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Identification of risk genes for autism spectrum disorder through copy number variation analysis in Austrian families

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Abstract

Autism or autism spectrum disorder (ASD) is a range of neurodevelopmental disorders starting in early childhood and is characterized by impairments in communication and reciprocal social interaction and presence of restricted and repetitive patterns of behavior. The contribution of genetic factors to autism is clear in twin and family studies. It is apparent that, overall, ASD is a complex non-Mendelian disorder. Recent studies suggest that copy number variations (CNVs) play a significant role in the etiology of ASD. For the current work, we recruited 245 family members from 73 ASD families from Styria, Austria. The DNA from probands was genotyped with Affymetrix single nucleotide polymorphism (SNP) 6.0 microarrays to screen for CNVs in their genomes. Analysis of the microarray data was performed using three different algorithms, and a list of stringent calls was compared to existing CNV data from over 2,357 controls of European ancestry. For stringent calls not present in controls, quantitative real-time PCR (qRT-PCR) was used to validate the CNVs in the probands and in their family members. Twenty-two CNVs were validated from this set (five of which are apparently de novo), many of which appear likely to disrupt genes that may be considered as good candidates for neuropsychiatric disorders, including DLG2, S100B, ARX, DIP2A, HPCAL1, and GPHN. Several others disrupt genes that have previously been implicated in autism, such as BDNF, AUTS2, DPP6, and C18orf22, and our data add to the growing evidence of their involvement in ASD.

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References

  1. Devlin B, Scherer SW (2012) Genetic architecture in autism spectrum disorder. Curr Opin Genet Dev 22:229–237. doi:10.1016/j.gde.2012.03.002

    Article  PubMed  CAS  Google Scholar 

  2. Malhotra D, Sebat J (2012) CNVs: harbingers of a rare variant revolution in psychiatric genetics. Cell 148:1223–1241. doi:10.1016/j.cell.2012.02.039

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  3. 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

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  4. 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. Am J Hum Genet 82:477–488. doi:10.1016/j.ajhg.2007.12.009

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  5. Levy D, Ronemus M, Yamrom B, Lee YH, Leotta A, Kendall J, Marks S, Lakshmi B, Pai D, Ye K, Buja A, Krieger A, Yoon S, Troge J, Rodgers L, Iossifov I, Wigler M (2011) Rare de novo and transmitted copy-number variation in autistic spectrum disorders. Neuron 70:886–897. doi:10.1016/j.neuron.2011.05.015

    Article  PubMed  CAS  Google Scholar 

  6. Sanders SJ, Ercan-Sencicek AG, Hus V, Luo R, Murtha MT, Moreno-De-Luca D, Chu SH, Moreau MP, Gupta AR, Thomson SA, Mason CE, Bilguvar K, Celestino-Soper PB, Choi M, Crawford EL, Davis L, Wright NR, Dhodapkar RM, DiCola M, DiLullo NM, Fernandez TV, Fielding-Singh V, Fishman DO, Frahm S, Garagaloyan R, Goh GS, Kammela S, Klei L, Lowe JK, Lund SC, McGrew AD, Meyer KA, Moffat WJ, Murdoch JD, O'Roak BJ, Ober GT, Pottenger RS, Raubeson MJ, Song Y, Wang Q, Yaspan BL, Yu TW, Yurkiewicz IR, Beaudet AL, Cantor RM, Curland M, Grice DE, Günel M, Lifton RP, Mane SM, Martin DM, Shaw CA, Sheldon M, Tischfield JA, Walsh CA, Morrow EM, Ledbetter DH, Fombonne E, Lord C, Martin CL, Brooks AI, Sutcliffe JS, Cook EH Jr, Geschwind D, Roeder K, Devlin B, State MW (2011) Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron 70:863–885. doi:10.1016/j.neuron.2011.05.002

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  7. 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, Autism Genome Project Consortium (2007) Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat Genet 39:319–328

    Article  PubMed  CAS  Google Scholar 

  8. 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. Nat Genet 39:25–27

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  9. Moessner R, Marshall CR, Sutcliffe JS, Skaug J, Pinto D, Vincent J, Zwaigenbaum L, Fernandez B, Roberts W, Szatmari P, Scherer SW (2007) Contribution of SHANK3 mutations to autism spectrum disorder. Am J Hum Genet 81:1289–1297

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  10. 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. Nat Genet 42:489–491. doi:10.1038/ng.589

    Article  PubMed  CAS  Google Scholar 

  11. Noor A, Whibley A, Marshall CR, Gianakopoulos PJ, Piton A, Carson AR, Orlic-Milacic M, Lionel AC, Sato D, Pinto D, Drmic I, Noakes C, Senman L, Zhang X, Mo R, Gauthier J, Crosbie J, Pagnamenta AT, Munson J, Estes AM, Fiebig A, Franke A, Schreiber S, Stewart AF, Roberts R, McPherson R, Guter SJ, Cook EH Jr, Dawson G, Schellenberg GD, Battaglia A, Maestrini E, Consortium Autism Genome Project, Jeng L, Hutchison T, Rajcan-Separovic E, Chudley AE, Lewis SM, Liu X, Holden JJ, Fernandez B, Zwaigenbaum L, Bryson SE, Roberts W, Szatmari P, Gallagher L, Stratton MR, Gecz J, Brady AF, Schwartz CE, Schachar RJ, Monaco AP, Rouleau GA, Hui CC, Lucy Raymond F, Scherer SW, Vincent JB (2010) Disruption at the PTCHD1 locus on Xp22.11 in autism spectrum disorder and intellectual disability. Sci Transl Med 2:49ra68. doi:10.1126/scitranslmed.3001267

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  12. Betancur C, Buxbaum JD (2013) SHANK3 haploinsufficiency: a “common” but underdiagnosed highly penetrant monogenic cause of autism spectrum disorders. Mol Autism 4:17. doi:10.1186/2040-2392-4-17

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  13. Grozeva D, Kirov G, Ivanov D, Jones IR, Jones L, Green EK, St Clair DM, Young AH, Ferrier N, Farmer AE, McGuffin P, Holmans PA, Owen MJ, O'Donovan MC, Craddock N, Wellcome Trust Case Control Consortium (2010) Rare copy number variants: a point of rarity in genetic risk for bipolar disorder and schizophrenia. Arch Gen Psychiatry 67:318–327. doi:10.1001/archgenpsychiatry.2010.25

    Article  PubMed  Google Scholar 

  14. Buizer-Voskamp JE, Muntjewerff JW, Strengman E, Sabatti C, Stefansson H, Vorstman JA, Ophoff RA, Genetic Risk and Outcome in Psychosis (GROUP) Consortium Members (2011) Genome-wide analysis shows increased frequency of copy number variation deletions in Dutch schizophrenia patients. Biol Psychiatry 70:655–662. doi:10.1016/j.biopsych.2011.02.015

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  15. 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. doi:10.1038/nature07953

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  16. Lionel AC, Crosbie J, Barbosa N, