Pathogenesis of autism: A patchwork of genetic causes

Future Neurology

Volumn 4, Issue 5, 2009, Pages 591-599

  Grigorenko, Elena L ^a  

^a YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Common genetic variants; Copy number variation; Familial risk; Heritability; Rare genetic variants

Indexed keywords

4 AMINOBUTYRIC ACID; FIBROBLAST GROWTH FACTOR; PHOSPHATIDYLINOSITOL 3 KINASE;

AUTISM; DISEASE ASSOCIATION; GENE DOSAGE; GENE MUTATION; GENE NUMBER; GENETIC HETEROGENEITY; GENETIC LINKAGE; GENETIC RISK; GENETIC SUSCEPTIBILITY; GENETIC VARIABILITY; HUMAN; IMMUNOPATHOLOGY; PATHOGENESIS; PRIORITY JOURNAL; REVIEW; RISK ASSESSMENT; RISK FACTOR;

EID: 75249094315     PISSN: 14796708     EISSN: None     Source Type: Journal    
DOI: 10.2217/fnl.09.29     Document Type: Review

References (104)

1. Abrahams BS, Geschwind DH: Advances in autism genetics: on the threshold of a new neurobiology. Nat. Rev. Genet. 9, 341-355 (2008). ■■ Provides a comprehensive overview of the 'state-of-the-art' research on the genetics of autism spectrum disorder (ASD).
2. Fombonne E: Epidemiology of autistic disorder and other pervasive developmental disorders. J. Clin. Psychiatry 66(Suppl. 10) 3-8 (2005).
3. Yeargin-Allsopp M, Rice C, Karapurkar T et al.: Prevalence of autism in a US metropolitan area. JAMA 289, 49-55 (2003).
4. Lord C, Risi S, DiLavore PS et al.: Autism from 2 to 9 years of age. Arch. Gen. Psychiatry 63, 694-701 (2006).
5. Lord C, Corsello C: Diagnostic instruments in autism spectrum disorders. In: Handbook of Autism and Pervasive Developmental Disorders, Vol. 1: Diagnosis, Development, Neurobiology, and Behavior (3rd Edition). Volkmar FR, Paul R, Klin A, Cohen D (Eds). Wiley and Sons, NY, USA, 730-798 (2005).
6. Lord C, Risi S, Lambrecht L et al.: The Autism Diagnostic Observation Schedule-Generic: a standard measure of social and communication deficits associated with the spectrum of autism. J. Autism Dev. Disord. 30, 205-223 (2000).
7. Hughes JR: A review of recent reports on autism: 1000 studies published in 2007. Epilepsy Behav. 13, 425-437 (2008).
8. Geschwind DH: Autism: many genes, common pathways? Cell 135, 391-395 (2008).
9. Walsh CA, Morrow EM, Rubenstein JL: Autism and brain development. Cell 135, 396-400 (2008).
10. Levitt P, Campbell DB: The genetic and neurobiologic compass points toward common signaling dysfunctions in autism spectrum disorders. J. Clin. Invest. 119, 747-754 (2009).
11. Vaccarino FM, Grigorenko EL, Smith KM, Stevens HE: Regulation of cerebral cortical size and neuron number by fibroblast growth factors: implications for autism. J. Autism Dev. Disord. 39, 511-520 (2009).
12. Geschwind DH, Levitt P: Autism spectrum disorders: developmental disconnection syndromes. Curr. Opin. Neurobiol. 17, 103-111 (2007).
13. Zoghbi HY: Postnatal neurodevelopmental disorders: meeting at the synapse? Science 302, 826-830 (2003).
14. Bodmer W, Bonilla C: Common and rare variants in multifactorial susceptibility to common diseases. Nat. Genet. 40, 695-701 (2008).
15. Ronald A, Happe F, Bolton P et al.: Genetic heterogeneity between the three components of the autism spectrum: a twin study. J. Am. Acad. Child Adolesc. Psychiatry 45, 691-699 (2006).
16. Yrigollen CM, Han SS, Kochetkova A et al.: Genes controlling affiliative behavior as candidate genes for autism. Biol. Psychiatry 63, 911-916 (2008). ■ Underlines the importance of considering ASD as a complex multifaceted disorder.
