Advances in genetic tools and sequencing technology in the past few years have vastly expanded our understanding of the genetics of neurodevelopmental disorders. Recent high-throughput sequencing analyses of structural brain malformations, cognitive and neuropsychiatric disorders, and localized cortical dysplasias have uncovered a diverse genetic landscape beyond classic Mendelian patterns of inheritance. The underlying genetic causes of neurodevelopmental disorders implicate numerous cell biological pathways critical for normal brain development.


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Literature Cited

  1. Absoud M, Parr JR, Halliday D, Pretorius P, Zaiwalla Z, Jayawant S. 1.  2010. A novel ARX phenotype: rapid neurodegeneration with Ohtahara syndrome and a dyskinetic movement disorder. Dev. Med. Child Neurol. 52:305–7 [Google Scholar]
  2. Alkuraya FS, Cai X, Emery C, Mochida GH, Al-Dosari MS. 2.  et al. 2011. Human mutations in NDE1 cause extreme microcephaly with lissencephaly. Am. J. Hum. Genet. 88:536–47 [Google Scholar]
  3. Alvarez RM, García-Díaz L, Márquez J, Fajardo M, Rivas E. 3.  et al. 2011. Hemimegalencephaly: prenatal diagnosis and outcome. Fetal Diagn. Ther. 30:234–38 [Google Scholar]
  4. Applegarth DA, Toone JR. 4.  2001. Nonketotic hyperglycinemia (glycine encephalopathy): laboratory diagnosis. Mol. Genet. Metab. 74:139–46 [Google Scholar]
  5. Applegarth DA, Toone JR. 5.  2004. Glycine encephalopathy (nonketotic hyperglycinaemia): review and update. J. Inherit. Metab. Dis. 27:417–22 [Google Scholar]
  6. Aronica E, Becker AJ, Spreafico R. 6.  2012. Malformations of cortical development. Brain Pathol. 22:380–401 [Google Scholar]
  7. Awadalla P, Gauthier J, Myers RA, Casals F, Hamdan FF. 7.  et al. 2010. Direct measure of the de novo mutation rate in autism and schizophrenia cohorts. Am. J. Hum. Genet. 87:316–24 [Google Scholar]
  8. Azevedo FAC, Carvalho LRB, Grinberg LT, Farfel JM, Ferretti REL. 8.  et al. 2009. Equal numbers of neuronal and nonneuronal cells make the human brain an isometrically scaled-up primate brain. J. Comp. Neurol. 513:532–41 [Google Scholar]
  9. Baek ST, Gibbs EM, Gleeson JG, Mathern GW. 9.  2013. Hemimegalencephaly, a paradigm for somatic postzygotic neurodevelopmental disorders. Curr. Opin. Neurol. 26:122–27 [Google Scholar]
  10. Bahi-Buisson N, Souville I, Fourniol FJ, Toussaint A, Moores CA. 10.  et al. 2013. New insights into genotype-phenotype correlations for the doublecortin-related lissencephaly spectrum. Brain 136:223–44 [Google Scholar]
  11. Bai J, Ramos RL, Ackman JB, Thomas AM, Lee RV, LoTurco JJ. 11.  2003. RNAi reveals doublecortin is required for radial migration in rat neocortex. Nat. Neurosci. 6:1277–83 [Google Scholar]
  12. Bakircioğlu M, Carvalho OP, Khurshid M, Cox JJ, Tüysüz B. 12.  et al. 2011. The essential role of centrosomal NDE1 in human cerebral cortex neurogenesis. Am. J. Hum. Genet. 88:523–35 [Google Scholar]
  13. Beltrán-Valero de Bernabé D, Voit T, Longman C, Steinbrecher A, Straub V. 13.  et al. 2004. Mutations in the FKRP gene can cause muscle-eye-brain disease and Walker-Warburg syndrome. J. Med. Genet. 41:e61 [Google Scholar]
  14. Bienvenu T, Poirier K, Friocourt G, Bahi N, Beaumont D. 14.  et al. 2002. ARX, a novel Prd-class-homeobox gene highly expressed in the telencephalon, is mutated in X-linked mental retardation. Hum. Mol. Genet. 11:981–91 [Google Scholar]
  15. Bilgüvar K, Öztürk AK, Louvi A, Kwan KY, Choi M. 15.  et al. 2010. Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations. Nature 467:207–10 [Google Scholar]
  16. Bond J, Roberts E, Mochida GH, Hampshire DJ, Scott S. 16.  et al. 2002. ASPM is a major determinant of cerebral cortical size. Nat. Genet. 32:316–20 [Google Scholar]
