecular analyses and targeted therapeutic options in the epilepsies. Curr. Neurol. Neurosci. Rep. 15:1070
    [Google Scholar]
  29. Ding D, Chen Z, Li K, Long Z, Ye W et al. 2016. Identification of a de novo DYNC1H1 mutation via WES according to published guidelines. Sci. Rep. 6:20423
    [Google Scholar]
  30. Dredge BK, Darnell RB. 2003. Nova regulates GABAA receptor γ2 alternative splicing via a distal downstream UCAU-rich intronic splicing enhancer. Mol. Cell. Biol. 23:134687–700
    [Google Scholar]
  31. Dredge BK, Polydorides AD, Darnell RB 2001. The splice of life: alternative splicing and neurological disease. Nat. Rev. Neurosci. 2:143–50
    [Google Scholar]
  32. Dredge BK, Stefani G, Engelhard CC, Darnell RB 2005. Nova autoregulation reveals dual functions in neuronal splicing. EMBO J 24:81608–20
    [Google Scholar]
  33. Durand CM, Betancur C, Boeckers TM, Bockmann J, Chaste P et al. 2007. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat. Genet. 39:125–27
    [Google Scholar]
  34. El Fatimy R, Tremblay S, Dury AY, Solomon S, De Koninck P et al. 2012. Fragile X mental retardation protein interacts with the RNA-binding protein Caprin1 in neuronal RiboNucleoProtein complexes. PLOS ONE 7:6e39338 Correction. 2012. PLOS ONE 7(9). https://doi.org/10.1371/annotation/05374d07-34cf-483f-80f4-ec87374cbeb6
    [Crossref] [Google Scholar]
  35. Eom T, Zhang C, Wang H, Lay K, Fak J et al. 2013. NOVA-dependent regulation of cryptic NMD exons controls synaptic protein levels after seizure. eLife 2:e00178
    [Google Scholar]
  36. Fang H, Bergmann EA, Arora K, Vacic V, Zody MC et al. 2016. Indel variant analysis of short-read sequencing data with Scalpel. Nat. Protoc. 11:122529–48
    [Google Scholar]
  37. Fang P, Lev-Lehman E, Tsai TF, Matsuura T, Benton CS et al. 1999. The spectrum of mutations in UBE3A causing Angelman syndrome. Hum. Mol. Genet. 8:1129–35
    [Google Scholar]
  38. Fogel BL, Wexler E, Wahnich A, Friedrich T, Vijayendran C et al. 2012. RBFOX1 regulates both splicing and transcriptional networks in human neuronal development. Hum. Mol. Genet. 21:194171–86
    [Google Scholar]
  39. Fromer M, Pocklington AJ, Kavanagh DH, Williams HJ, Dwyer S et al. 2014. De novo mutations in schizophrenia implicate synaptic networks. Nature 506:7487179–84
    [Google Scholar]
  40. Gambin T, Yuan B, Bi W, Liu P, Rosenfeld JA et al. 2017. Identification of novel candidate disease genes from de novo exonic copy number variants. Genome Med 9:183
    [Google Scholar]
  41. Gandal MJ, Zhang P, Hadjimichael E, Walker RL, Chen C et al. 2018. Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder. Science 362:6420eaat8127
    [Google Scholar]
  42. Glock C, Heumüller M, Schuman EM 2017. mRNA transport & local translation in neurons. Curr. Opin. Neurobiol. 45:169–77
    [Google Scholar]
  43. Gonatopoulos-Pournatzis T, Niibori R, Salter EW, Weatheritt RJ, Tsang B et al. 2020. Autism-misregulated eIF4G microexons control synaptic translation and higher order cognitive functions. Mol. Cell 77:1176–92
    [Google Scholar]
  44. Grove J, Ripke S, Als TD, Mattheisen M, Walters RK et al. 2019. Identification of common genetic risk variants for autism spectrum disorder. Nat. Genet. 51:3431–44
    [Google Scholar]
  45. Hafner A-S, Donlin-Asp PG, Leitch B, Herzog E, Schuman EM 2019. Local protein synthesis is a ubiquitous feature of neuronal pre- and postsynaptic compartments. Science 364:6441eaau3644
    [Google Scholar]
  46. Hall JM, Lee MK, Newman B, Morrow JE, Anderson LA et al. 1990. Linkage of early-onset familial breast cancer to chromosome 17q21. Science 250:49881684–89
    [Google Scholar]
  47. Hermann BP, Sager MA, Koscik RL, Young K, Nakamura K 2017. Vascular, inflammatory, and metabolic factors associated with cognition in aging persons with chronic epilepsy. Epilepsia 58:11e152–56
    [Google Scholar]
  48. Hippolyte L, Maillard AM, Rodriguez-Herreros B, Pain A, Martin-Brevet S et al. 2016. The number of genomic copies at the 16p11.2 locus modulates language, verbal memory, and inhibition. Biol. Psychiatry 80:2129–39
    [Google Scholar]
  49. Hodges E, Xuan Z, Balija V, Kramer M, Molla MN et al. 2007. Genome-wide in situ exon capture for selective resequencing. Nat. Genet. 39:121522–27
    [Google Scholar]
  50. Huber KM, Gallagher SM, Warren ST, Bear MF 2002. Altered synaptic plasticity in a mouse model of fragile X mental retardation. PNAS 99:117746–50
    [Google Scholar]
  51. Huber KM, Kayser MS, Bear MF 2000. Role for rapid dendritic protein synthesis in hippocampal mGluR-dependent long-term depression. Science 288:54691254–57
    [Google Scholar]
  52. Iakoucheva LM, Muotri AR, Sebat J 2019. Getting to the cores of autism. Cell 178:61287–98
    [Google Scholar]
  53. Ince-Dunn G, Okano HJ, Jensen KB, Park W-Y, Zhong R et al. 2012. Neuronal Elav-like (Hu) proteins regulate RNA splicing and abundance to control glutamate levels and neuronal excitability. Neuron 75:61067–80
    [Google Scholar]
  54. Indjeian VB, Kingman GA, Jones FC, Guenther CA, Grimwood J et al. 2016. Evolving new skeletal traits by cis-regulatory changes in bone morphogenetic proteins. Cell 164:1–245–56
    [Google Scholar]
  55. Iossifov I, O'Roak BJ, Sanders SJ, Ronemus M, Krumm N et al. 2014. The contribution of de novo coding mutations to autism spectrum disorder. Nature 515:7526216–21
    [Google Scholar]
  56. Iossifov I, Ronemus M, Levy D, Wang Z, Hakker I et al. 2012. De novo gene disruptions in children on the autistic spectrum. Neuron 74:2285–99
    [Google Scholar]
  57. Irimia M, Weatheritt RJ, Ellis JD, Parikshak NN, Gonatopoulos-Pournatzis T et al. 2014. A highly conserved program of neuronal microexons is misregulated in autistic brains. Cell 159:71511–23
    [Google Scholar]
  58. Jensen KB, Dredge BK, Stefani G, Zhong R, Buckanovich RJ et al. 2000. Nova-1 regulates neuron-specific alternative splicing and is essential for neuronal viability. Neuron 25:2359–71
    [Google Scholar]
  59. Jiang YH, Ehlers MD. 2013. Modeling autism by SHANK gene mutations in mice. Neuron 78:108–27
    [Google Scholar]
  60. Kang H, Schuman EM. 1996. A requirement for local protein synthesis in neurotrophin-induced hippocampal synaptic plasticity. Science 273:52801402–6
    [Google Scholar]
  61. Kasherman MA, Premarathne S, Burne TH, Wood SA, Piper M 2020. The ubiquitin system: a regulatory hub for intellectual disability and autism spectrum disorder. Mol. Neurobiol. 57:2179–93
    [Google Scholar]
  62. Khatri N, Man H-Y. 2019. The autism and Angelman syndrome protein Ube3A/E6AP: the gene, E3 ligase ubiquitination targets and neurobiological functions. Front. Mol. Neurosci. 12:109
    [Google Scholar]
  63. Kim H-G, Kim H-T, Leach NT, Lan F, Ullmann R et al. 2012. Translocations disrupting PHF21A in the Potocki-Shaffer-syndrome region are associated with intellectual disability and craniofacial anomalies. Am. J. Hum. Genet. 91:156–72
    [Google Scholar]
  64. Kim TH, Tsang B, Vernon RM, Sonenberg N, Kay LE, Forman-Kay JD 2019. Phospho-dependent phase separation of FMRP and CAPRIN1 recapitulates regulation of translation and deadenylation. Science 365:825–29
    [Google Scholar]
  65. Kishino T, Lalande M, Wagstaff J 1997. UBE3A/E6-AP mutations cause Angelman syndrome. Nat. Genet. 15:170–73
    [Google Scholar]
  66. Klein RJ, Zeiss C, Chew EY, Tsai J-Y, Sackler RS et al. 2005. Complement factor H polymorphism in age-related macular degeneration. Science 308:5720385–89
    [Google Scholar]
  67. Korb E, Herre M, Zucker-Scharff I, Darnell RB, Allis CD 2015. BET protein Brd4 activates transcription in neurons and BET inhibitor Jq1 blocks memory in mice. Nat. Neurosci. 18:101464–73
    [Google Scholar]
  68. Korb E, Herre M, Zucker-Scharff I, Gresack J, Allis CD, Darnell RB 2017. Excess translation of epigenetic regulators contributes to fragile X syndrome and is alleviated by Brd4 inhibition. Cell 170:61209–23.e20
    [Google Scholar]
  69. Krishnan A, Zhang R, Yao V, Theesfeld CL, Wong AK et al. 2016. Genome-wide prediction and functional characterization of the genetic basis of autism spectrum disorder. Nat. Neurosci. 19:111454–62
    [Google Scholar]
  70. Krueger DD, Bear MF. 2011. Toward fulfilling the promise of molecular medicine in fragile X syndrome. Annu. Rev. Med. 62:411–29
    [Google Scholar]
  71. Krumm N, O'Roak BJ, Shendure J, Eichler EE 2014. A de novo convergence of autism genetics and molecular neuroscience. Trends Neurosci 37:295–105
    [Google Scholar]
  72. Laggerbauer B, Ostareck D, Keidel EM, Ostareck-Lederer A, Fischer U 2001. Evidence that fragile X mental retardation protein is a negative regulator of translation. Hum. Mol. Genet. 10:4329–38
    [Google Scholar]
  73. Lal D, Reinthaler EM, Altmüller J, Toliat MR et al. 2013a. RBFOX1 and RBFOX3 mutations in Rolandic epilepsy. PLOS ONE 8:e73323
    [Google Scholar]
  74. Lal D, Trucks H, Møller RS, Hjalgrim H et al. 2013b. Rare exonic deletions of the RBFOX1 gene increase risk of idiopathic generalized epilepsy. Epilepsia 54:265–71
    [Google Scholar]
  75. Lee BH, Smith T, Paciorkowski AR 2015. Autism spectrum disorder and epilepsy: disorders with a shared biology. Epilepsy Behav 47:191–201
    [Google Scholar]
  76. Lee C, Kang EY, Gandal MJ, Eskin E, Geschwind DH 2019. Profiling allele-specific gene expression in brains from individuals with autism spectrum disorder reveals preferential minor allele usage. Nat. Neurosci. 22:91521–32
    [Google Scholar]
  77. Lee HY, Ge W-P, Huang W, He Y, Wang GX et al. 2011. Bidirectional regulation of dendritic voltage-gated potassium channels by the fragile X mental retardation protein. Neuron 72:4630–42
    [Google Scholar]
  78. Lee J-A, Damianov A, Lin C-H, Fontes M, Parikshak NN et al. 2016. Cytoplasmic Rbfox1 regulates the expression of synaptic and autism-related genes. Neuron 89:1113–28
    [Google Scholar]
  79. Licatalosi DD, Mele A, Fak JJ, Ule J, Kayikci M et al. 2008. HITS-CLIP yields genome-wide insights into brain alternative RNA processing. Nature 456:7221464–69
