Genetics of autism spectrum disorders



Autism spectrum disorders (ASDs) are a clinically complex group of childhood disorders that have firm evidence of an underlying genetic etiology. Many techniques have been used to characterize the genetic bases of ASDs. Linkage studies have identified several replicated susceptibility loci, including 2q24–2q31, 7q, and 17q11–17q21. Association studies and mutation analysis of candidate genes have implicated the synaptic genes NRXN1, NLGN3, NLGN4, SHANK3, and CNTNAP2 in ASDs. Traditional cytogenetic approaches highlight the high frequency of large chromosomal abnormalities (3%–7% of patients), including the most frequently observed maternal 15q11–13 duplications (1%–3% of patients). Newly developed techniques include high-resolution DNA microarray technologies, which have discovered formerly undetectable submicroscopic copy number variants, and genomewide association studies, which allow simultaneous detection of multiple genes associated with ASDs. Although great progress has been made in autism genetics, the molecular bases of most ASDs remains enigmatic.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Fombonne E: Epidemiology of autistic disorder and other pervasive developmental disorders. J Clin Psychiatry 2005, 66(Suppl 10):3–8.PubMedGoogle Scholar
  2. 2.
    Folstein SE, Rosen-Sheidley B: Genetics of autism: complex aetiology for a heterogeneous disorder. Nat Rev Genet 2001, 2:943–955.PubMedCrossRefGoogle Scholar
  3. 3.
    Geschwind DH, Levitt P: Autism spectrum disorders: developmental disconnection syndromes. Curr Opin Neurobiol 2007, 17:103–111.PubMedCrossRefGoogle Scholar
  4. 4.
    Lander E, Kruglyak L: Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 1995, 11:241–247.PubMedCrossRefGoogle Scholar
  5. 5.
    Laumonnier F, Bonnet-Brilhault F, Gomot M, et al.: X-linked mental retardation and autism are associated with a mutation in the NLGN4 gene, a member of the neuroligin family. Am J Hum Genet 2004, 74:552–557.PubMedCrossRefGoogle Scholar
  6. 6.
    Moretti P, Zoghbi HY: MeCP2 dysfunction in Rett syndrome and related disorders. Curr Opin Genet Dev 2006, 16:276–281.PubMedCrossRefGoogle Scholar
  7. 7.
    Strauss KA, Puffenberger EG, Huentelman MJ, et al.: Recessive symptomatic focal epilepsy and mutant contactinassociated protein-like 2. N Engl J Med 2006, 354:1370–1377.PubMedCrossRefGoogle Scholar
  8. 8.
    Abrahams B, Geschwind D: Advances in autism genetics: on the threshold of a new neurobiology. Nat Rev 2008, 9:1–15.Google Scholar
  9. 9.
    Szatmari P, Paterson AD, Zwaigenbaum L, et al.: Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat Genet 2007, 39:319–328.PubMedCrossRefGoogle Scholar
  10. 10.
    Alarcon M, Cantor RM, Liu J, et al.: Evidence for a language quantitative trait locus on chromosome 7q in multiplex autism families. Am J Hum Genet 2002, 70:60–71.PubMedCrossRefGoogle Scholar
  11. 11.
    Pardo CA, Eberhart CG: The neurobiology of autism. Brain Pathol 2007, 17:434–447.PubMedCrossRefGoogle Scholar
  12. 12.
    Alarcon M, Abrahams BS, Stone JL, et al.: Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene. Am J Hum Genet 2008, 82:150–159.PubMedCrossRefGoogle Scholar
  13. 13.
    Arking DE, Cutler DJ, Brune CW, et al.: A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism. Am J Hum Genet 2008, 82:160–164.PubMedCrossRefGoogle Scholar
  14. 14.
    Fatemi SH, Snow AV, Stary JM, et al.: Reelin signaling is impaired in autism. Biol Psychiatry 2005, 57:777–787.PubMedCrossRefGoogle Scholar
