Advertisement

Recent Advances in the Genetics of Autism Spectrum Disorder

  • Silvia De Rubeis
  • Joseph D. BuxbaumEmail author
Genetics (V Bonifati, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Genetics

Abstract

Autism spectrum disorder (ASD) is a devastating neurodevelopmental disorder with high prevalence in the population and a pronounced male preponderance. ASD has a strong genetic basis, but until recently, a large fraction of the genetic factors contributing to liability was still unknown. Over the past 3 years, high-throughput next-generation sequencing on large cohorts has exposed a heterogeneous and complex genetic landscape and has revealed novel risk genes. Here, we provide an overview of the recent advances on the ASD genetic architecture, with an emphasis on the estimates of heritability, the contribution of common variants, and the role of inherited and de novo rare variation. We also examine the genetic components of the reported gender bias. Finally, we discuss the emerging findings from sequencing studies and how they illuminate crucial aspects of ASD pathophysiology.

Keywords

Autism spectrum disorder Autism risk genes Exome sequencing Copy number variation De novo variation Heritability 

Notes

Compliance with Ethics Guidelines

Conflict of Interest

Silvia De Rubeis and Joseph D. Buxbaum declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Levy SE, Mandell DS, Schultz RT. Autism. Lancet. 2009;374:1627–38.CrossRefPubMedCentralPubMedGoogle Scholar
  2. 2.••
    Jacquemont S, Coe BP, Hersch M, Duyzend MH, Krumm N, Bergmann S, et al. A higher mutational burden in females supports a “female protective model” in neurodevelopmental disorders. Am J Human Gene. 2014;94:415–25. This study analyzed the genetic variation in a cohort of 15,585 individuals with neurodevelopmental disorders to understand whether gender bias might be due to a higher mutational burden in females.Google Scholar
  3. 3.
    Kohane IS, McMurry A, Weber G, MacFadden D, Rappaport L, Kunkel L, et al. The co-morbidity burden of children and young adults with autism spectrum disorders. PLoS One. 2012;7:e33224.CrossRefPubMedCentralPubMedGoogle Scholar
  4. 4.
    Betancur C. Etiological heterogeneity in autism spectrum disorders: more than 100 genetic and genomic disorders and still counting. Brain Res. 2011;1380:42–77.CrossRefPubMedGoogle Scholar
  5. 5.
    Visscher PM, Hill WG, Wray NR. Heritability in the genomics era—concepts and misconceptions. Nat Rev Genet. 2008;9:255–66.CrossRefPubMedGoogle Scholar
  6. 6.
    Boomsma D, Busjahn A, Peltonen L. Classical twin studies and beyond. Nat Rev Genet. 2002;3:872–82.CrossRefPubMedGoogle Scholar
  7. 7.
    Bailey A, Le Couteur A, Gottesman I, Bolton P, Simonoff E, Yuzda E, et al. Autism as a strongly genetic disorder: evidence from a British twin study. Psychol Med. 1995;25:63–77.CrossRefPubMedGoogle Scholar
  8. 8.
    Ritvo ER, Freeman BJ, Mason-Brothers A, Mo A, Ritvo AM. Concordance for the syndrome of autism in 40 pairs of afflicted twins. Am J Psychiatry. 1985;142:74–7.CrossRefPubMedGoogle Scholar
  9. 9.
    Steffenburg S, Gillberg C, Hellgren L, Andersson L, Gillberg IC, Jakobsson G, et al. A twin study of autism in Denmark, Finland, Iceland, Norway and Sweden. J Child Psychol Psychiatry. 1989;30:405–16.CrossRefPubMedGoogle Scholar
  10. 10.
    Folstein S, Rutter M. Infantile autism: a genetic study of 21 twin pairs. J Child Psychol Psychiatry. 1977;18:297–321.CrossRefPubMedGoogle Scholar
  11. 11.••
    Gaugler T, Klei L, Sanders SJ, Bodea CA, Goldberg AP, Lee AB, et al. Most genetic risk for autism resides with common variation. Nat Gene. 2014;46:881–5. This study used an epidemiologically ascertained population from Sweden to assess the contribution of rare and common variation to narrow-sense heritability. The study authors estimated that half of the variance in liability is due to common variants.Google Scholar
  12. 12.
    Hallmayer J, Cleveland S, Torres A, Phillips J, Cohen B, Torigoe T et al. Genetic heritability and shared environmental factors among twin pairs with autism. Arch Gene Psychiatry. 2011.Google Scholar
  13. 13.••
    Sandin S, Lichtenstein P, Kuja-Halkola R, Larsson H, Hultman CM, Reichenberg A. The familial risk of autism. JAMA. 2014;311:1770–7. This is the largest population-based study on autism heritiability to date, with 2.5 million Swedish families including twins, full siblings and half siblings. The study has calculated the relative recurrence risk for relatives of ASD probands and provided an estimate of ASD heritability.Google Scholar
  14. 14.•
    Klei L, Sanders SJ, Murtha MT, Hus V, Lowe JK, Willsey AJ, et al. Common genetic variants, acting additively, are a major source of risk for autism. Mole Autism. 2012;3:9. This study was the first to make use of SNP data to estimate narrow-sense heritability in ASD using simplex and multiplex families and demonstrated the significant contribution of polygenic SNP load in ASD risk architecture.Google Scholar
  15. 15.
    Gronborg TK, Schendel DE, Parner ET. Recurrence of autism spectrum disorders in full- and half-siblings and trends over time: a population-based cohort study. JAMA Pediatrics. 2013;167:947–53.CrossRefPubMedGoogle Scholar
  16. 16.
    Frazer KA, Murray SS, Schork NJ, Topol EJ. Human genetic variation and its contribution to complex traits. Nat Rev Genet. 2009;10:241–51.CrossRefPubMedGoogle Scholar
  17. 17.
    Wang K, Zhang H, Ma D, Bucan M, Glessner JT, Abrahams BS, et al. Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature. 2009;459:528–33.CrossRefPubMedCentralPubMedGoogle Scholar
  18. 18.
    Weiss LA, Arking DE, Daly MJ, Chakravarti A. A genome-wide linkage and association scan reveals novel loci for autism. Nature. 2009;461:802–8.CrossRefPubMedCentralPubMedGoogle Scholar
  19. 19.
    Anney R, Klei L, Pinto D, Regan R, Conroy J, Magalhaes TR, et al. A genome-wide scan for common alleles affecting risk for autism. Hum Mol Genet. 2010;19:4072–82.CrossRefPubMedCentralPubMedGoogle Scholar
  20. 20.
    Devlin B, Melhem N, Roeder K. Do common variants play a role in risk for autism? Evidence and theoretical musings. Brain Res. 2011;1380:78–84.CrossRefPubMedCentralPubMedGoogle Scholar
  21. 21.
    Anney R, Klei L, Pinto D, Almeida J, Bacchelli E, Baird G, et al. Individual common variants exert weak effects on the risk for autism spectrum disorderspi. Hum Mol Genet. 2012;21:4781–92.CrossRefPubMedCentralPubMedGoogle Scholar
  22. 22.
    Devlin B, Scherer SW. Genetic architecture in autism spectrum disorder. Curr Opin Gene Dev. 2012;22:229–37.CrossRefGoogle Scholar
  23. 23.
    Depienne C, Moreno-De-Luca D, Heron D, Bouteiller D, Gennetier A, Delorme R, et al. Screening for genomic rearrangements and methylation abnormalities of the 15q11-q13 region in autism spectrum disorders. Biol Psychiatry. 2009;66:349–59.CrossRefPubMedGoogle Scholar
  24. 24.••
    Pinto D, Delaby E, Merico D, Barbosa M, Merikangas A, Klei L, et al. Convergence of genes and cellular pathways dysregulated in autism spectrum disorders. Am J Human Gene. 2014;94:677–94. This study analyzed the burden of copy number variation in 2,446 ASD-affected families from the Autism Genome Project. The study confirmed an excess of deletions and duplications in affected versus control groups and highlighted the large heterogeneity of pathogenic CNVs.CrossRefGoogle Scholar
  25. 25.