    [Google Scholar]
  80. Liu X, Li YI, Pritchard JK 2019. Trans effects on gene expression can drive omnigenic inheritance. Cell 177:41022–34.e6
    [Google Scholar]
  81. Malhotra D, Sebat J. 2012. CNVs: harbingers of a rare variant revolution in psychiatric genetics. Cell 148:61223–41
    [Google Scholar]
  82. Mannino EA, Miyawaki H, Santen G, Schrier Vergano SA 2018. First data from a parent-reported registry of 81 individuals with Coffin-Siris syndrome: natural history and management recommendations. Am. J. Med. Genet. A 176:112250–58
    [Google Scholar]
  83. Martin CL, Duvall JA, Ilkin Y, Simon JS, Arreaza MG et al. 2007. Cytogenetic and molecular characterization of A2BP1/FOX1 as a candidate gene for autism. Am. J. Med. Genet. B Neuropsychiatr. Genet. 144B:7869–76
    [Google Scholar]
  84. Matsuura T, Sutcliffe JS, Fang P, Galjaard RJ, Jiang YH et al. 1997. De novo truncating mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome. Nat. Genet. 15:174–77
    [Google Scholar]
  85. Matthews AM, Tarailo-Graovac M, Price EM, Blydt-Hansen I, Ghani A et al. 2017. A de novo mosaic mutation in SPAST with two novel alternative alleles and chromosomal copy number variant in a boy with spastic paraplegia and autism spectrum disorder. Eur. J. Med. Genet. 60:10548–52
    [Google Scholar]
  86. McLean CY, Reno PL, Pollen AA, Bassan AI, Capellini TD et al. 2011. Human-specific loss of regulatory DNA and the evolution of human-specific traits. Nature 471:7337216–19
    [Google Scholar]
  87. Mei Y, Monteiro P, Zhou Y, Kim J-A, Gao X et al. 2016. Adult restoration of Shank3 expression rescues selective autistic-like phenotypes. Nature 530:7591481–84
    [Google Scholar]
  88. Miceli F, Soldovieri MV, Joshi N, Weckhuysen S, Cooper EC, Taglialatela M 2014. KCNQ3-related disorders. GeneReviews MP Adam, HH Ardinger, RA Pagon, SE Wallace, LJH Bean et al. Seattle, WA: Univ. Washington
    [Google Scholar]
  89. Miska NJ, Richter LM, Cary BA, Gjorgjieva J, Turrigiano GG 2018. Sensory experience inversely regulates feedforward and feedback excitation-inhibition ratio in rodent visual cortex. eLife 7:e38846
    [Google Scholar]
  90. Monteiro P, Feng G. 2017. SHANK proteins: roles at the synapse and in autism spectrum disorder. Nat. Rev. Neurosci. 18:3147–57
    [Google Scholar]
  91. Moretti P, Zoghbi HY. 2006. MeCP2 dysfunction in Rett syndrome and related disorders. Curr. Opin. Genet. Dev. 16:3276–81
    [Google Scholar]
  92. Muddashetty RS, Nalavadi VC, Gross C, Yao X, Xing L et al. 2011. Reversible inhibition of PSD-95 mRNA translation by miR-125a, FMRP phosphorylation, and mGluR signaling. Mol. Cell 42:5673–88
    [Google Scholar]
  93. Musunuru K, Darnell RB. 2001. Paraneoplastic neurologic disease antigens: RNA-binding proteins and signaling proteins in neuronal degeneration. Annu. Rev. Neurosci. 24:239–62
    [Google Scholar]
  94. Myers RA, Casals F, Gauthier J, Hamdan FF, Keebler J et al. 2011. A population genetic approach to mapping neurological disorder genes using deep resequencing. PLOS Genet 7:2e1001318
    [Google Scholar]
  95. Myrick LK, Nakamoto-Kinoshita M, Lindor NM, Kirmani S, Cheng X, Warren ST 2014. Fragile X syndrome due to a missense mutation. Eur. J. Hum. Genet. 22:101185–89
    [Google Scholar]
