Detection and Characterization of Copy Number Variation in Autism Spectrum Disorder

Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 838)

Abstract

There now exist multiple lines of evidence pointing to a significant genetic component underlying the aetiology of autism spectrum disorders (ASDs). The advent of methodologies for scanning the human genome at high resolution, coupled with the recognition of copy number variation (CNV) as a prevalent source of genomic variation, has led to new strategies in the identification of clinically relevant loci. Balanced genomic changes, such as translocations and inversions, also contribute to ASD, but current studies have shown that screening with microarrays has up to fivefold increase in diagnostic yield. Recent work by our group and others has shown unbalanced genomic alterations that are likely pathogenic in upwards of 10% of cases, highlighting an important role for CNVs in the genetic aetiology of ASD. A trend in our empirical data has shifted focus for discovery of candidate loci towards individually rare but highly penetrant CNVs instead of looking for common variants of low penetrance. This strategy has proven largely successful in identifying ASD-susceptibility candidate loci, including gains and losses at 16p11.2, SHANK2, NRXN1, and PTCHD1. Another emerging and intriguing trend is the identification of the same genes implicated by rare CNVs across neurodevelopmental disorders, including schizophrenia, attention deficit hyperactivity disorder, and intellectual disability. These observations indicate that similar pathways may be involved in phenotypically distinct outcomes. Although interrogation of the genome at high resolution has led to these novel discoveries, it has also made cataloguing, characterization, and clinical interpretation of the increasing amount of CNV data difficult. Herein, we describe the history of genomic structural variation in ASD and how CNV discovery has been used to pinpoint novel ASD-susceptibility loci. We also discuss the overlap of CNVs across neurodevelopmental disorders and comment on the current challenges of understanding the relationship between CNVs and associated phenotypes in a clinical context.

Key words

Autism spectrum disorder Copy number variation Genetics Genome variation Microarray Neurodevelopmental disorders 

References

  1. 1.
    Kanner L (1943). Autistic disturbances of affected contact. Nervous Child, 2, 217–250.Google Scholar
  2. 2.
    Asperger H (1944). Die autistischen psychopathen im kindesalter. Arch fur Psychiatrie und Nerenkrankheiten, 117, 76–136.CrossRefGoogle Scholar
  3. 3.
    Fombonne E (2001). Is there an epidemic of autism? Pediatrics, 107, 411–2.PubMedCrossRefGoogle Scholar
  4. 4.
    Folstein SE and Rosen-Sheidley B (2001). Genetics of autism: complex aetiology for a heterogeneous disorder. Nature Reviews Genetics, 12:943–55.CrossRefGoogle Scholar
  5. 5.
    Szatmari P, Jones MB, Zwaigenbaum L, MacLean JE (1998). Genetics of autism: overview and new directions. Journal of Autism and Developmental Disorders, 28, 351–68.PubMedCrossRefGoogle Scholar
  6. 6.
    Abrahams BS, Geschwind DH. (2008). Advances in autism genetics: on the threshold of a new neurobiology. Nature Reviews Genetics, 9, 341–355.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Zwaigenbaum L, Bryson S, Roberts W, Brian J, Szatmari P (2005). Behavioral markers of autism in the first year of life. International Journal of Developmental Neurosciences, 23, 143–152.CrossRefGoogle Scholar
  8. 8.
    Bailey A, Le Couteur A, Gottesman I, Bolton P, Simonoff E, Yuzda E, Rutter M (1995). Autism as a strongly genetic disorder: Evidence from a British twin study. Psychological Medicine, 25, 63–77.PubMedCrossRefGoogle Scholar
  9. 9.
    Folstein S, Rutter M (1977). Infantile autism: a genetic study of 21 twin pairs. Journal of Child Psychology and Psychiatry, 18, 297–321.PubMedCrossRefGoogle Scholar
  10. 10.
    Zwaigenbaum L, Szatmari P, Mahoney WJ, Bryson SE, Bartolucci G, MacLean JE (2000). High functioning autism and childhood disintegrative disorder in halfbrothers. Journal of Autism and Developmental Disorders, 30, 121–26.PubMedCrossRefGoogle Scholar
  11. 11.
    MacLean JE, Szatmari P, Jones MB, Bryson SE, Mahoney WJ, Bartolucci G, Tuff L (1999). Familial factors influence level of functioning in pervasive developmental disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 38, 746–53.PubMedCrossRefGoogle Scholar
  12. 12.
    Szatmari P, Bryson SE, Boyle MH, Streiner DL, Duku E (2003). Predictors of outcome among high functioning children with autism and Asperger syndrome. Journal of Child Psychology and Psychiatry, and Allied Disciplines, 44, 520–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Veenstra-VanderWeele J, Cook EH (2004). Molecular genetics of autism spectrum disorder. Molecular Psychiatry, 9, 819–32.PubMedCrossRefGoogle Scholar
  14. 14.