  15. 15.
    Freitag CM: The genetics of autistic disorders and its clinical relevance: a review of the literature. Mol Psychiatry 2007, 12:2–22.PubMedCrossRefGoogle Scholar
  16. 16.
    Weiss LA, Arking DE, Green T, et al.: Genome-wide association mapping in multiplex autism families [abstract 1890]. Presented at 58th annual meeting of the American Society of Human Genetics. Philadelphia; November 11–15, 2008.Google Scholar
  17. 17.
    Thomas NS, Sharp AJ, Browne CE, et al.: Xp deletions associated with autism in three females. Hum Genet 1999, 104:43–48.PubMedCrossRefGoogle Scholar
  18. 18.
    Jamain S, Quach H, Betancur C, et al.: Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat Genet 2003, 34:27–29.PubMedCrossRefGoogle Scholar
  19. 19.
    Feng J, Schroer R, Yan J, et al.: High frequency of neurexin 1beta signal peptide structural variants in patients with autism. Neurosci Lett 2006, 409:10–13.PubMedCrossRefGoogle Scholar
  20. 20.
    Kim HG, Kishikawa S, Higgins AW, et al.: Disruption of neurexin 1 associated with autism spectrum disorder. Am J Hum Genet 2008, 82:199–207.PubMedCrossRefGoogle Scholar
  21. 21.
    Durand CM, Betancur C, Boeckers TM, et al.: Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat Genet 2007, 39:25–27.PubMedCrossRefGoogle Scholar
  22. 22.
    Moessner R, Marshall CR, Sutcliffe JS, et al.: Contribution of SHANK3 mutations to autism spectrum disorder. Am J Hum Genet 2007, 81:1289–1297.PubMedCrossRefGoogle Scholar
  23. 23.
    Bakkaloglu B, O’Roak BJ, Louvi A, et al.: Molecular cytogenetic analysis and resequencing of contactin associated protein-like 2 in autism spectrum disorders. Am J Hum Genet 2008, 82:165–173.PubMedCrossRefGoogle Scholar
  24. 24.
    Veenstra-Vanderweele J, Christian SL, Cook EH Jr: Autism as a paradigmatic complex genetic disorder. Annu Rev Genomics Hum Genet 2004, 5:379–405.PubMedCrossRefGoogle Scholar
  25. 25.
    Vorstman JA, Staal WG, van Daalen E, et al.: Identification of novel autism candidate regions through analysis of reported cytogenetic abnormalities associated with autism. Mol Psychiatry 2006, 11:118–128.CrossRefGoogle Scholar
  26. 26.
    Xu J, Zwaigenbaum L, Szatmari P, Scherer S: Molecular cytogenetics of autism. Curr Genomics 2004, 5:1–18.CrossRefGoogle Scholar
  27. 27.
    Hogart A, Wu D, Lasalle JM, Schanen NC: The comorbidity of autism with the genomic disorders of chromosome 15q11.2–q13. Neurobiol Dis 2008 Sep 18 (Epub ahead of print).Google Scholar
  28. 28.
    Niklasson L, Rasmussen P, Oskarsdottir S, Gillberg C: Autism, ADHD, mental retardation and behavior problems in 100 individuals with 22q11 deletion syndrome. Res Dev Disabil 2009, 30:763–773.PubMedCrossRefGoogle Scholar
  29. 29.
    Hay BN: Deletion 22q11: spectrum of associated disorders. Semin Pediatr Neurol 2007, 14:136–139.PubMedCrossRefGoogle Scholar
  30. 30.
    Falk RE, Casas KA: Chromosome 2q37 deletion: clinical and molecular aspects. Am J Med Genet C Semin Med Genet 2007, 145C:357–371.PubMedCrossRefGoogle Scholar
  31. 31.
    Wassink TH, Piven J, Vieland VJ, et al.: Evaluation of the chromosome 2q37.3 gene CENTG2 as an autism susceptibility gene. Am J Med Genet B Neuropsychiatr Genet 2005, 136B:36–44.PubMedCrossRefGoogle Scholar
  32. 32.
    Potocki L, Bi W, Treadwell-Deering D, et al.: Characterization of Potocki-Lupski syndrome (dup(17)(p11.2p11.2)) and delineation of a dosage-sensistive critical interval that can convey an autism phenotype. Am J Hum Genet 2007, 80:633–649.PubMedCrossRefGoogle Scholar