  96. Niu M, Han Y, Dy ABC, Du J, Jin H et al. 2017. Autism symptoms in fragile X syndrome. J. Child Neurol. 32:10903–9
    [Google Scholar]
  97. Novarino G, El-Fishawy P, Kayserili H, Meguid NA, Scott EM et al. 2012. Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy. Science 338:6105394–97
    [Google Scholar]
  98. O'Roak BJ, Vives L, Girirajan S, Karakoc E, Krumm N et al. 2012. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485:7397246–50
    [Google Scholar]
  99. Ostroff LE, Fiala JC, Allwardt B, Harris KM 2002. Polyribosomes redistribute from dendritic shafts into spines with enlarged synapses during LTP in developing rat hippocampal slices. Neuron 35:3535–45
    [Google Scholar]
  100. Packer A. 2016. Neocortical neurogenesis and the etiology of autism spectrum disorder. Neurosci. Biobehav. Rev. 64:185–95
    [Google Scholar]
  101. Pardiñas AF, Holmans P, Pocklington AJ, Escott-Price V, Ripke S et al. 2018. Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection. Nat. Genet. 50:3381–89
    [Google Scholar]
  102. Parras A, Anta H, Santos-Galindo M, Swarup V, Elorza A et al. 2018. Autism-like phenotype and risk gene mRNA deadenylation by CPEB4 mis-splicing. Nature 560:7719441–46
    [Google Scholar]
  103. Petrovski S, Wang Q, Heinzen EL, Allen AS, Goldstein DB 2013. Genic intolerance to functional variation and the interpretation of personal genomes. PLOS Genet 9:8e1003709
    [Google Scholar]
  104. Phan AT, Kuryavyi V, Darnell JC, Serganov A, Majumdar A et al. 2011. Structure-function studies of FMRP RGG peptide recognition of an RNA duplex-quadruplex junction. Nat. Struct. Mol. Biol. 18:7796–804
    [Google Scholar]
  105. Pizzo L, Jensen M, Polyak A, Rosenfeld JA, Mannik K et al. 2019. Rare variants in the genetic background modulate cognitive and developmental phenotypes in individuals carrying disease-associated variants. Genet. Med. 21:4816–25
    [Google Scholar]
  106. Porter RS, Murata-Nakamura Y, Nagasu H, Kim H-G, Iwase S 2018. Transcriptome analysis revealed impaired cAMP responsiveness in PHF21A-deficient human cells. Neuroscience 370:170–80
    [Google Scholar]
  107. Potocki L, Chen KS, Park SS, Osterholm DE, Withers MA et al. 2000. Molecular mechanism for duplication 17p11.2—the homologous recombination reciprocal of the Smith-Magenis microdeletion. Nat. Genet. 24:184–87
    [Google Scholar]
  108. Quesnel-Vallières T, Weatheritt RJ, Cordes SP, Blencowe BJ 2019. Autism spectrum disorder: insights into convergent mechanisms from transcriptomics. Nat. Rev. Genet. 20:151–63
    [Google Scholar]
  109. Ramaswami G, Geschwind DH. 2018. Genetics of autism spectrum disorder. Handb. Clin. Neurol. 147:321–29
    [Google Scholar]
  110. Rosenfeld JA, Coppinger J, Bejjani BA, Girirajan S, Eichler EE et al. 2010. Speech delays and behavioral problems are the predominant features in individuals with developmental delays and 16p11.2 microdeletions and microduplications. J. Neurodev. Disord. 2:126–38
    [Google Scholar]
  111. Rubenstein JL, Merzenich MM. 2003. Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes Brain Behav 2:5255–67
    [Google Scholar]
  112. Ruzzo EK, Pérez-Cano L, Jung J-Y, Wang L-K, Kashef-Haghighi D et al. 2019. Inherited and de novo genetic risk for autism impacts shared networks. Cell 178:4850–66.e26
    [Google Scholar]
  113. Saito Y, Yuan Y, Zucker-Scharff I, Fak JJ, Jereb S et al. 2019. Differential NOVA2-mediated splicing in excitatory and inhibitory neurons regulates cortical development and cerebellar function. Neuron 101:4707–20.e5
    [Google Scholar]
  114. Sanders SJ, He X, Willsey AJ, Ercan-Sencicek AG, Samocha KE et al. 2015. Insights into autism spectrum disorder genomic architecture and biology from 71 risk loci. Neuron 87:61215–33
    [Google Scholar]
  115. Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ et al. 2012. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485:7397237–41
    [Google Scholar]
  116. Sands TT, Miceli F, Lesca G, Beck AE, Sadleir LG et al. 2019. Autism and developmental disability caused by KCNQ3 gain-of-function variants. Ann. Neurol. 86:2181–92
    [Google Scholar]
  117. Santen GWE, Aten E, Sun Y, Almomani R, Gilissen C et al. 2012. Mutations in SWI/SNF chromatin remodeling complex gene ARID1B cause Coffin-Siris syndrome. Nat. Genet. 44:4379–80
    [Google Scholar]
  118. Santoro MR, Bray SM, Warren ST 2012. Molecular mechanisms of fragile X syndrome: a twenty-year perspective. Annu. Rev. Pathol. 7:219–45
    [Google Scholar]
  119. Satterstrom FK, Kosmicki JA, Wang J, Breen MS, De Rubeis S et al. 2020. Large-scale exome sequencing study implicates both developmental and functional changes in the neurobiology of autism. Cell 180:568–84.e23
    [Google Scholar]
  120. Scheckel C, Darnell RB. 2015. Microexons–tiny but mighty. EMBO J 34:3273–74
    [Google Scholar]
  121. Schinzel AA, Brecevic L, Bernasconi F, Binkert F, Berthet F et al. 1994. Intrachromosomal triplication of 15q11-q13. J. Med. Genet. 31:10798–803
    [Google Scholar]
  122. Sebat J, Lakshmi B, Malhotra D, Troge J, Lese-Martin C et al. 2007. Strong association of de novo copy number mutations with autism. Science 316:5823445–49
    [Google Scholar]
  123. Shcheglovitov A, Shcheglovitova O, Yazawa M, Portmann T, Shu R et al. 2013. SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients. Nature 503:7475267–71
    [Google Scholar]
  124. Sheng M, Hoogenraad CC. 2007. The postsynaptic architecture of excitatory synapses: a more quantitative view. Annu. Rev. Biochem. 76:823–47
    [Google Scholar]
  125. Speed HE, Kouser M, Xuan Z, Liu S, Duong A, Powell CM 2019. Apparent genetic rescue of adult Shank3 exon 21 insertion mutation mice tempered by appropriate control experiments. eNeuro 6:5 ENEURO.0317-19.2019
    [Google Scholar]
  126. Speed HE, Kouser M, Xuan Z, Reimers JM, Ochoa CF et al. 2015. Autism-associated insertion mutation (InsG) of Shank3 exon 21 causes impaired synaptic transmission and behavioral deficits. J. Neurosci. 35:269648–65
    [Google Scholar]
  127. Sragovich S, Ziv Y, Vaisvaser S, Shomron N, Hendler T, Gozes I 2019. The autism-mutated ADNP plays a key role in stress response. Transl. Psychiatry 9:1235
    [Google Scholar]
  128. Stefani G, Fraser CE, Darnell JC, Darnell RB 2004. Fragile X mental retardation protein is associated with translating polyribosomes in neuronal cells. J. Neurosci. 24:337272–76
    [Google Scholar]
  129. Sutcliffe JS, Jiang YH, Galijaard RJ, Matsuura T, Fang P et al. 1997. The E6-Ap ubiquitin-protein ligase (UBE3A) gene is localized within a narrowed Angelman syndrome critical region. Genome Res 7:4368–77
    [Google Scholar]
  130. Tatavarty V, Torrado Pacheco A, Lin H, Miska NJ, Hengen KB et al. 2018. Autism-associated Shank3 is essential for homeostatic plasticity and neuronal circuit stability. bioRxiv 365445. https://doi.org/10.1101/365445
    [Crossref]
  131. Tick B, Bolton P, Happé F, Rutter M, Rijsdijk F 2016. Heritability of autism spectrum disorders: a meta-analysis of twin studies. J. Child Psychol. Psychiatry 57:5585–95
    [Google Scholar]
  132. Turner TN, Coe BP, Dickel DE, Hoekzema K, Nelson BJ et al. 2017. Genomic patterns of de novo mutation in simplex autism. Cell 171:3710–22.e12
    [Google Scholar]
  133. Turrigiano GG, Leslie KR, Desai NS, Rutherford LC, Nelson SB 1998. Activity-dependent scaling of quantal amplitude in neocortical neurons. Nature 391:6670892–96
    [Google Scholar]
  134. Turrigiano GG, Nelson SB. 2004. Homeostatic plasticity in the developing nervous system. Nat. Rev. Neurosci. 5:297–107
    [Google Scholar]
  135. Tushev G, Glock C, Heumüller M, Biever A, Jovanovic M, Schuman EM 2018. Alternative 3′ UTRs modify the localization, regulatory potential, stability, and plasticity of mRNAs in neuronal compartments. Neuron 98:3495–511.e6
    [Google Scholar]
  136. Udagawa T, Farny NG, Jakovcevski M, Kaphzan H, Alarcon JM et al. 2013. Genetic and acute CPEB1 depletion ameliorate fragile X pathophysiology. Nat. Med. 19:111473–77
    [Google Scholar]
  137. Ule J, Hwang H-W, Darnell RB 2018. The future of Cross-Linking and Immunoprecipitation (CLIP). Cold Spring Harb. Perspect. Biol. 10:8a032243
    [Google Scholar]
  138. Ule J, Jensen KB, Ruggiu M, Mele A, Ule A, Darnell RB 2003. CLIP identifies Nova-regulated RNA networks in the brain. Science 302:56481212–15
    [Google Scholar]
  139. Ule J, Stefani G, Mele A, Ruggiu M, Wang X et al. 2006. An RNA map predicting Nova-dependent splicing regulation. Nature 444:7119580–86
    [Google Scholar]
  140. Ule J, Ule A, Spencer J, Williams A, Hu J-S et al. 2005. Nova regulates brain-specific splicing to shape the synapse. Nat. Genet. 37:8844–52
    [Google Scholar]
  141. Van Driesche SJ, Sawicka K, Zhang C, Hung SKY, Park CY et al. 2019. FMRP binding to a ranked subset of long genes is revealed by coupled CLIP and TRAP in specific neuronal cell types. bioRxiv 762500. https://doi.org/10.1101/762500
    [Crossref]
  142. Van Esch H, Bauters M, Ignatius J, Jansen M, Raynaud M et al. 2005. Duplication of the MECP2 region is a frequent cause of severe mental retardation and progressive neurological symptoms in males. Am. J. Hum. Genet. 77:3442–53
    [Google Scholar]
  143. Vasilyev N, Polonskaia A, Darnell JC, Darnell RB, Patel DJ, Serganov A 2015. Crystal structure reveals specific recognition of a G-quadruplex RNA by a β-turn in the RGG motif of FMRP. PNAS 112:39E5391–400
    [Google Scholar]
  144. Voineagu I, Wang X, Johnston P, Lowe JK, Tian Y et al. 2011. Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature 474:7351380–84
    [Google Scholar]
  145. Wagnon JL, Briese M, Sun W, Mahaffey CL, Curk T et al. 2012. CELF4 regulates translation and local abundance of a vast set of mRNAs, including genes associated with regulation of synaptic function. PLOS Genet 8:11e1003067
    [Google Scholar]
  146. Walsh CA, Morrow EM, Rubenstein JL 2008. Autism and brain development. Cell 135:396–400
    [Google Scholar]
  147. Weiss LA, Arking DE, Daly MJ, Chakravarti A. 2009. A genome-wide linkage and association scan reveals novel loci for autism. Nature 461:7265802–8
    [Google Scholar]
  148. Werling DM, Brand H, An J-Y, Stone MR, Zhu L et al. 2018. An analytical framework for whole-genome sequence association studies and its implications for autism spectrum disorder. Nat. Genet. 50:5727–36
    [Google Scholar]
  149. Weyn-Vanhentenryck SM, Mele A, Yan Q, Sun S, Farny N et al. 2014. HITS-CLIP and integrative modeling define the Rbfox splicing-regulatory network linked to brain development and autism. Cell Rep 6:61139–52
    [Google Scholar]
  150. Wilson HL, Wong ACC, Shaw SR, Tse W-Y, Stapleton GA et al. 2003. Molecular characterisation of the 22q13 deletion syndrome supports the role of haploinsufficiency of SHANK3/PROSAP2 in the major neurological symptoms. J. Med. Genet. 40:8575–84
    [Google Scholar]
  151. Wiśniowiecka-Kowalnik B, Nesteruk M, Peters SU, Xia Z, Cooper ML et al. 2010. Intragenic rearrangements in NRXN1 in three families with autism spectrum disorder, developmental delay, and speech delay. Am. J. Med. Genet. B Neuropsychiatr. Genet. 153B:5983–93
    [Google Scholar]
  152. Xu X, Hu Y, Xiong Y, Li Z, Wang W et al. 2016. Association of microtubule dynamics with chronic epilepsy. Mol. Neurobiol. 53:75013–24
    [Google Scholar]
  153. Yang YY, Yin GL, Darnell RB 1998. The neuronal RNA-binding protein Nova-2 is implicated as the autoantigen targeted in POMA patients with dementia. PNAS 95:2213254–59
    [Google Scholar]
  154. Yuen RKC, Merico D, Bookman M, Howe JL, Thiruvahindrapuram B et al. 2017. Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. Nat. Neurosci. 20:4602–11
    [Google Scholar]
  155. Zang JB, Nosyreva ED, Spencer CM, Volk LJ, Musunuru K et al. 2009. A mouse model of the human fragile X syndrome I304N mutation. PLOS Genet 5:12e1000758
    [Google Scholar]
  156. Zhang C, Frias MA, Mele A, Ruggiu M, Eom T et al. 2010. Integrative modeling defines the Nova splicing-regulatory network and its combinatorial controls. Science 329:5990439–43
    [Google Scholar]
  157. Zhang C, Zhang Z, Castle J, Sun S, Johnson J et al. 2008. Defining the regulatory network of the tissue-specific splicing factors Fox-1 and Fox-2. Genes Dev 22:182550–63
    [Google Scholar]
  158. Zhang J, Hou L, Klann E, Nelson DL 2009. Altered hippocampal synaptic plasticity in the FMR1 gene family knockout mouse models. J. Neurophysiol. 101:52572–80
    [Google Scholar]
  159. Zhou J, Park CY, Theesfeld CL, Wong AK, Yuan Y et al. 2019. Whole-genome deep-learning analysis identifies contribution of noncoding mutations to autism risk. Nat. Genet. 51:6973–80
    [Google Scholar]
  160. Zuk O, Schaffner SF, Samocha K, Do R, Hechter E et al. 2014. Searching for missing heritability: designing rare variant association studies. PNAS 111:4E455–64
    [Google Scholar]
  161. Zweier M, Begemann A, McWalter K, Cho MT, Abela L et al. 2019. Spatially clustering de novo variants in CYFIP2, encoding the cytoplasmic FMRP interacting protein 2, cause intellectual disability and seizures. Eur. J. Hum. Genet. 27:5747–59
    [Google Scholar]
/content/journals/10.1146/annurev-neuro-100119-024851
Loading
/content/journals/10.1146/annurev-neuro-100119-024851
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error