17. Bailey A, Le Couteur A, Gottesman I et al.: Autism as a strongly genetic disorder: evidence from a British twin study. Psychol. Med. 25, 63-77 (1995).
18. Steffenburg S, Gillberg C, Hellgren L et al.: A twin study of autism in Denmark, Finland, Iceland, Norway and Sweden. J. Child Psychol. Psychiatry 30, 405-416 (1989).
19. Folstein S, Rutter M: Infantile autism: a genetic study of 21 twin pairs. J. Child Psychol. Psychiatry 18, 297-321 (1977).
20. Jorde LB, Hasstedt SJ, Ritvo ER et al.: Complex segregation analysis of autism. Am. J. Hum. Genet. 49, 932-938 (1991).
21. Bishop DV, Maybery M, Maley A et al.: Using self-report to identify the broad phenotype in parents of children with autistic spectrum disorders: a study using the Autism-Spectrum Quotient. J. Child Psychol. Psychiatry 45, 1431-1436 (2004).
22. Bolton P, Macdonald H, Pickles A et al.: A case - control family history study of autism. J. Child Psychol. Psychiatry 35, 877-900 (1994).
23. Constantino JN, Todd RD: Intergenerational transmission of subthreshold autistic traits in the general population. Biol. Psychiatry 57, 655-660 (2005).
24. Constantino JN, Davis SA, Todd RD et al.: Validation of a brief quantitative measure of autistic traits: comparison of the social responsiveness scale with the autism diagnostic interview-revised. J. Autism Dev. Disord. 33, 427-433 (2003).
25. Constantino JN, Todd RD: Autistic traits in the general population: a twin study. Arch. Gen. Psychiatry 60, 524-530 (2003).
26. Hoekstra RA, Bartels M, Verweij CJ, Boomsma DI: Heritability of autistic traits in the general population. Arch. Pediatr. Adolesc. Med. 161, 372-377 (2007).
27. Ronald A, Happe F, Plomin R: The genetic relationship between individual differences in social and nonsocial behaviors characteristic of autism. Dev. Sci. 8, 444-458 (2005).
28. Trikalinos TA, Karvouni A, Zintzaras E et al.: A heterogeneity-based genome search meta-analysis for autism-spectrum disorders. Mol. Psychiatry 11, 29-36 (2006).
29. Basu SN, Kollu R, Banerjee-Basu S: AutDB: a gene reference resource for autism research. Nucleic Acids Res. 37(Database issue), D832-D836 (2009). ■ Directs the reader's attention to the existence of a comprehensive online database documenting candidate genes for ASD.
30. Comoletti D, De Jaco A, Jennings LL et al.: The Arg451Cys-neuroligin-3 mutation associated with autism reveals a defect in protein processing. J. Neurosci. 24, 4889-4893 (2004).
31. Jamain S, Quach H, Betancur C et al.: Paris Autism Research International Sibpair Study. Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat. Genet. 34, 27-29 (2003).
32. 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. 74, 552-557 (2004).
33. Strauss KA, Puffenberger EG, Huentelman MJ et al.: Recessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2. N. Engl. J. Med. 354, 1370-1377 (2006).
34. Weiss LA, Shen Y, Korn JM et al.; for the Autism Consortium: Association between microdeletion and microduplication at 16p11.2 and autism. N. Engl. J. Med. 358, 667-675 (2008). ■ Largest linkage/association study of ASD to date. This study recovered multiple new loci that had not been registered in previous studies.
35. The Autism Genome Project (AGP) Consortium; Szatmari P, Paterson AD, Zwaigenbaum L et al.: Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat. Genet. 39, 319-328 (2007).
36. Feng J, Schroer R, Yan J et al.: High frequency of neurexin 1β signal peptide structural variants in patients with autism. Neurosci. Lett. 409, 10-13 (2006).
37. 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. 39, 25-27 (2007).
38. Moessner R, Marshall CR, Sutcliffe JS et al.: Contribution of SHANK3 mutations to autism spectrum disorder. Am. J. Hum. Genet. 81, 1289-1297 (2007).
39. Meyer G, Varoqueaux F, Neeb A, Oschlies M, Brose N: The complexity of PDZ domain-mediated interactions at glutamatergic synapses: a case study on neuroligin. Neuropharmacology 47, 724-733 (2004).
40. Bear MF, Huber KM, Warren ST: The mGluR theory of fragile X mental retardation. Trends Neurosci. 27, 370-377 (2004).
41. Dolen G, Osterweil E, Rao BS et al.: Correction of fragile X syndrome in mice. Neuron 56, 955-962 (2007).
42. Tabuchi K, Blundell J, Etherton MR et al.: A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice. Science 318, 71-76 (2007).
43. Tuchman R, Moshe SL, Rapin I: Convulsing toward the pathophysiology of autism. Brain Dev. 31, 95-103 (2009). ■ Presents a thorough account of the current knowledge of the connection between ASD and epilepsy.
44. Chugani DC: Serotonin in autism and pediatric epilepsies. Ment. Retard. Dev. Disabil. Res. Rev. 10, 112-116 (2004).
45. 2+ signaling. Curr. Opin. Neurobiol. 17, 112-119 (2007).
46. Amaral DG, Schumann CM, Nordahl CW: Neuroanatomy of autism. Trends Neurosci. 31, 137-145 (2008). ■■ Provides an extensive overview of the current understanding of the neuroanatomy of ASD.
47. Bailey A, Luthert P, Dean A et al.: A clinicopathological study of autism. Brain 121(Pt 5), 889-905 (1998).
48. Courchesne E, Carper R, Akshoomoff N: Evidence of brain overgrowth in the first year of life in autism. JAMA 290, 337-344 (2003).
49. Herbert MR, Ziegler DA, Deutsch CK et al.: Brain asymmetries in autism and developmental language disorder: a nested whole-brain analysis. Brain 128(Pt 1), 213-226 (2005).
50. Pardo CA, Eberhart CG: The neurobiology of autism. Brain Pathol. 17, 434-447 (2007).
51. Hughes JR: Autism: the first firm finding = underconnectivity? Epilepsy Behav. 11, 20-24 (2007).
52. Mundy P: Annotation: the neural basis of social impairments in autism: the role of the dorsal medial-frontal cortex and anterior cingulate system. J. Child Psychol. Psychiatry 44, 793-809 (2003).
53. Miles JH, Hadden LL, Takahashi TN, Hillman RE: Head circumference is an independent clinical finding associated with autism. Am. J. Med. Genet. 95, 339-350 (2000).
54. Turner G, Partington M, Kerr B, Mangelsdorf M, Gecz J: 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, 405-411 (2002).
55. Sherr EH: The ARX story (epilepsy, mental retardation, autism, and cerebral malformations): one gene leads to many phenotypes. Curr. Opin. Pediatr. 15, 567-571 (2003).
56. Chaste P, Nygren G, Anckarsater H et al.: Mutation screening of the ARX gene in patients with autism. Am. J. Med. Genet. B Neuropsychiatr. Genet. 144B(2), 228-230 (2007).
57. Campbell DB, Sutcliffe JS, Ebert PJ et al.: A genetic variant that disrupts MET transcription is associated with autism. Proc. Natl Acad. Sci. USA 103, 16834-16839 (2006).
58. Butler MG, Dasouki MJ, Zhou XP et al.: Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations. J. Med. Genet. 42, 318-321 (2005).
59. Goffin A, Hoefsloot LH, Bosgoed E, Swillen A, Fryns JP: PTEN mutation in a family with Cowden syndrome and autism. Am. J. Med. Genet. 105, 521-524 (2001).