    Pickles A, Bolton P, Macdonald H, Bailey A, Le Couteur A, Sim CH, Rutter M (1995). Latent-class analysis of recurrence risks for complex phenotypes with selection and measurement error: a twin and family history study of autism. American Journal of Human Genetics, 3, 717–26.Google Scholar
  15. 15.
    Risch N, Spiker D, Lotspeich L, Nouri N, Hinds D, Hallmayer J, Kalaydjieva L, McCague P, Dimiceli S, Pitts T, Nguyen L, Yang J, Harper C, Thorpe D, Vermeer S, Young H, Hebert J, Lin A, Ferguson J, Chiotti C, Wiese-Slater S, Rogers T, Salmon B, Nicholas P, Myers RM, et al (1999). A genomic screen of autism:evidence for a multilocus etiology. American Journal of Human Genetics, 65, 493–507.PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Zhao X, Leotta A, Kustanovich V, Lajonchere C, Geschwind DH, Law K, Law P, Qiu S, Lord C, Sebat J, Ye K, Wigler M. (2007). A unified genetic theory for sporadic and inherited autism. Proceedings of the National Academy of Sciences USA, 104, 12831–12836.CrossRefGoogle Scholar
  17. 17.
    Lord C, Cook EH, Leventhal B, Amaral, DG (2000). Autism Spectrum Disorders. Cell, 28, 355–63.Google Scholar
  18. 18.
    Xu, J, Zwaigenbaum, L Szatmari, P and Scherer SW (2004). Molecular cytogenetics of autism. Current Genomics, 5, 347–64.Google Scholar
  19. 19.
    Buchanan JA, Scherer SW. (2008). Contem­plating effects of genomic structural variation. Genetics inMedicine, 10, 639–647.Google Scholar
  20. 20.
    Marshall CR, Noor A, Vincent JB, Lionel AC, Feuk L, Skaug J, Shago M, Moessner R, Pinto D, Ren Y, Thiruvahindrapduram B, Fiebig A, Schreiber S, Friedman J, Ketelaars CE, Vos YJ, Ficicioglu C, Kirkpatrick S, Nicolson R, Sloman L, Summers A, Gibbons CA, Teebi A, Chitayat D, Weksberg R, Thompson A, Vardy C, Crosbie V, Luscombe S, Baatjes R, Zwaigenbaum L, Roberts W, Fernandez B, Szatmari P, Scherer SW. (2008). Structural variation of chromosomes in autism spectrum disorder. American Journal of Human Genetics, 82, 477–488.PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Miller DT, Adam MP, Aradhya S, Biesecker LG, Brothman AR, Carter NP, Church DM, Crolla JA, Eichler EE, Epstein CJ, Faucett WA, Feuk L, Friedman JM, Hamosh A, Jackson L, Kaminsky EB, Kok K, Krantz ID, Kuhn RM, Lee C, Ostell JM, Rosenberg C, Scherer SW, Spinner NB, Stavropoulos DJ, Tepperberg JH, Thorland EC, Vermeesch JR, Waggoner DJ, Watson MS, Martin CL, Ledbetter DH (2010). Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. American Journal of Human Genetics, 86, 749–64.PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Shen Y, Dies KA, Holm IA, Bridgemohan C, Sobeih MM, Caronna EB, Miller KJ, Frazier JA, Silverstein I, Picker J, Weissman L, Raffalli P, Jeste S, Demmer LA, Peters HK, Brewster SJ, Kowalczyk SJ, Rosen-Sheidley B, McGowan C, Duda AW 3rd, Lincoln SA, Lowe KR, Schonwald A, Robbins M, Hisama F, Wolff R, Becker R, Nasir R, Urion DK, Milunsky JM, Rappaport L, Gusella JF, Walsh CA, Wu BL, Miller DT; Autism Consortium Clinical Genetics/DNA Diagnostics Collaboration (2010). Clinical genetic testing for patients with autism spectrum disorders. Pediatrics, 125, e727–35.CrossRefGoogle Scholar
  23. 23.
    Jamain S, Quach H, Betancur C, Råstam M, Colineaux C, Gillberg IC, Soderstrom H, Giros B, Leboyer M, Gillberg C, Bourgeron T; Paris Autism Research International Sibpair Study. (2003). Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nature Genetics, 34, 27–29.CrossRefGoogle Scholar
  24. 24.