  17. Bond J, Roberts E, Springell K, Lizarraga SB, Lizarraga S. 17.  et al. 2005. A centrosomal mechanism involving CDK5RAP2 and CENPJ controls brain size. Nat. Genet. 37:353–55 [Google Scholar]
  18. Bornens M. 18.  2012. The centrosome in cells and organisms. Science 335:422–26 [Google Scholar]
  19. Braverman N, Chen L, Lin P, Obie C, Steel G. 19.  et al. 2002. Mutation analysis of PEX7 in 60 probands with rhizomelic chondrodysplasia punctata and functional correlations of genotype with phenotype. Hum. Mutat. 20:284–97 [Google Scholar]
  20. Braverman N, Steel G, Obie C, Moser A, Moser H. 20.  et al. 1997. Human PEX7 encodes the peroxisomal PTS2 receptor and is responsible for rhizomelic chondrodysplasia punctata. Nat. Genet. 15:369 [Google Scholar]
  21. Brenner S. 21.  2003. Nature's gift to science (Nobel lecture). ChemBioChem 4:683–87 [Google Scholar]
  22. Breuss M, Heng JI-T, Poirier K, Tian G, Jaglin XH. 22.  et al. 2012. Mutations in the β-tubulin gene TUBB5 cause microcephaly with structural brain abnormalities. Cell Rep. 2:1554–62 [Google Scholar]
  23. Brockington M, Blake DJ, Prandini P, Brown SC, Torelli S. 23.  et al. 2001. Mutations in the fukutin-related protein gene (FKRP) cause a form of congenital muscular dystrophy with secondary laminin α2 deficiency and abnormal glycosylation of α-dystroglycan. Am. J. Hum. Genet. 69:1198–209 [Google Scholar]
  24. Brockington M, Yuva Y, Prandini P, Brown SC, Torelli S. 24.  et al. 2001. Mutations in the fukutin-related protein gene (FKRP) identify limb girdle muscular dystrophy 2I as a milder allelic variant of congenital muscular dystrophy MDC1C. Hum. Mol. Genet. 10:2851–59 [Google Scholar]
  25. Clement E, Mercuri E, Godfrey C, Smith J, Robb S. 25.  et al. 2008. Brain involvement in muscular dystrophies with defective dystroglycan glycosylation. Ann. Neurol. 64:573–82 [Google Scholar]
  26. Collins FS. 26.  1995. Positional cloning moves from perditional to traditional. Nat. Genet. 9:347–50 [Google Scholar]
  27. Cooper GM, Coe BP, Girirajan S, Rosenfeld JA, Vu TH. 27.  et al. 2011. A copy number variation morbidity map of developmental delay. Nat. Genet. 43:838–46 [Google Scholar]
  28. de Ligt J, Willemsen MH, van Bon BWM, Kleefstra T, Yntema HG. 28.  et al. 2012. Diagnostic exome sequencing in persons with severe intellectual disability. N. Engl. J. Med. 367:1921–29 [Google Scholar]
  29. des Portes V, Pinard JM, Billuart P, Vinet MC, Koulakoff A. 29.  et al. 1998. A novel CNS gene required for neuronal migration and involved in X-linked subcortical laminar heterotopia and lissencephaly syndrome. Cell 92:51–61 [Google Scholar]
  30. Diesen C, Saarinen A, Pihko H, Rosenlew C, Cormand B. 30.  et al. 2004. POMGnT1 mutation and phenotypic spectrum in muscle-eye-brain disease. J. Med. Genet. 41:e115 [Google Scholar]
  31. Dinopoulos A, Matsubara Y, Kure S. 31.  2005. Atypical variants of nonketotic hyperglycinemia. Mol. Genet. Metab. 86:61–69 [Google Scholar]
  32. Douzgou S, Petersen MB. 32.  2011. Clinical variability of genetic isolates of Cohen syndrome. Clin. Genet. 79:501–6 [Google Scholar]
  33. Ekşioğlu YZ, Pong AW, Takeoka M. 33.  2011. A novel mutation in the aristaless domain of the ARX gene leads to Ohtahara syndrome, global developmental delay, and ambiguous genitalia in males and neuropsychiatric disorders in females. Epilepsia 52:984–92 [Google Scholar]
  34. 34. Eur. Chromosome 16 Tuberous Scler. Consort 1993. Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell 75:1305–15 [Google Scholar]
  35. Evrony GD, Cai X, Lee E, Hills LB, Elhosary PC. 35.  et al. 2012. Single-neuron sequencing analysis of L1 retrotransposition and somatic mutation in the human brain. Cell 151:483–96 [Google Scholar]