60. Ong SH, Hadari YR, Gotoh N et al.: Stimulation of phosphatidylinositol 3-kinase by fibroblast growth factor receptors is mediated by coordinated recruitment of multiple docking proteins. Proc. Natl Acad. Sci. USA 98, 6074-6079 (2001).
61. Iafrate AJ, Feuk L, Rivera MN et al.: Detection of large-scale variation in the human genome. Nat. Genet. 36, 949-951 (2004).
62. Sebat J, Lakshmi B, Troge J et al.: Large-scale copy number polymorphism in the human genome. Science 305, 525-528 (2004).
63. Feuk L, Carson AR, Scherer SW: Structural variation in the human genome. Nat. Rev. Genet. 7, 85-97 (2006).
64. Xu J, Zwaigenbaum L, Szatmari P, Scherer SW: Molecular cytogenetics of autism. Curr. Genomics 5, 347-364 (2004).
65. Pagnamenta AT, Wing K, Akha ES et al.: A 15q13.3 microdeletion segregating with autism. Eur. J. Hum. Genet. 17, 687-692 (2009).
66. Redon R, Ishikawa S, Fitch KR et al.: Global variation in copy number in the human genome. Nature 444, 444-454 (2006).
67. Korbel JO, Urban AE, Affourtit JP et al.: Paired-end mapping reveals extensive structural variation in the human genome. Science 318, 420-426 (2007).
68. Goidts V, Cooper DN, Armengol L et al.: Complex patterns of copy number variation at sites of segmental duplications: an important category of structural variation in the human genome. Hum. Genet. 120, 270-284 (2006).
69. Rodriguez-Revenga L, Mila M, Rosenberg C, Lab A, Lee C: Structural variation in the human genome: the impact of copy number variants on clinical diagnosis. Genet. Med. 9, 600-606 (2007).
70. Cook EHJ, Scherer SW: Copy-number variations associated with neuropsychiatric conditions. Nature 455, 919-923 (2008). ■■ Contains a detailed overview of the state of knowledge of copy-number variations and their role in developmental disorders.
71. Sebat J, Lakshmi B, Malhotra D et al.: Strong association of de novo copy number mutations with autism. Science 316, 445-449 (2007).
72. Morrow EM, Yoo SY, Flavell SW et al.: Identifying autism loci and genes by tracing recent shared ancestry. Science 321, 218-223 (2008).
73. Christian SL, Brune CW, Sudi J et al.: Novel submicroscopic chromosomal abnormalities detected in autism spectrum disorder. Biol. Psychiatry 63, 1111-1117 (2008).
74. Szatmari P, Maziade M, Zwaigenbaum L et al.: Informative phenotypes for genetic studies of psychiatric disorders. Am. J. Med. Genet. B Neuropsychiatr. Genet. 144, 581-588 (2007).
75. Marshall CR, Noor A, Vincent JB et al.: Structural variation of chromosomes in autism spectrum disorder. Am. J. Hum. Genet. 82, 477-488 (2008).
76. 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. 43, 843-849 (2006).
77. Kumar RA, KaraMohamed S, Sudi J et al.: Recurrent 16p11.2 microdeletions in autism. Hum. Mol. Genet. 17, 628-638 (2008).
78. van Gent T, Heijnen CJ, Treffers PD: Autism and the immune system. J. Child Psychol. Psychiatry 38, 337-349 (1997).
79. Money J, Bobrow NA, Clarke FC: Autism and autoimmune disease: a family study. J. Autism Child. Schizophr. 1, 146-160 (1971).
80. Comi AM, Zimmerman AW, Frye VH, Law PA, Peeden JN: Familial clustering of autoimmune disorders and evaluation of medical risk factors in autism. J. Child Neurol. 14, 388-394 (1999).
81. Sweeten TL, Bowyer SL, Posey DJ, Halberstadt GM, McDougle CJ: Increased prevalence of familial autoimmunity in probands with pervasive developmental disorders. Pediatrics 112, E420 (2003).
82. Connolly AM, Chez MG, Pestronk A et al.: Serum autoantibodies to brain in Landau-Kleffner variant, autism, and other neurologic disorders. J. Pediatr. 134, 607-613 (1999).
83. Singh VK, Rivas WH: Prevalence of serum antibodies to caudate nucleus in autistic children. Neurosci. Lett. 355, 53-56 (2004).
84. Singh VK, Warren RP, Odell JD, Warren WL, Cole P: Antibodies to myelin basic protein in children with autistic behavior. Brain Behav. Immun. 7, 97-103 (1993).
85. Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA: Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann. Neurol. 57, 67-81 (2005).
86. Ashwood P, Van de Water J: Is autism an autoimmune disease? Autoimmun. Rev. 3, 557-562 (2004).
87. Ashwood P, Van de Water J: A review of autism and the immune response. Clin. Dev. Immunol. 11, 165-174 (2004).
88. Dalton P, Deacon R, Blamire A et al.: Maternal neuronal antibodies associated with autism and a language disorder. Ann. Neurol. 53, 533-537 (2003).
89. Herbert MR: Autism: a brain disorder or a disorder that affects the brain? Clin. Neuropsychiatry 6, 354-379 (2005).
90. Stubbs EG, Crawford ML: Depressed lymphocyte responsiveness in autistic children. J. Autism Child. Schizophr. 7, 49-55 (1977).
91. Warren RP, Margaretten NC, Pace NC, Foster A: Immune abnormalities in patients with autism. J. Autism Dev. Disord. 16, 189-197 (1986).
92. Denney DR, Frei BW, Gaffney GR: Lymphocyte subsets and interleukin-2 receptors in autistic children. J. Autism Dev. Disord. 26, 87-97 (1996).
93. Plioplys AV, Greaves A, Kazemi K, Silverman EK: Lymphocyte function in autism and Rett syndrome. Neuropsychobiology 29, 12-16 (1994).
94. Warren RP, Yonk J, Burger RW, Odell D, Warren WL: DR-positive T cells in autism: association with decreased plasma levels of the complement C4B protein. Neuropsychobiology 31, 53-57 (1995).
95. Weizman A, Weizman R, Szekely GA, Wijsenbeek H, Livni E: Abnormal immune response to brain tissue antigen in the syndrome of autism. Am. J. Psychiatry 139, 1462-1465 (1982).
96. Hollander E, DelGiudice-Asch G, Simon L et al.: B lymphocyte antigen D8/17 and repetitive behaviors in autism. Am. J. Psychiatry 156, 317-320 (1999).
97. Crow MK, DelGiudice-Asch G, Zehetbauer JB et al.: Autoantigen-specific T cell proliferation induced by the ribosomal P2 protein in patients with systemic lupus erythematosus. J. Clin. Invest. 94, 345-352 (1994).
98. Torres AR, Maciulis A, Stubbs EG, Cutler A, Odell D: The transmission disequilibrium test suggests that HLA-DR4 and DR13 are linked to autism spectrum disorder. Hum. Immunol. 63, 311-316 (2002).
99. Warren RP, Singh VK, Cole P et al.: Possible association of the extended MHC haplotype B44-SC30-DR4 with autism. Immunogenetics 36, 203-207 (1992).
100. Rogers T, Kalaydjieva L, Hallmayer J et al.: Exclusion of linkage to the HLA region in ninety multiplex sibships with autism. J. Autism Dev. Disord. 29, 195-201 (1999).
101. Grigorenko EL, Han SS, Yrigollen CM et al.: Macrophage migration inhibitory factor and stereotypical behavior in autism. Pediatrics 22, E438-E445 (2008). ■ Exemplifies how a common genetic variant can introduce specificity into the manifestations of particular facets of ASD.
102. Zimmerman AW, Jyonouchi H, Comi AM et al.: Cerebrospinal fluid and serum markers of inflammation in autism. Pediatr. Neurol. 33, 195-201 (2005).
103. Pardo CA, Vargas DL, Zimmerman AW: Immunity, neuroglia and neuroinflammation in autism. Int. Rev. Psychiatry 17, 485-495 (2005).
104. An Interface to Autism Research www.mindspec.org/autdb.html