    Wang K, Zhang H, Ma D, Bucan M, Glessner JT, Abrahams BS, Salyakina D, Imielinski M, Bradfield JP, Sleiman PM, Kim CE, Hou C, Frackelton E, Chiavacci R, Takahashi N, Sakurai T, Rappaport E, Lajonchere CM, Munson J, Estes A, Korvatska O, Piven J, Sonnenblick LI, Alvarez Retuerto AI, Herman EI, Dong H, Hutman T, Sigman M, Ozonoff S, Klin A, Owley T, Sweeney JA, Brune CW, Cantor RM, Bernier R, Gilbert JR, Cuccaro ML, McMahon WM, Miller J, State MW, Wassink TH, Coon H, Levy SE, Schultz RT, Nurnberger JI, Haines JL, Sutcliffe JS, Cook EH, Minshew NJ, Buxbaum JD, Dawson G, Grant SF, Geschwind DH, Pericak-Vance MA, Schellenberg GD, Hakonarson H. (2009). Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature, 459, 528–533.Google Scholar
  25. 25.
    Weiss LA, Arking DE; Gene Discovery Project of Johns Hopkins & the Autism Consortium, Daly MJ, Chakravarti A (2009) A genome-wide linkage and association scan reveals novel loci for autism. Nature, 461, 802–8.CrossRefGoogle Scholar
  26. 26.
    Arking DE, Cutler DJ, Brune CW, Teslovich TM, West K, Ikeda M, Rea A, Guy M, Lin S, Cook EH, Chakravarti A (2008). A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism. American Journal of Human Genetics, 82, 160–4.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Cook EH Jr, Scherer SW. (2008). Copy-number variations associated with neuropsychiatric conditions. Nature, 16, 919–923.CrossRefGoogle Scholar
  28. 28.
    Cook EH Jr, Lindgren V, Leventhal BL, Courchesne R, Lincoln A, Shulman C, Lord C, Courchesne E.(1997). Autism or atypical autism in maternally but not paternally derived proximal 15q duplication. American Journal of Human Genetics, 60, 928–934.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Potocki L, Bi W, Treadwell-Deering D, Carvalho CM, Eifert A, Friedman EM, Glaze D, Krull K, Lee JA, Lewis RA, Mendoza-Londono R, Robbins-Furman P, Shaw C, Shi X, Weissenberger G, Withers M, Yatsenko SA, Zackai EH, Stankiewicz P, Lupski JR. (2007). Characterization of Potocki-Lupski syndrome (dup(17)(p11.2p11.2)) and delineation of a dosage-sensitive critical interval that can conveyan autism phenotype. American Journal of Human Genetics, 80, 633–649.Google Scholar
  30. 30.
    Autism Genome Project Consortium, Szatmari P, Paterson AD, Zwaigenbaum L, Roberts W, Brian J, Liu XQ, Vincent JB, Skaug JL, Thompson AP, Senman L, Feuk L, Qian C, Bryson SE, Jones MB, Marshall CR, Scherer SW, Vieland VJ, Bartlett C, Mangin LV, Goedken R, Segre A, Pericak-Vance MA, Cuccaro ML, Gilbert JR, Wright HH, Abramson RK, Betancur C, Bourgeron T, Gillberg C, Leboyer M, Buxbaum JD, Davis KL, Hollander E, Silverman JM, Hallmayer J, Lotspeich L, Sutcliffe JS, Haines JL, Folstein SE, Piven J, Wassink TH, Sheffield V, Geschwind DH, Bucan M, Brown WT, Cantor RM, Constantino JN, Gilliam TC, Herbert M, Lajonchere C, Ledbetter DH, Lese-Martin C, Miller J, Nelson S, Samango-Sprouse CA, Spence S, State M, Tanzi RE, Coon H, Dawson G, Devlin B, Estes A, Flodman P, Klei L, McMahon WM, Minshew N, Munson J, Korvatska E, Rodier PM, Schellenberg GD, Smith M, Spence MA, Stodgell C, Tepper PG, Wijsman EM, Yu CE, Rogé B, Mantoulan C, Wittemeyer K, Poustka A, Felder B, Klauck SM, Schuster C, Poustka F, Bölte S, Feineis-Matthews S, Herbrecht E, Schmötzer G, Tsiantis J, Papanikolaou K, Maestrini E, Bacchelli E, Blasi F, Carone S, Toma C, Van Engeland H, de Jonge M, Kemner C, Koop F, Langemeijer M, Hijmans C, Staal WG, Baird G, Bolton PF, Rutter ML, Weisblatt E, Green J, Aldred C, Wilkinson JA, Pickles A, Le Couteur A, Berney T, McConachie H, Bailey AJ, Francis K, Honeyman G, Hutchinson A, Parr JR, Wallace S, Monaco AP, Barnby G, Kobayashi K, Lamb JA, Sousa I, Sykes N, Cook EH, Guter SJ, Leventhal BL, Salt J, Lord C, Corsello C, Hus V, Weeks DE, Volkmar F, Tauber M, Fombonne E, Shih A, Meyer KJ. (2007). Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nature Genetics, 39, 319–328.CrossRefGoogle Scholar
  31. 31.