  36. Faulkner NE, Dujardin DL, Tai CY, Vaughan KT, O'Connell CB. 36.  et al. 2000. A role for the lissencephaly gene LIS1 in mitosis and cytoplasmic dynein function. Nat. Cell Biol. 2:784–91 [Google Scholar]
  37. Feng Y, Olson EC, Stukenberg PT, Flanagan LA, Kirschner MW, Walsh CA. 37.  2000. LIS1 regulates CNS lamination by interacting with mNudE, a central component of the centrosome. Neuron 28:665–79 [Google Scholar]
  38. Feng Y, Walsh CA. 38.  2004. Mitotic spindle regulation by Nde1 controls cerebral cortical size. Neuron 44:279–93 [Google Scholar]
  39. Francis F, Koulakoff A, Boucher D, Chafey P, Schaar B. 39.  et al. 1999. Doublecortin is a developmentally regulated, microtubule-associated protein expressed in migrating and differentiating neurons. Neuron 23:247–56 [Google Scholar]
  40. Friocourt G, Poirier K, Rakić S, Parnavelas JG, Chelly J. 40.  2006. The role of ARX in cortical development. Eur. J. Neurosci. 23:869–76 [Google Scholar]
  41. Geis T, Marquard K, Rödl T, Reihle C, Schirmer S. 41.  et al. 2013. Homozygous dystroglycan mutation associated with a novel muscle-eye-brain disease-like phenotype with multicystic leucodystrophy. Neurogenetics 14:205–13 [Google Scholar]
  42. Genin A, Désir J, Lambert N, Biervliet M, Van Der Aa N. 42.  et al. 2012. Kinetochore KMN network gene CASC5 mutated in primary microcephaly. Hum. Mol. Genet. 21:5306–17 [Google Scholar]
  43. Gleeson JG, Allen KM, Fox JW, Lamperti ED, Berkovic S. 43.  et al. 1998. Doublecortin, a brain-specific gene mutated in human X-linked lissencephaly and double cortex syndrome, encodes a putative signaling protein. Cell 92:63–72 [Google Scholar]
  44. Gleeson JG, Lin PT, Flanagan LA, Walsh CA. 44.  1999. Doublecortin is a microtubule-associated protein and is expressed widely by migrating neurons. Neuron 23:257–71 [Google Scholar]
  45. Gleeson JG, Minnerath S, Kuzniecky RI, Dobyns WB, Young ID. 45.  et al. 2000. Somatic and germline mosaic mutations in the doublecortin gene are associated with variable phenotypes. Am. J. Hum. Genet. 67:574–81 [Google Scholar]
  46. Godfrey C, Clement E, Mein R, Brockington M, Smith J. 46.  et al. 2007. Refining genotype phenotype correlations in muscular dystrophies with defective glycosylation of dystroglycan. Brain 130:2725–35 [Google Scholar]
  47. Godfrey C, Foley AR, Clement E, Muntoni F. 47.  2011. Dystroglycanopathies: coming into focus. Curr. Opin. Genet. Dev. 21:278–85 [Google Scholar]
  48. Greig LC, Woodworth MB, Galazo MJ, Padmanabhan H, Macklis JD. 48.  2013. Molecular logic of neocortical projection neuron specification, development and diversity. Nat. Rev. Neurosci. 14:755–69 [Google Scholar]
  49. Guernsey DL, Jiang H, Hussin J, Arnold M, Bouyakdan K. 49.  et al. 2010. Mutations in centrosomal protein CEP152 in primary microcephaly families linked to MCPH4. Am. J. Hum. Genet. 87:40–51 [Google Scholar]
  50. Guerrini R, Moro F, Andermann E, Hughes E, D'Agostino D. 50.  et al. 2003. Nonsyndromic mental retardation and cryptogenic epilepsy in women with Doublecortin gene mutations. Ann. Neurol. 54:30–37 [Google Scholar]
  51. Hamosh AJM. 51.  2001. Non-ketotic hyperglycinemia. The Metabolic and Molecular Bases of Inherited Disease CR Scriver, WS Sly, B Childs, AL Beaudet, D Valle , et al., pp. 2065–78 New York: McGraw-Hill, 8th ed.. [Google Scholar]
  52. Hara Y, Balci-Hayta B, Yoshida-Moriguchi T, Kanagawa M, Beltrán-Valero de Bernabé D. 52.  et al. 2011. A dystroglycan mutation associated with limb-girdle muscular dystrophy. N. Engl. J. Med. 364:939–46 [Google Scholar]
  53. Harms MB, Ori-McKenney KM, Scoto M, Tuck EP, Bell S. 53.  et al. 2012. Mutations in the tail domain of DYNC1H1 cause dominant spinal muscular atrophy. Neurology 78:1714–20 [Google Scholar]