  33. 33.
    Zafeiriou DI, Ververi A, Vargiami E.: Childhood autism and associated comorbidities. Brain Dev 2007, 29:257–272.PubMedCrossRefGoogle Scholar
  34. 34.
    Jacquemont ML, Sanlaville D, Redon R, et al.: Array-based comparative genomic hybridisation identifies high frequency of cryptic chromosomal rearrangements in patients with syndromic autism spectrum disorders. J Med Genet 2006, 43:843–849.PubMedCrossRefGoogle Scholar
  35. 35.
    Christian SL, Brune CW, Sudi J, et al.: Novel submicroscopic chromosomal abnormalities detected in autism spectrum disorder. Biol Psychiatry 2008, 63:1111–1117.PubMedCrossRefGoogle Scholar
  36. 36.
    Sebat J, Lakshmi B, Malhotra D, et al.: Strong association of de novo copy number mutations with autism. Science 2007, 316:445–449.PubMedCrossRefGoogle Scholar
  37. 37.
    Weiss LA, Shen Y, Korn JM, et al.: Association between microdeletion and microduplication at 16p11.2 and autism. N Engl J Med 2008, 358:667–775.PubMedCrossRefGoogle Scholar
  38. 38.
    Marshall CR, Noor A, Vincent JB, et al.: Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet 2008, 82:477–488.PubMedCrossRefGoogle Scholar
  39. 39.
    Kumar RA, KaraMohamed S, Sudi J, et al.: Recurrent 16p11.2 microdeletions in autism. Hum Mol Genet 2008, 17:628–638.PubMedCrossRefGoogle Scholar
  40. 40.
    Walsh T, McClellan JM, McCarthy SE, et al.: Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 2008, 320:539–543.PubMedCrossRefGoogle Scholar
  41. 41.
    Sharp AJ, Mefford HC, Li K, et al.: A recurrent 15q13.3 microdeletion syndrome associated with mental retardation and seizures. Nat Genet 2008, 40:322–328.PubMedCrossRefGoogle Scholar
  42. 42.
    Miller DT, Shen Y, Weiss LA, et al.: Microdeletion/duplication at 15q13.2q13.3 among individuals with features of autism and other neuropsychiatirc disorders. J Med Genet 2008 Nov 26 (Epub ahead of print).Google Scholar
  43. 43.
    Pagnamenta AT, Wing K, Akha ES, et al.: A 15q13.3 microdeletion segregating with3autism. Eur J Hum Genet 2008 Dec 3 (Epub ahead of print).Google Scholar
  44. 44.
    Brunetti-Pierri N, Berg JS, Scaglia F, et al.: Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities. Nat Genet 2008, 40:1466–1471.PubMedCrossRefGoogle Scholar
  45. 45.
    Mefford HC, Sharp AJ, Baker C, et al.: Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. N Engl J Med 2008, 359:1685–1699.PubMedCrossRefGoogle Scholar
  46. 46.
    International Schizophrenia Consortium: Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 2008, 455:237–241.CrossRefGoogle Scholar
  47. 47.
    Stefansson H, Rujescu D, Cichon S, et al.: Large recurrent microdeletions associated with schizophrenia. Nature 2008, 455:232–236.PubMedCrossRefGoogle Scholar
  48. 48.
    Manzi B, Loizzo AL, Giana G, Curatolo P.: Autism and metabolic diseases. J Child Neurol 2008, 23:307–314.PubMedCrossRefGoogle Scholar
  49. 49.
    Garber KB, Visootsak J, Warren ST: Fragile X syndrome. Eur J Hum Genet 2008, 16:666–672.PubMedCrossRefGoogle Scholar
  50. 50.
    Yang MS, Gill M: A review of gene linkage, association and expression studies in autism and an assessment of convergent evidence. Int J Dev Neurosci 2007, 25:69–85.PubMedCrossRefGoogle Scholar

Copyright information

© Current Medicine Group, LLC 2009

Authors and Affiliations

  1. 1.Department of Human GeneticsUniversity of ChicagoChicagoUSA

Personalised recommendations