    Sebat J, Lakshmi B, Malhotra D, Troge J, Lese-Martin C, Walsh T, Yamrom B, Yoon S, Krasnitz A, Kendall J, Leotta A, Pai D, Zhang R, Lee YH, Hicks J, Spence SJ, Lee AT, Puura K, Lehtimäki T, Ledbetter D, Gregersen PK, Bregman J, Sutcliffe JS, Jobanputra V, Chung W, Warburton D, King MC, Skuse D, Geschwind DH, Gilliam TC, Ye K, Wigler M. (2007) Strong association of de novo copy number mutations with autism. Science, 316, 445–449.PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Weiss LA, Shen Y, Korn JM, Arking DE, Miller DT, Fossdal R, Saemundsen E, Stefansson H, Ferreira MA, Green T, Platt OS, Ruderfer DM, Walsh CA, Altshuler D, Chakravarti A, Tanzi RE, Stefansson K, Santangelo SL, Gusella JF, Sklar P, Wu BL, Daly MJ; Autism Consortium. (2008). Association between microdeletion and microduplication at 16p11.2 and autism. New England Journal of Medicine, 358, 667–675.Google Scholar
  33. 33.
    Kumar RA, KaraMohamed S, Sudi J, Conrad DF, Brune C, Badner JA, Gilliam TC, Nowak NJ, Cook EH Jr, Dobyns WB, Christian SL. (2008). Recurrent 16p11.2 microdeletions in autism. Human Molecular Genetics, 17, 628–638.Google Scholar
  34. 34.
    Christian SL, Brune CW, Sudi J, Kumar RA, Liu S, Karamohamed S, Badner JA, Matsui S, Conroy J, McQuaid D, Gergel J, Hatchwell E, Gilliam TC, Gershon ES, Nowak NJ, Dobyns WB, Cook EH Jr. (2008). Novel submicroscopic chromosomal abnormalities detected in autism spectrum disorder. Biological Psychiatry, 63, 1111–1117.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Jacquemont ML, Sanlaville D, Redon R, Raoul O, Cormier-Daire V, Lyonnet S, Amiel J, Le Merrer M, Heron D, de Blois MC, Prieur M, Vekemans M, Carter NP, Munnich A, Colleaux L, Philippe A. (2006). Array-based comparative genomic hybridisation identifies high frequency of cryptic chromosomal rearrangements in patients with syndromic autism spectrum disorders. Journal of Medical Genetics, 43, 843–849.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Morrow EM, Yoo SY, Flavell SW, Kim TK, Lin Y, Hill RS, Mukaddes NM, Balkhy S, Gascon G, Hashmi A, Al-Saad S, Ware J, Joseph RM, Greenblatt R, Gleason D, Ertelt JA, Apse KA, Bodell A, Partlow JN, Barry B, Yao H, Markianos K, Ferland RJ, Greenberg ME, Walsh CA. (2008). Identifying autism loci and genes by tracing recent shared ancestry. Science, 321, 218–223.PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Glessner JT, Wang K, Cai G, Korvatska O, Kim CE, Wood S, Zhang H, Estes A, Brune CW, Bradfield JP, Imielinski M, Frackelton EC, Reichert J, Crawford EL, Munson J, Sleiman PM, Chiavacci R, Annaiah K, Thomas K, Hou C, Glaberson W, Flory J, Otieno F, Garris M, Soorya L, Klei L, Piven J, Meyer KJ, Anagnostou E, Sakurai T, Game RM, Rudd DS, Zurawiecki D, McDougle CJ, Davis LK, Miller J, Posey DJ, Michaels S, Kolevzon A, Silverman JM, Bernier R, Levy SE, Schultz RT, Dawson G, Owley T, McMahon WM, Wassink TH, Sweeney JA, Nurnberger JI, Coon H, Sutcliffe JS, Minshew NJ, Grant SF, Bucan M, Cook EH, Buxbaum JD, Devlin B, Schellenberg GD, Hakonarson H. (2009). Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature, 459, 569–573.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Pinto D et al. Autism Genome Project Consortium (2010). Functional impact of global rare copy number variation in autism spectrum disorder. Nature, In press.Google Scholar
  39. 39.
    Fernandez B, Roberts W, Chung B, Weksberg R, Meyn S, Szatmari P, Joseph-George AM, MacKay S, Whitten K, Noble B, Vardy C, Crosbie V, Luscombe S, Tucker E, Turner L, Marshall CR, Scherer SW. (2010). Phenotypic spectrum associated with de novo and inherited deletions and duplications at 16p11.2 in individuals ascertained for diagnosis of autism spectrum disorder. Journal of Medical Genetics, 47, 195–203Google Scholar
  40. 40.
    Berkel S, Marshall CR, Weiss B, Howe J, Roeth R, Moog U, Endris V, Roberts W, Szatmari P, Pinto D, Bonin M, Riess A, Engels H, Sprengel R, Scherer SW, Rappold GA (2010). Mutations in the SHANK2 synaptic scaffolding gene in autism spectrum disorder and mental retardation. Nature Genetics, 42, 489–91.PubMedCrossRefGoogle Scholar
  41. 41.
    Noor A, Whibley A, Marshall CR, Gianakopoulos PJ, Piton A, Orlic M, Fernandez B, Pinto D, Baatjes-Young R, Zhang X, Mo R, Gauthier J, Roberts R, Szatmari P, Gallagher L, Stratton M, Gecz J, Brady A, Schwartz CE, Monaco AP, Rouleau GA, Hui C-C, Raymond FL, Scherer SW and Vincent JB.(2009). Disruption at the PTCHD1 locus on Xp22.11 in autism spectrum disorder and intellectual disability. Science Translational Medicine, In review.Google Scholar
  42. 42.
    Durand CM, Betancur C, Boeckers TM, Bockmann J, Chaste P, Fauchereau F, Nygren G, Rastam M, Gillberg IC, Anckarsäter H, Sponheim E, Goubran-Botros H, Delorme R, Chabane N, Mouren-Simeoni MC, de Mas P, Bieth E, Rogé B, Héron D, Burglen L, Gillberg C, Leboyer M, Bourgeron T. (2007). Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nature Genetics, 39, 25–27.PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Jamain S, Quach H, Betancur C, Råstam M, Colineaux C, Gillberg IC, Soderstrom H, Giros B, Leboyer M, Gillberg C, Bourgeron T; Paris Autism Research International Sibpair Study. (2003). Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nature Genetics, 34, 27–29.CrossRefGoogle Scholar
  44. 44.
    Willemsen MH, Fernandez BA, Bacino C, Gerkes E, de Brouwer APM, Pfundt R, Sikkema-Raddatz B, Scherer SW, Marshall CR, Potocki L, van Bokhoven H, Kleefstra T. (2010). Identification of ANKRD11 and ZNF778 as candidate genes for autism and variable cognitive impairment in the 16q24.3 microdeletion syndrome. European Journal of Human Genetics, 18, 429–35.Google Scholar
  45. 45.
    Bhalla K, Luo Y, Buchan T, Beachem MA, Guzauskas GF, Ladd S, Bratcher SJ, Schroer RJ, Balsamo J, DuPont BR, Lilien J, Srivastava AK. (2008). Alterations in CDH15 and KIRREL3 in patients with mild to severe intellectual disability. American Journal of Human Genetics, 83, 703–713PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Rapoport J, Chavez A, Greenstein D, Addington A, Gogtay N. (2009). Autism spectrum disorders and childhood-onset schizophrenia: clinical and biological contributions to a relation revisited. Journal of the American Academy of Child and Adolescent Psychiatry, 48, 10–18.PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Hofvander B, Delorme R, Chaste P, Nydén A, Wentz E, Ståhlberg O, Herbrecht E, Stopin A, Anckarsäter H, Gillberg C, Råstam M, Leboyer M. (2009). Psychiatric and psychosocial problems in adults with normal-intelligence autism spectrum disorders. BMC Psychiatry, 9, 35–44.PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Sporn AL, Addington AM, Gogtay N, Ordoñez AE, Gornick M, Clasen L, Greenstein D, Tossell JW, Gochman P, Lenane M, Sharp WS, Straub RE, Rapoport JL. (2004). Pervasive developmental disorder and childhood-onset schizophrenia: comorbid disorder or a phenotypic variant of a very early onset illness? Biological Psychiatry, 55, 989–994.PubMedCrossRefGoogle Scholar
  49. 49.
    Bassett AS, Chow EW. (2008). Schizophrenia and 22q11.2 deletion syndrome. Current Psychiatry Reports, 10, 148–157.Google Scholar
  50. 50.
    Fine SE, Weissman A, Gerdes M, Pinto-Martin J, Zackai EH, McDonald-McGinn DM, Emanuel BS. (2005). Autism spectrum disorders and symptoms in children with molecularly confirmed 22q11.2 deletion syndrome. Journal of Autism and Developmental Disorders, 35, 461–470.Google Scholar
  51. 51.
    Walsh T, McClellan JM, McCarthy SE, Addington AM, Pierce SB, Cooper GM, Nord AS, Kusenda M,Malhotra D, Bhandari A, Stray SM, Rippey CF, Roccanova P, Makarov V, Lakshmi B, Findling RL, Sikich L, Stromberg T, Merriman B, Gogtay N, Butler P, Eckstrand K, Noory L, Gochman P, Long R, Chen Z, Davis S, Baker C, Eichler EE, Meltzer PS, Nelson SF, Singleton AB, Lee MK, Rapoport JL, King MC, Sebat J. (2008). Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science, 320, 539–543.PubMedCrossRefGoogle Scholar
  52. 52.
    Xu B, Roos JL, Levy S, van Rensburg EJ, Gogos JA, Karayiorgou M. (2008). Strong association of de novo copy number mutations with sporadic schizophrenia. Nature Genetics, 40, 880–885.PubMedCrossRefGoogle Scholar
  53. 53.
    Goldstein S, Schwebach AJ. (2004). The comorbidity of Pervasive Developmental Disorder and Attention Deficit Hyperactivity Disorder: results of a retrospective chart review. Journal of Autism and Developmental Disorders, 34, 329–339.PubMedCrossRefGoogle Scholar
  54. 54.
    Clark T, Feehan C, Tinline C, Vostanis P. (1999) Autistic symptoms in children with attention deficithyperactivity disorder. European Child & Adolescent Psychiatry, 8, 50–55.CrossRefGoogle Scholar
  55. 55.
    Mulligan A, Anney RJ, O’Regan M, Chen W, Butler L, Fitzgerald M, Buitelaar J, Steinhausen HC, Rothenberger A, Minderaa R, Nijmeijer J, Hoekstra PJ, Oades RD, Roeyers H, Buschgens C, Christiansen H, Franke B, Gabriels I, Hartman C, Kuntsi J, Marco R, Meidad S, Mueller U, Psychogiou L, Rommelse N, Thompson M, Uebel H, Banaschewski T, Ebstein R, Eisenberg J, Manor I, Miranda A, Mulas F, Sergeant J, Sonuga-Barke E, Asherson P, Faraone SV, Gill M. (2009). Autism symptoms in Attention-Deficit/Hyperactivity Disorder: a familial trait which correlates with conduct, oppositional defiant, language and motor disorders. Journal of Autism and Developmental Disorders, 39, 197–209.PubMedCrossRefGoogle Scholar
  56. 56.
    Smalley SL, Kustanovich V, Minassian SL, Stone JL, Ogdie MN, McGough JJ, McCracken JT, MacPhie IL, Francks C, Fisher SE, Cantor RM, Monaco AP, Nelson SF. (2002). Genetic linkage of attention-deficit/hyperactivity disorder on chromosome 16p13, in a region implicated in autism. American Journal of Human Genetics, 71, 959–963.PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Ogdie MN, Fisher SE, Yang M, Ishii J, Francks C, Loo SK, Cantor RM, McCracken JT, McGough JJ, Smalley SL, Nelson SF. (2004). Attention deficit hyperactivity disorder: fine mapping supports linkage to 5p13, 6q12, 16p13, and 17p11. American Journal of Human Genetics, 75, 661–668.PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Elia J, Gai X, Xie HM, Perin JC, Geiger E, Glessner JT, D’arcy M, Deberardinis R, Frackelton E, Kim C, Lantieri F, Muganga BM, Wang L, Takeda T, Rappaport EF, Grant SF, Berrettini W, Devoto M, Shaikh TH, Hakonarson H, White PS. (2010). Rare structural variants found in attention-deficit hyperactivity disorder are preferentially associated with neurodevelopmental genes. Molecular Psychiatry, 15, 637–46.PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    O’Brien G, Pearson J. (2004). Autism and learning disability. Autism, 8, 125–140.PubMedCrossRefGoogle Scholar
  60. 60.
    Oti M, Huynen MA, Brunner HG (2008). Phenome connections. Trends in Genetics, 24, 103–106.PubMedCrossRefGoogle Scholar
  61. 61.
    Brunner HG, van Driel MA. (2004). From syndrome families to functional genomics. Nature Reviews Genetics, 5, 545–551.PubMedCrossRefGoogle Scholar
  62. 62.
    Rzhetsky A, Wajngurt D, Park N, Zheng T. (2007). Probing genetic overlap among complex human phenotypes. Proceedings of the National Academy of Sciences of the USA, 104, 11694–11699.PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Korn JM, Kuruvilla FG, McCarroll SA, Wysoker A, Nemesh J, Cawley S, Hubbell E, Veitch J, Collins PJ, Darvishi K, Lee C, Nizzari MM, Gabriel SB, Purcell S, Daly MJ, Altshuler D (2008). Integrated genotype calling and association analysis of SNPs, common copy number polymorphisms and rare CNVs. Nature Genetics, 40, 1253–60.PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Zhang J, Pinto D, Thiruvahindrapduram B, Wang Z, Prasad A, Marshall CR, Lionel A, Hu P, Greenwood CM, Feuk L, Wintle RF, Scherer SW (2010). iPattern: a cross-sample copy number variation discovery method for multiple array platforms. Nucleic Acid Research, In Review.Google Scholar
  65. 65.
    Alarcón M, Abrahams BS, Stone JL, Duvall JA, Perederiy JV, Bomar JM, Sebat J, Wigler M, Martin CL, Ledbetter DH, Nelson SF, Cantor RM, Geschwind DH (2008). Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene. American Journal of Human Genetics, 82, 150–9.PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    Bucan M, Abrahams BS, Wang K, Glessner JT, Herman EI, Sonnenblick LI, Alvarez, Retuerto AI, Imielinski M, Hadley D, Bradfield JP, Kim C, Gidaya NB, Lindquist I, Hutman T, Sigman M, Kustanovich V, Lajonchere CM, Singleton A, Kim J, Wassink TH, McMahon WM, Owley T, Sweeney JA, Coon H, Nurnberger JI, Li M, Cantor RM, Minshew NJ, Sutcliffe JS, Cook EH, Dawson G, Buxbaum JD, Grant SF, Schellenberg GD, Geschwind DH, Hakonarson H (2009). Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes. PLoS Genetics, 6, e1000536.CrossRefGoogle Scholar
  67. 67.
    Friedman JI, Vrijenhoek T, Markx S, Janssen IM, van der Vliet WA, Faas BH, Knoers NV, Cahn W, Kahn RS, Edelmann L, Davis KL, Silverman JM, Brunner HG, van Kessel AG, Wijmenga C, Ophoff RA, Veltman JA (2008). CNTNAP2 gene dosage variation is associated with schizophrenia and epilepsy. Molecular Psychiatry, 3, 261–6.CrossRefGoogle Scholar
  68. 68.
    International Schizophrenia Consortium (2008). Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature, 455, 237–41.CrossRefGoogle Scholar
  69. 69.
    Kirov G, Gumus D, Chen W, Norton N, Georgieva L, Sari M, O’Donovan MC, Erdogan F, Owen MJ, Ropers HH, Ullmann R (2008). Comparative genome hybridization suggests a role for NRXN1 and APBA2 in schizophrenia. Human Molecular Genetics, 17, 458–65.PubMedCrossRefGoogle Scholar
  70. 70.
    Kirov G, Grozeva D, Norton N, Ivanov D, Mantripragada KK, Holmans P; International Schizophrenia Consortium; Wellcome Trust Case Control Consortium, Craddock N, Owen MJ, O’Donovan MC (2009). Support for the involvement of large copy number variants in the pathogenesis of schizophrenia. Human Molecular Genetics, 18, 1497–503.CrossRefGoogle Scholar
  71. 71.
    Martin CL, Duvall JA, Ilkin Y, Simon JS, Arreaza MG, Wilkes K, Alvarez-Retuerto A, Whichello A, Powell CM, Rao K, Cook E, Geschwind DH (2007). Cytogenetic and molecular characterization of A2BP1/FOX1 as a candidate gene for autism. American Journal of Medical Genetics B Neuropsychiatric Genetics, 144B, 869–76.CrossRefGoogle Scholar
  72. 72.
    Need AC, Ge D, Weale ME, Maia J, Feng S, Heinzen EL, Shianna KV, Yoon W, Kasperaviciūte D, Gennarelli M, Strittmatter WJ, Bonvicini C, Rossi G, Jayathilake K, Cola PA, McEvoy JP, Keefe RS, Fisher EM, St Jean PL, Giegling I, Hartmann AM, Möller HJ, Ruppert A, Fraser G, Crombie C, Middleton LT, St Clair D, Roses AD, Muglia P, Francks C, Rujescu D, Meltzer HY, Goldstein DB (2009). A genome-wide investigation of SNPs and CNVs in schizophrenia. PLoS Genetics, 5, e1000373.PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Rodríguez-Santiago B, Brunet A, Sobrino B, Serra-Juhé C, Flores R, Armengol L, Vilella E, Gabau E, Guitart M, Guillamat R, Martorell L, Valero J, Gutiérrez-Zotes A, Labad A, Carracedo A, Estivill X, Pérez-Jurado LA (2009). Association of common copy number variants at the glutathione S-transferase genes and rare novel genomic changes with schizophrenia. Molecular Psychiatry. June 16 epub.Google Scholar
  74. 74.