  54. Hauptman JS, Mathern GW. 54.  2012. Surgical treatment of epilepsy associated with cortical dysplasia: 2012 update. Epilepsia 53:Suppl. 498–104 [Google Scholar]
  55. Hehir-Kwa JY, Rodríguez-Santiago B, Vissers LE, de Leeuw N, Pfundt R. 55.  et al. 2011. De novo copy number variants associated with intellectual disability have a paternal origin and age bias. J. Med. Genet. 48:776–78 [Google Scholar]
  56. Hennies HC, Rauch A, Seifert W, Schumi C, Moser E. 56.  et al. 2004. Allelic heterogeneity in the COH1 gene explains clinical variability in Cohen syndrome. Am. J. Hum. Genet. 75:138–45 [Google Scholar]
  57. Henske EP, Scheithauer BW, Short MP, Wollmann R, Nahmias J. 57.  et al. 1996. Allelic loss is frequent in tuberous sclerosis kidney lesions but rare in brain lesions. Am. J. Hum. Genet. 59:400–6 [Google Scholar]
  58. Hochstenbach R, van Binsbergen E, Engelen J, Nieuwint A, Polstra A. 58.  et al. 2009. Array analysis and karyotyping: workflow consequences based on a retrospective study of 36,325 patients with idiopathic developmental delay in the Netherlands. Eur. J. Med. Genet. 52:161–69 [Google Scholar]
  59. Huguet G, Ey E, Bourgeron T. 59.  2013. The genetic landscapes of autism spectrum disorders. Annu. Rev. Genomics Hum. Genet. 14:191–213 [Google Scholar]
  60. Hussain MS, Baig SM, Neumann S, Nürnberg G, Farooq M. 60.  et al. 2012. A truncating mutation of CEP135 causes primary microcephaly and disturbed centrosomal function. Am. J. Hum. Genet. 90:871–78 [Google Scholar]
  61. Jackson AP, Eastwood H, Bell SM, Adu J, Toomes C. 61.  et al. 2002. Identification of microcephalin, a protein implicated in determining the size of the human brain. Am. J. Hum. Genet. 71:136–42 [Google Scholar]
  62. Jaglin XH, Poirier K, Saillour Y, Buhler E, Tian G. 62.  et al. 2009. Mutations in the β-tubulin gene TUBB2B result in asymmetrical polymicrogyria. Nat. Genet. 41:746–52 [Google Scholar]
  63. Jamieson CR, Govaerts C, Abramowicz MJ. 63.  1999. Primary autosomal recessive microcephaly: homozygosity mapping of MCPH4 to chromosome 15. Am. J. Hum. Genet. 65:1465–69 [Google Scholar]
  64. Kato M, Das S, Petras K, Kitamura K, Morohashi K-I. 64.  et al. 2004. Mutations of ARX are associated with striking pleiotropy and consistent genotype-phenotype correlation. Hum. Mutat. 23:147–59 [Google Scholar]
  65. Keays DA, Tian G, Poirier K, Huang G-J, Siebold C. 65.  et al. 2007. Mutations in α-tubulin cause abnormal neuronal migration in mice and lissencephaly in humans. Cell 128:45–57 [Google Scholar]
  66. Kitamura K, Yanazawa M, Sugiyama N, Miura H, Iizuka-Kogo A. 66.  et al. 2002. Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans. Nat. Genet. 32:359–69 [Google Scholar]
  67. Kolehmainen J, Black GC, Saarinen A, Chandler K, Clayton-Smith J. 67.  et al. 2003. Cohen syndrome is caused by mutations in a novel gene, COH1, encoding a transmembrane protein with a presumed role in vesicle-mediated sorting and intracellular protein transport. Am. J. Hum. Genet. 72:1359–69 [Google Scholar]
  68. Kumar A, Girimaji SC, Duvvari MR, Blanton SH. 68.  2009. Mutations in STIL, encoding a pericentriolar and centrosomal protein, cause primary microcephaly. Am. J. Hum. Genet. 84:286–90 [Google Scholar]
  69. Kure S, Kojima K, Kudo T, Kanno K, Aoki Y. 69.  et al. 2001. Chromosomal localization, structure, single-nucleotide polymorphisms, and expression of the human H-protein gene of the glycine cleavage system (GCSH), a candidate gene for nonketotic hyperglycinemia. J. Hum. Genet. 46:378–84 [Google Scholar]
  70. Kurek KC, Luks VL, Ayturk UM, Alomari AI, Fishman SJ. 70.  et al. 2012. Somatic mosaic activating mutations in PIK3CA cause CLOVES syndrome. Am. J. Hum. Genet. 90:1108–15 [Google Scholar]