    Sebat J, Lakshmi B, Malhotra D, Troge J, Lese-Martin C, Walsh T, et al. Strong association of de novo copy number mutations with autism. Science. 2007;316:445–9.CrossRefPubMedCentralPubMedGoogle Scholar
  26. 26.
    Sanders SJ, Ercan-Sencicek AG, Hus V, Luo R, Murtha MT, Moreno-De-Luca D, et al. Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron. 2011;70:863–85.CrossRefPubMedCentralPubMedGoogle Scholar
  27. 27.
    Levy D, Ronemus M, Yamrom B, Lee YH, Leotta A, Kendall J, et al. Rare de novo and transmitted copy-number variation in autistic spectrum disorders. Neuron. 2011;70:886–97.CrossRefPubMedGoogle Scholar
  28. 28.
    Marshall CR, Noor A, Vincent JB, Lionel AC, Feuk L, Skaug J, et al. Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet. 2008;82:477–88.CrossRefPubMedCentralPubMedGoogle Scholar
  29. 29.
    Pinto D, Pagnamenta AT, Klei L, Anney R, Merico D, Regan R, et al. Functional impact of global rare copy number variation in autism spectrum disorders. Nature. 2010;466:368–72.CrossRefPubMedCentralPubMedGoogle Scholar
  30. 30.
    Glessner JT, Wang K, Cai G, Korvatska O, Kim CE, Wood S, et al. Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature. 2009;459:569–73.CrossRefPubMedCentralPubMedGoogle Scholar
  31. 31.••
    Poultney CS, Goldberg AP, Drapeau E, Kou Y, Harony-Nicolas H, Kajiwara Y, et al. Identification of small exonic CNV from whole-exome sequence data and application to autism spectrum disorder. Am J Human Gene. 2013;93:607–19. One of two first studies detecting small deletions and duplucations in subjects with ASD using whole-exome sequencing data. By detecting and analyzing such variation in a case-control sample, the study showed a burden for small deletions and duplications, which could not be detected by earlier microarray studies.Google Scholar
  32. 32.••
    Krumm N, O'Roak BJ, Karakoc E, Mohajeri K, Nelson B, Vives L, et al. Transmission disequilibrium of small CNVs in simplex autism. Am J Human Gene. 2013;93:595–606. One of two first studies detecting small deletions and duplications in subjects with ASD using whole-exome sequencing data. By detecting and analyzing such variation in 411 ASD families, this study showed a burden for small deletions and duplications, which could not be detected by earlier microarray studies. Google Scholar
  33. 33.
    Fromer M, Moran JL, Chambert K, Banks E, Bergen SE, Ruderfer DM, et al. Discovery and statistical genotyping of copy-number variation from whole-exome sequencing depth. Am J Hum Genet. 2012;91:597–607.CrossRefPubMedCentralPubMedGoogle Scholar
  34. 34.