    Rossi E, Verri AP, Patricelli MG, Destefani V, Ricca I, Vetro A, Ciccone R, Giorda R, Toniolo D, Maraschio P, Zuffardi O (2008). A 12Mb deletion at 7q33-q35 associated with autism spectrum disorders and primary amenorrhea. European Journal of Medical Genetics, 51, 631–8.PubMedCrossRefGoogle Scholar
  75. 75.
    Rujescu D, Ingason A, Cichon S, Pietiläinen OP, Barnes MR, Toulopoulou T, Picchioni M, Vassos E, Ettinger U, Bramon E, Murray R, Ruggeri M, Tosato S, Bonetto C, Steinberg S, Sigurdsson E, Sigmundsson T, Petursson H, Gylfason A, Olason PI, Hardarsson G, Jonsdottir GA, Gustafsson O, Fossdal R, Giegling I, Möller HJ, Hartmann AM, Hoffmann P, Crombie C, Fraser G, Walker N, Lonnqvist J, Suvisaari J, Tuulio-Henriksson A, Djurovic S, Melle I, Andreassen OA, Hansen T, Werge T, Kiemeney LA, Franke B, Veltman J, Buizer-Voskamp JE; GROUP Investigators, Sabatti C, Ophoff RA, Rietschel M, Nöthen MM, Stefansson K, Peltonen L, St Clair D, Stefansson H, Collier DA (2009). Disruption of the neurexin 1 gene is associated with schizophrenia. Human Molecular Genetics, 18, 988–96.Google Scholar
  76. 76.
    Stefansson H, Rujescu D, Cichon S, Pietiläinen OP, Ingason A, Steinberg S, Fossdal R, Sigurdsson E, Sigmundsson T, Buizer-Voskamp JE, Hansen T, Jakobsen KD, Muglia P, Francks C, Matthews PM, Gylfason A, Halldorsson BV, Gudbjartsson D, Thorgeirsson TE, Sigurdsson A, Jonasdottir A, Jonasdottir A, Bjornsson A, Mattiasdottir S, Blondal T, Haraldsson M, Magnusdottir BB, Giegling I, Möller HJ, Hartmann A, Shianna KV, Ge D, Need AC, Crombie C, Fraser G, Walker N, Lonnqvist J, Suvisaari J, Tuulio-Henriksson A, Paunio T, Toulopoulou T, Bramon E, Di Forti M, Murray R, Ruggeri M, Vassos E, Tosato S, Walshe M, Li T, Vasilescu C, Mühleisen TW, Wang AG, Ullum H, Djurovic S, Melle I, Olesen J, Kiemeney LA, Franke B; GROUP, Sabatti C, Freimer NB, Gulcher JR, Thorsteinsdottir U, Kong A, Andreassen OA, Ophoff RA, Georgi A, Rietschel M, Werge T, Petursson H, Goldstein DB, Nöthen MM, Peltonen L, Collier DA, St Clair D, Stefansson K (2008). Large recurrent microdeletions associated with schizophrenia. Nature, 455, 232–6.CrossRefGoogle Scholar
  77. 77.
    van der Zwaag B, Franke L, Poot M, Hochstenbach R, Spierenburg HA, Vorstman JA, van Daalen E, de Jonge MV, Verbeek NE, Brilstra EH, van ‘t Slot R, Ophoff RA, van Es MA, Blauw HM, Veldink JH, Buizer-Voskamp JE, Beemer FA, van den Berg LH, Wijmenga C, van Amstel HK, van Engeland H, Burbach JP, Staal WG (2009). Gene-network analysis identifies susceptibility genes related to glycobiology in autism. PLoS One, 4, e5324.Google Scholar
  78. 78.
    Vrijenhoek T, Buizer-Voskamp JE, van der Stelt I, Strengman E, Genetic Risk and Outcome in Psychosis (GROUP) Consortium, Sabatti C, Geurts van Kessel A, Brunner HG, Ophoff RA, Veltman JA (2008). Recurrent CNVs disrupt three candidate genes in schizophrenia patients. American Journal of Human Genetics, 83, 504–10.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Christian R. Marshall
    • 1
    • 2
  • Stephen W. Scherer
    • 1
    • 2
    • 3
  1. 1.The Centre for Applied GenomicsThe Hospital for Sick ChildrenTorontoCanada
  2. 2.Program in Genetics and Genome BiologyThe Hospital for Sick ChildrenTorontoCanada
  3. 3.Department of Molecular GeneticsUniversity of TorontoTorontoCanada

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