  71. Lee JH, Huynh M, Silhavy JL, Kim S, Dixon-Salazar T. 71.  et al. 2012. De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly. Nat. Genet. 44:941–45 [Google Scholar]
  72. Levy D, Ronemus M, Yamrom B, Lee Y-H, Leotta A. 72.  et al. 2011. Rare de novo and transmitted copy-number variation in autistic spectrum disorders. Neuron 70:886–97 [Google Scholar]
  73. Lindhurst MJ, Parker VER, Payne F, Sapp JC, Rudge S. 73.  et al. 2012. Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA. Nat. Genet. 44:928–33 [Google Scholar]
  74. Lindhurst MJ, Sapp JC, Teer JK, Johnston JJ, Finn EM. 74.  et al. 2011. A mosaic activating mutation in AKT1 associated with the Proteus syndrome. N. Engl. J. Med. 365:611–19 [Google Scholar]
  75. Liu JS, Schubert CR, Fu X, Fourniol FJ, Jaiswal JK. 75.  et al. 2012. Molecular basis for specific regulation of neuronal kinesin-3 motors by doublecortin family proteins. Mol. Cell 47:707–21 [Google Scholar]
  76. Lo Nigro C, Chong CS, Smith AC, Dobyns WB, Carrozzo R, Ledbetter DH. 76.  1997. Point mutations and an intragenic deletion in LIS1, the lissencephaly causative gene in isolated lissencephaly sequence and Miller-Dieker syndrome. Hum. Mol. Genet. 6:157–64 [Google Scholar]
  77. Louhichi N, Triki C, Quijano-Roy S, Richard P, Makri S. 77.  et al. 2004. New FKRP mutations causing congenital muscular dystrophy associated with mental retardation and central nervous system abnormalities. Identification of a founder mutation in Tunisian families. Neurogenetics 5:27–34 [Google Scholar]
  78. Lui JH, Hansen DV, Kriegstein AR. 78.  2011. Development and evolution of the human neocortex. Cell 146:18–36 [Google Scholar]
  79. Mardis ER. 79.  2011. A decade's perspective on DNA sequencing technology. Nature 470:198–203 [Google Scholar]
  80. Marsh ED, Golden JA. 80.  2012. Developing models of Aristaless-related homeobox mutations. Jasper's Basic Mechanisms of the Epilepsies JL Noebels, M Avoli, MA Rogawski, RW Olsen, AV Delgado-Escueta Bethesda, MD: Natl. Cent. Biotechnol. Inf 4th ed. http://www.ncbi.nlm.nih.gov/books/NBK98176 [Google Scholar]
  81. Mercuri E, Messina S, Bruno C, Mora M, Pegoraro E. 81.  et al. 2009. Congenital muscular dystrophies with defective glycosylation of dystroglycan: a population study. Neurology 72:1802–9 [Google Scholar]
  82. Mercuri E, Topaloglu H, Brockington M, Berardinelli A, Pichiecchio A. 82.  et al. 2006. Spectrum of brain changes in patients with congenital muscular dystrophy and FKRP gene mutations. Arch. Neurol. 63:251–57 [Google Scholar]
  83. Michaelson JJ, Shi Y, Gujral M, Zheng H, Malhotra D. 83.  et al. 2012. Whole-genome sequencing in autism identifies hot spots for de novo germline mutation. Cell 151:1431–42 [Google Scholar]
  84. Michele DE, Barresi R, Kanagawa M, Saito F, Cohn RD. 84.  et al. 2002. Post-translational disruption of dystroglycan-ligand interactions in congenital muscular dystrophies. Nature 418:417–22 [Google Scholar]
  85. Mochida GH, Rajab A, Eyaid W, Lu A, Al-Nouri D. 85.  et al. 2004. Broader geographical spectrum of Cohen syndrome due to COH1 mutations. J. Med. Genet. 41:e87 [Google Scholar]
  86. Motley AM, Hettema EH, Hogenhout EM, Brites P, ten Asbroek AL. 86.  et al. 1997. Rhizomelic chondrodysplasia punctata is a peroxisomal protein targeting disease caused by a non-functional PTS2 receptor. Nat. Genet. 15:377–80 [Google Scholar]
  87. Neale BM, Kou Y, Liu L, Ma'ayan A, Samocha KE. 87.  et al. 2012. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 485:242–45 [Google Scholar]
  88. Ng SB, Bigham AW, Buckingham KJ, Hannibal MC, McMillin MJ. 88.  et al. 2010. Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nat. Genet. 42:790–93 [Google Scholar]