    Chahrour M, Zoghbi HY. The story of Rett syndrome: from clinic to neurobiology. Neuron. 2007;56:422–37.CrossRefPubMedGoogle Scholar
  35. 35.••
    De Rubeis S, He X, Goldberg AP, Poultney CS, Samocha K, Ercument Cicek A et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature. 2014. One of two recent large whole-exome sequencing studies for ASD. By sequencing 3,871 ASD cases and 9,937 ancestry-matched or parental controls from the Autism Sequencing Consortium, the study identified 33 risk genes with a false-discovery rate of <0.1 and implicated synaptic networks, transcriptional regulation and chromatin remodeling in ASD pathophysiology. Google Scholar
  36. 36.••
    Neale BM, Kou Y, Liu L, Ma'ayan A, Samocha KE, Sabo A, et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature. 2012;485:242–5. One of the initial four whole-exome sequencing studies in ASD. The four studies collectively sequenced ∼1000 trios, showed the contribution of de novo SNVs and indels in ASD risk architecture, and uncovered 9 ASD risk genes.CrossRefPubMedCentralPubMedGoogle Scholar
  37. 37.••
    Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ, Willsey AJ, et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature. 2012;485:237–41. One of the initial four whole-exome sequencing studies in ASD. The four studies collectively sequenced ∼1000 trios, showed the contribution of de novo SNVs and indels in ASD risk architecture, and uncovered 9 ASD risk genes.CrossRefPubMedCentralPubMedGoogle Scholar
  38. 38.••
    O'Roak BJ, Vives L, Girirajan S, Karakoc E, Krumm N, Coe BP, et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature. 2012;485:246–50. One of the initial four whole-exome sequencing studies in ASD. The four studies collectively sequenced ∼1000 trios, showed the contribution of de novo SNVs and indels in ASD risk architecture, and uncovered 9 ASD risk genes.CrossRefPubMedCentralPubMedGoogle Scholar
  39. 39.••
    Iossifov I, Ronemus M, Levy D, Wang Z, Hakker I, Rosenbaum J, et al. De novo gene disruptions in children on the autistic spectrum. Neuron. 2012;74:285–99. One of the initial four whole-exome sequencing studies in ASD. The four studies collectively sequenced ∼1000 trios, showed the contribution of de novo SNVs and indels in ASD risk architecture, and uncovered 9 ASD risk genes.CrossRefPubMedCentralPubMedGoogle Scholar
  40. 40.••
    Iossifov I, O'Roak BJ, Sanders SJ, Ronemus M, Krumm N, Levy D, et al. The contribution of de novo coding mutations to autism spectrum disorder. Nature. 2014;515:216–21. One of two recent large whole-exome sequencing studies for ASD. By sequencing approximately 2,500 families from the Simons Simplex Collection, the study identified 27 ASD genes with recurrent de novo loss-of-function mutations.Google Scholar
  41. 41.••
    Lim ET, Raychaudhuri S, Sanders SJ, Stevens C, Sabo A, MacArthur DG, et al. Rare complete knockouts in humans: population distribution and significant role in autism spectrum disorders. Neuron. 2013;77:235–42. One of two whole-exome sequencing studies showing the role of inherited variation in ASD risk architecture. Using a case-control sample, this study showed a significant contribution of autosomal recessive and X-linked variation in ASD liability.Google Scholar
  42. 42.••
    Yu TW, Chahrour MH, Coulter ME, Jiralerspong S, Okamura-Ikeda K, Ataman B, et al. Using whole-exome sequencing to identify inherited causes of autism. Neuron. 2013;77:259–73. One of two whole-exome sequencing studies showing the role of inherited variation in ASD risk architecture. By analyzing genetic variation in consanguineous families, this study highlighted hypomorphic and other alleles in recessive genes in familial ASD.Google Scholar
  43. 43.
    MacArthur DG, Balasubramanian S, Frankish A, Huang N, Morris J, Walter K, et al. A systematic survey of loss-of-function variants in human protein-coding genes. Science. 2012;335:823–8.CrossRefPubMedCentralPubMedGoogle Scholar
  44. 44.
    Chahrour MH, Yu TW, Lim ET, Ataman B, Coulter ME, Hill RS, et al. Whole-exome sequencing and homozygosity analysis implicate depolarization-regulated neuronal genes in autism. PLoS Genet. 2012;8, e1002635.CrossRefPubMedCentralPubMedGoogle Scholar
  45. 45.
    Casey JP, Magalhaes T, Conroy JM, Regan R, Shah N, Anney R, et al. A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder. Hum Genet. 2012;131:565–79.CrossRefPubMedCentralPubMedGoogle Scholar
  46. 46.
    Veltman JA, Brunner HG. De novo mutations in human genetic disease. Nat Rev Genet. 2012;13:565–75.CrossRefPubMedGoogle Scholar
  47. 47.
    Conrad DF, Keebler JE, DePristo MA, Lindsay SJ, Zhang Y, Casals F, et al. Variation in genome-wide mutation rates within and between human families. Nat Genet. 2011;43:712–4.CrossRefPubMedCentralPubMedGoogle Scholar
  48. 48.
    Roach JC, Glusman G, Smit AF, Huff CD, Hubley R, Shannon PT, et al. Analysis of genetic inheritance in a family quartet by whole-genome sequencing. Science. 2010;328:636–9.CrossRefPubMedCentralPubMedGoogle Scholar
  49. 49.
    Kong A, Frigge ML, Masson G, Besenbacher S, Sulem P, Magnusson G, et al. Rate of de novo mutations and the importance of father’s age to disease risk. Nature. 2012;488:471–5.CrossRefPubMedCentralPubMedGoogle Scholar
  50. 50.
    Michaelson JJ, Shi Y, Gujral M, Zheng H, Malhotra D, Jin X, et al. Whole-genome sequencing in autism identifies hot spots for de novo germline mutation. Cell. 2012;151:1431–42.CrossRefPubMedCentralPubMedGoogle Scholar
  51. 51.
    Kirov G, Pocklington AJ, Holmans P, Ivanov D, Ikeda M, Ruderfer D, et al. De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia. Mol Psychiatry. 2012;17:142–53.CrossRefPubMedCentralPubMedGoogle Scholar
  52. 52.
    Soemedi R, Wilson IJ, Bentham J, Darlay R, Topf A, Zelenika D, et al. Contribution of global rare copy-number variants to the risk of sporadic congenital heart disease. Am J Hum Genet. 2012;91:489–501.CrossRefPubMedCentralPubMedGoogle Scholar
  53. 53.
    Hehir-Kwa JY, Rodriguez-Santiago B, Vissers LE, de Leeuw N, Pfundt R, Buitelaar JK, et al. De novo copy number variants associated with intellectual disability have a paternal origin and age bias. J Med Genet. 2011;48:776–8.CrossRefPubMedGoogle Scholar
  54. 54.•
    Dong S, Walker MF, Carriero NJ, DiCola M, Willsey AJ, Ye AY, et al. De novo insertions and deletions of predominantly paternal origin are associated with autism spectrum disorder. Cell Reports. 2014;9:16–23. This study applied robust approaches for the identification of indels from whole-exome sequencing data in 787 ASD families from the Simons Simplex Collection, and extended the contribution of indels in ASD liability.Google Scholar
  55. 55.
    McGrath JJ, Petersen L, Agerbo E, Mors O, Mortensen PB, Pedersen CB. A comprehensive assessment of parental age and psychiatric disorders. JAMA Psychiatry. 2014;71:301–9.Google Scholar
  56. 56.
    Frans EM, Sandin S, Reichenberg A, Langstrom N, Lichtenstein P, McGrath JJ, et al. Autism risk across generations: a population-based study of advancing grandpaternal and paternal age. JAMA Psychiatry. 2013;70:516–21.CrossRefPubMedCentralPubMedGoogle Scholar
  57. 57.
    Hultman CM, Sandin S, Levine SZ, Lichtenstein P, Reichenberg A. Advancing paternal age and risk of autism: new evidence from a population-based study and a meta-analysis of epidemiological studies. Mol Psychiatry. 2011;16:1203–12.CrossRefPubMedGoogle Scholar
  58. 58.
    Fombonne E. Epidemiology of autistic disorder and other pervasive developmental disorders. J Clin Psychiatry. 2005;66 Suppl 10:3–8.PubMedGoogle Scholar
  59. 59.
    Baron-Cohen S, Lombardo MV, Auyeung B, Ashwin E, Chakrabarti B, Knickmeyer R. Why are autism spectrum conditions more prevalent in males? PLoS Biol. 2011;9:e1001081.CrossRefPubMedCentralPubMedGoogle Scholar
  60. 60.
    Bagni C, Tassone F, Neri G, Hagerman R. Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics. J Clin Invest. 2012;122:4314–22.CrossRefPubMedCentralPubMedGoogle Scholar
  61. 61.
    Tropeano M, Ahn JW, Dobson RJ, Breen G, Rucker J, Dixit A, et al. Male-biased autosomal effect of 16p13.11 copy number variation in neurodevelopmental disorders. PLoS One. 2013;8:e61365.CrossRefPubMedCentralPubMedGoogle Scholar
  62. 62.
    Sato D, Lionel AC, Leblond CS, Prasad A, Pinto D, Walker S, et al. SHANK1 deletions in males with autism spectrum disorder. Am J Hum Genet. 2012;90:879–87.CrossRefPubMedCentralPubMedGoogle Scholar
  63. 63.
    Girirajan S, Rosenfeld JA, Coe BP, Parikh S, Friedman N, Goldstein A, et al. Phenotypic heterogeneity of genomic disorders and rare copy-number variants. N Engl J Med. 2012;367:1321–31.CrossRefPubMedCentralPubMedGoogle Scholar
  64. 64.••
    Robinson EB, Lichtenstein P, Anckarsater H, Happe F, Ronald A. Examining and interpreting the female protective effect against autistic behavior. Proc Natl Acad Sci U S A. 2013;110:5258–62. This study has assessed quantitative ASD traits in females and males of two large populations of monozygotic and dizygotic twins and has provided support for the female protective effect theory.Google Scholar
  65. 65.•
    He X, Sanders SJ, Liu L, De Rubeis S, Lim ET, Sutcliffe JS, et al. Integrated model of de novo and inherited genetic variants yields greater power to identify risk genes. PLoS Gene. 2013;9:e1003671. This paper describes an innovative statistical method to assess disease association of genes by integrating information on de novo and inherited variation, as well as variation identified in case-control samples.Google Scholar
  66. 66.
    Buxbaum JD, Daly MJ, Devlin B, Lehner T, Roeder K, State MW. The autism sequencing consortium: large-scale, high-throughput sequencing in autism spectrum disorders. Neuron. 2012;76:1052–6.CrossRefPubMedGoogle Scholar
  67. 67.
    Fischbach GD, Lord C. The Simons Simplex Collection: a resource for identification of autism genetic risk factors. Neuron. 2010;68:192–5.CrossRefPubMedGoogle Scholar
  68. 68.
    Zoghbi HY. Postnatal neurodevelopmental disorders: meeting at the synapse? Science. 2003;302:826–30.CrossRefPubMedGoogle Scholar
  69. 69.••
    Fromer M, Pocklington AJ, Kavanagh DH, Williams HJ, Dwyer S, Gormley P, et al. De novo mutations in schizophrenia implicate synaptic networks. Nature. 2014;506:179–84. This is the largest whole-exome sequencing of de novo mutations on schizophrenia to date, with over 600 trios sequenced.CrossRefPubMedCentralPubMedGoogle Scholar
  70. 70.
    Verpelli C, Sala C. Molecular and synaptic defects in intellectual disability syndromes. Curr Opin Neurobiol. 2012;22:530–6.CrossRefPubMedGoogle Scholar
  71. 71.
    Delorme R, Ey E, Toro R, Leboyer M, Gillberg C, Bourgeron T. Progress toward treatments for synaptic defects in autism. Nat Med. 2013;19:685–94.CrossRefPubMedGoogle Scholar
  72. 72.
    Kang HJ, Kawasawa YI, Cheng F, Zhu Y, Xu X, Li M, et al. Spatio-temporal transcriptome of the human brain. Nature. 2011;478:483–9.CrossRefPubMedCentralPubMedGoogle Scholar
  73. 73.
    Miller JA, Ding SL, Sunkin SM, Smith KA, Ng L, Szafer A, et al. Transcriptional landscape of the prenatal human brain. Nature. 2014;508:199–206.CrossRefPubMedCentralPubMedGoogle Scholar
  74. 74.••
    Parikshak NN, Luo R, Zhang A, Won H, Lowe JK, Chandran V, et al. Integrative functional genomic analyses implicate specific molecular pathways and circuits in autism. Cell. 2013;155:1008–21. This is one of the recent studies that have leveraged the BrainSpan transcriptome dataset of multiple human brain regions across develoment. This study has used a top-down weighted gene co-expression network approach integrating a broad set of genes associated with ASD and intellectual disability.Google Scholar
  75. 75.••
    Willsey AJ, Sanders SJ, Li M, Dong S, Tebbenkamp AT, Muhle RA, et al. Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism. Cell. 2013;155:997–1007. This is one of the recent studies that have leveraged the BrainSpan transcriptome dataset of multiple human brain regions across develoment. This study has used a bottom-up co-expression network approach incorporating high confidence ASD risk genes identified by the large-scale sequencing studies on ASD families.CrossRefPubMedCentralPubMedGoogle Scholar
  76. 76.
    Xu X, Wells AB, O'Brien DR, Nehorai A, Dougherty JD. Cell type-specific expression analysis to identify putative cellular mechanisms for neurogenetic disorders. J Neurosci. 2014;34:1420–31.CrossRefPubMedCentralPubMedGoogle Scholar
  77. 77.
    Uddin M, Tammimies K, Pellecchia G, Alipanahi B, Hu P, Wang Z, et al. Brain-expressed exons under purifying selection are enriched for de novo mutations in autism spectrum disorder. Nat Genet. 2014;46:742–7.CrossRefPubMedGoogle Scholar
  78. 78.••
    Bernier R, Golzio C, Xiong B, Stessman HA, Coe BP, Penn O, et al. Disruptive CHD8 mutations define a subtype of autism early in development. Cell. 2014;158:263–76. This study is a first phenotypic characterization of 15 subjects carrying mutations in the newly discovered ASD risk gene CHD8.Google Scholar
  79. 79.
    Sugathan A, Biagioli M, Golzio C, Erdin S, Blumenthal I, Manavalan P, et al. CHD8 regulates neurodevelopmental pathways associated with autism spectrum disorder in neural progenitors. Proc Natl Acad Sci U S A. 2014;111:E4468–4477.CrossRefPubMedCentralPubMedGoogle Scholar
  80. 80.
    Chaste P, Klei L, Sanders SJ, Murtha MT, Hus V, Lowe JK, et al. Adjusting head circumference for covariates in autism: clinical correlates of a highly heritable continuous trait. Biol Psychiatry. 2013;74:576–84.CrossRefPubMedCentralPubMedGoogle Scholar
  81. 81.
    Deriziotis P, O'Roak BJ, Graham SA, Estruch SB, Dimitropoulou D, Bernier RA, et al. De novo TBR1 mutations in sporadic autism disrupt protein functions. Nat Commun. 2014;5:4954.CrossRefPubMedCentralPubMedGoogle Scholar
  82. 82.
    Chang KJ, Zollinger DR, Susuki K, Sherman DL, Makara MA, Brophy PJ, et al. Glial ankyrins facilitate paranodal axoglial junction assembly. Nat Neurosci. 2014;17:1673–81.CrossRefPubMedGoogle Scholar
  83. 83.••
    Huang TN, Chuang HC, Chou WH, Chen CY, Wang HF, Chou SJ, et al. Tbr1 haploinsufficiency impairs amygdalar axonal projections and results in cognitive abnormality. Nat Neurosci. 2014;17:240–7. This study is a first report on the neuroanatomical and behavioral characterization of a mouse model for the haploinsufficiency of the newly discovered ASD risk gene TBR1.Google Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Seaver Autism Center for Research and TreatmentIcahn School of Medicine at Mount SinaiNew YorkUSA
  2. 2.Department of PsychiatryIcahn School of Medicine at Mount SinaiNew YorkUSA
  3. 3.Department of Genetics and Genomic SciencesIcahn School of Medicine at Mount SinaiNew YorkUSA
  4. 4.Department of NeuroscienceIcahn School of Medicine at Mount SinaiNew YorkUSA
  5. 5.Friedman Brain InstituteIcahn School of Medicine at Mount SinaiNew YorkUSA
  6. 6.The Mindich Child Health and Development InstituteIcahn School of Medicine at Mount SinaiNew YorkUSA

Personalised recommendations