  89. Ng SB, Buckingham KJ, Lee C, Bigham AW, Tabor HK. 89.  et al. 2010. Exome sequencing identifies the cause of a Mendelian disorder. Nat. Genet. 42:30–35 [Google Scholar]
  90. Nicholas AK, Khurshid M, Désir J, Carvalho OP, Cox JJ. 90.  et al. 2010. WDR62 is associated with the spindle pole and is mutated in human microcephaly. Nat. Genet. 42:1010–14 [Google Scholar]
  91. Niethammer M, Smith DS, Ayala R, Peng J, Ko J. 91.  et al. 2000. NUDEL is a novel Cdk5 substrate that associates with LIS1 and cytoplasmic dynein. Neuron 28:697–711 [Google Scholar]
  92. Nigg EA, Raff JW. 92.  2009. Centrioles, centrosomes, and cilia in health and disease. Cell 139:663–78 [Google Scholar]
  93. Niida Y, Stemmer-Rachamimov AO, Logrip M, Tapon D, Perez R. 93.  et al. 2001. Survey of somatic mutations in tuberous sclerosis complex (TSC) hamartomas suggests different genetic mechanisms for pathogenesis of TSC lesions. Am. J. Hum. Genet. 69:493–503 [Google Scholar]
  94. O'Roak BJ, Deriziotis P, Lee C, Vives L, Schwartz JJ. 94.  et al. 2011. Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nat. Genet. 43:585–89 [Google Scholar]
  95. O'Roak BJ, Vives L, Fu W, Egertson JD, Stanaway IB. 95.  et al. 2012. Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science 338:1619–22 [Google Scholar]
  96. O'Roak BJ, Vives L, Girirajan S, Karakoc E, Krumm N. 96.  et al. 2012. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485:246–50 [Google Scholar]
  97. Oegema R, Maat-Kievit A, Lequin MH, Schot R, Nanninga-van den Neste VMH. 97.  et al. 2012. Asymmetric polymicrogyria and periventricular nodular heterotopia due to mutation in ARX. Am. J. Med. Genet. A 158A:1472–76 [Google Scholar]
  98. Ohira R, Zhang YH, Guo W, Dipple K, Shih SL. 98.  et al. 2002. Human ARX gene: genomic characterization and expression. Mol. Genet. Metab. 77:179–88 [Google Scholar]
  99. Pilz DT, Matsumoto N, Minnerath S, Mills P, Gleeson JG. 99.  et al. 1998. LIS1 and XLIS (DCX) mutations cause most classical lissencephaly, but different patterns of malformation. Hum. Mol. Genet. 7:2029–37 [Google Scholar]
  100. Pinto D, Pagnamenta AT, Klei L, Anney R, Merico D. 100.  et al. 2010. Functional impact of global rare copy number variation in autism spectrum disorders. Nature 466:368–72 [Google Scholar]
  101. Poduri A, Evrony GD, Cai X, Elhosary PC, Beroukhim R. 101.  et al. 2012. Somatic activation of AKT3 causes hemispheric developmental brain malformations. Neuron 74:41–48 [Google Scholar]
  102. Poirier K, Lebrun N, Broix L, Tian G, Saillour Y. 102.  et al. 2013. Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly. Nat. Genet. 45:639–47 [Google Scholar]
  103. Qin W, Chan JA, Vinters HV, Mathern GW, Franz DN. 103.  et al. 2010. Analysis of TSC cortical tubers by deep sequencing of TSC1, TSC2 and KRAS demonstrates that small second-hit mutations in these genes are rare events. Brain Pathol. 20:1096–105 [Google Scholar]
  104. Rauch A, Wieczorek D, Graf E, Wieland T, Endele S. 104.  et al. 2012. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet 380:1674–82 [Google Scholar]
  105. Reiner O, Carrozzo R, Shen Y, Wehnert M, Faustinella F. 105.  et al. 1993. Isolation of a Miller–Dieker lissencephaly gene containing G protein β-subunit-like repeats. Nature 364:717–21 [Google Scholar]
  106. Rivière J-B, Mirzaa GM, O'Roak BJ, Beddaoui M, Alcantara D. 106.  et al. 2012. De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nat. Genet. 44:934–40 [Google Scholar]
  107. Roberts E, Hampshire DJ, Pattison L, Springell K, Jafri H. 107.  et al. 2002. Autosomal recessive primary microcephaly: an analysis of locus heterogeneity and phenotypic variation. J. Med. Genet. 39:718–21 [Google Scholar]
  108. Roberts E, Jackson AP, Carradice AC, Deeble VJ, Mannan J. 108.  et al. 1999. The second locus for autosomal recessive primary microcephaly (MCPH2) maps to chromosome 19q13.1–13.2. Eur. J. Hum. Genet. 7:815–20 [Google Scholar]
  109. Ronan L, Voets N, Rua C, Alexander-Bloch A, Hough M. 109.  et al. 2014. Differential tangential expansion as a mechanism for cortical gyrification. Cereb. Cortex In press. doi: 10.1093/cercor/bht082
  110. Sanders SJ, Ercan-Sencicek AG, Hus V, Luo R, Murtha MT. 110.  et al. 2011. Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron 70:863–85 [Google Scholar]
  111. Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ. 111.  et al. 2012. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485:237–41 [Google Scholar]
  112. Sapir T, Horesh D, Caspi M, Atlas R, Burgess HA. 112.  et al. 2000. Doublecortin mutations cluster in evolutionarily conserved functional domains. Hum. Mol. Genet. 9:703–12 [Google Scholar]
  113. Sasaki M, Hashimoto T, Furushima W, Okada M, Kinoshita S. 113.  et al. 2005. Clinical aspects of hemimegalencephaly by means of a nationwide survey. J. Child Neurol. 20:337–41 [Google Scholar]
  114. Sasaki S, Shionoya A, Ishida M, Gambello MJ, Yingling J. 114.  et al. 2000. A LIS1/NUDEL/cytoplasmic dynein heavy chain complex in the developing and adult nervous system. Neuron 28:681–96 [Google Scholar]
  115. Scheffer IE, Wallace RH, Phillips FL, Hewson P, Reardon K. 115.  et al. 2002. X-linked myoclonic epilepsy with spasticity and intellectual disability: mutation in the homeobox gene ARX. Neurology 59:348–56 [Google Scholar]
  116. Schramm J, Kuczaty S, Sassen R, Elger CE, von Lehe M. 116.  2012. Pediatric functional hemispherectomy: outcome in 92 patients. Acta Neurochir. 154:2017–28 [Google Scholar]
  117. Sebat J, Lakshmi B, Malhotra D, Troge J, Lese-Martin C. 117.  et al. 2007. Strong association of de novo copy number mutations with autism. Science 316:445–49 [Google Scholar]
  118. Seifert W, Holder-Espinasse M, Spranger S, Hoeltzenbein M, Rossier E. 118.  et al. 2006. Mutational spectrum of COH1 and clinical heterogeneity in Cohen syndrome. J. Med. Genet. 43:e22 [Google Scholar]
  119. Shen J, Eyaid W, Mochida GH, Al-Moayyad F, Bodell A. 119.  et al. 2005. ASPM mutations identified in patients with primary microcephaly and seizures. J. Med. Genet. 42:725–29 [Google Scholar]
  120. Shu T, Ayala R, Nguyen M-D, Xie Z, Gleeson JG, Tsai L-H. 120.  2004. Ndel1 operates in a common pathway with LIS1 and cytoplasmic dynein to regulate cortical neuronal positioning. Neuron 44:263–77 [Google Scholar]
  121. Sicca F, Kelemen A, Genton P, Das S, Mei D. 121.  et al. 2003. Mosaic mutations of the LIS1 gene cause subcortical band heterotopia. Neurology 61:1042–46 [Google Scholar]
  122. Sir J-H, Barr AR, Nicholas AK, Carvalho OP, Khurshid M. 122.  et al. 2011. A primary microcephaly protein complex forms a ring around parental centrioles. Nat. Genet. 43:1147–53 [Google Scholar]
  123. Strømme P, Mangelsdorf ME, Scheffer IE, Gécz J. 123.  2002. Infantile spasms, dystonia, and other X-linked phenotypes caused by mutations in Aristaless related homeobox gene, ARX. Brain Dev. 24:266–68 [Google Scholar]
  124. Strømme P, Mangelsdorf ME, Shaw MA, Lower KM, Lewis SME. 124.  et al. 2002. Mutations in the human ortholog of Aristaless cause X-linked mental retardation and epilepsy. Nat. Genet. 30:441–45 [Google Scholar]
  125. Tanaka T, Serneo FF, Higgins C, Gambello MJ, Wynshaw-Boris A, Gleeson JG. 125.  2004. Lis1 and doublecortin function with dynein to mediate coupling of the nucleus to the centrosome in neuronal migration. J. Cell Biol. 165:709–21 [Google Scholar]
  126. Taylor KR, Holzer AK, Bazan JF, Walsh CA, Gleeson JG. 126.  2000. Patient mutations in doublecortin define a repeated tubulin-binding domain. J. Biol. Chem. 275:34442–50 [Google Scholar]
  127. Teber S, Sezer T, Kafali M, Manzini MC, Konuk Yüksel B. 127.  et al. 2008. Severe muscle-eye-brain disease is associated with a homozygous mutation in the POMGnT1 gene. Eur. J. Paediatr. Neurol. 12:133–36 [Google Scholar]
  128. Tischfield MA, Baris HN, Wu C, Rudolph G, Van Maldergem L. 128.  et al. 2010. Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance. Cell 140:74–87 [Google Scholar]
  129. Topaloglu H, Brockington M, Yuva Y, Talim B, Haliloglu G. 129.  et al. 2003. FKRP gene mutations cause congenital muscular dystrophy, mental retardation, and cerebellar cysts. Neurology 60:988–92 [Google Scholar]
  130. Tsai J-W, Chen Y, Kriegstein AR, Vallee RB. 130.  2005. LIS1 RNA interference blocks neural stem cell division, morphogenesis, and motility at multiple stages. J. Cell Biol. 170:935–45 [Google Scholar]
  131. Turner G, Partington M, Kerr B, Mangelsdorf M, Gécz J. 131.  2002. Variable expression of mental retardation, autism, seizures, and dystonic hand movements in two families with an identical ARX gene mutation. Am. J. Med. Genet. 112:405–11 [Google Scholar]
  132. Uyanik G, Aigner L, Martin P, Gross C, Neumann D. 132.  et al. 2003. ARX mutations in X-linked lissencephaly with abnormal genitalia. Neurology 61:232–35 [Google Scholar]
  133. van Slegtenhorst M, de Hoogt R, Hermans C, Nellist M, Janssen B. 133.  et al. 1997. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 277:805–8 [Google Scholar]
  134. Walsh CA. 134.  1999. Genetic malformations of the human cerebral cortex. Neuron 23:19–29 [Google Scholar]
  135. Walsh CA, Engle EC. 135.  2010. Allelic diversity in human developmental neurogenetics: insights into biology and disease. Neuron 68:245–53 [Google Scholar]
  136. Weedon MN, Hastings R, Caswell R, Xie W, Paszkiewicz K. 136.  et al. 2011. Exome sequencing identifies a DYNC1H1 mutation in a large pedigree with dominant axonal Charcot-Marie-Tooth disease. Am. J. Hum. Genet. 89:308–12 [Google Scholar]
  137. Wetterstrand KA. 137.  2013. DNA sequencing costs: data from the NHGRI Genome Sequencing Program (GSP) http://www.genome.gov/sequencingcosts
  138. Wonders CP, Anderson SA. 138.  2006. The origin and specification of cortical interneurons. Nat. Rev. Neurosci. 7:687–96 [Google Scholar]
  139. Wynshaw-Boris A, Pramparo T, Youn YH, Hirotsune S. 139.  2010. Lissencephaly: mechanistic insights from animal models and potential therapeutic strategies. Semin. Cell Dev. Biol. 21:823–30 [Google Scholar]
  140. Yoshida A, Kobayashi K, Manya H, Taniguchi K, Kano H. 140.  et al. 2001. Muscular dystrophy and neuronal migration disorder caused by mutations in a glycosyltransferase, POMGnT1. Dev. Cell 1:717–24 [Google Scholar]
  141. Youn YH, Pramparo T, Hirotsune S, Wynshaw-Boris A. 141.  2009. Distinct dose-dependent cortical neuronal migration and neurite extension defects in Lis1 and Ndel1 mutant mice. J. Neurosci. 29:15520–30 [Google Scholar]
  142. Yu TW, Chahrour MH, Coulter ME, Jiralerspong S, Okamura-Ikeda K. 142.  et al. 2013. Using whole-exome sequencing to identify inherited causes of autism. Neuron 77:259–73 [Google Scholar]
  143. Yu TW, Mochida GH, Tischfield DJ, Sgaier SK, Flores-Sarnat L. 143.  et al. 2010. Mutations in WDR62, encoding a centrosome-associated protein, cause microcephaly with simplified gyri and abnormal cortical architecture. Nat. Genet. 42:1015–20 [Google Scholar]
  144. Zecavati N, Spence SJ. 144.  2009. Neurometabolic disorders and dysfunction in autism spectrum disorders. Curr. Neurol. Neurosci. Rep. 9:129–36 [Google Scholar]
  145. Zilles K, Palomero-Gallagher N, Amunts K. 145.  2013. Development of cortical folding during evolution and ontogeny. Trends Neurosci. 36:275–84 [Google Scholar]

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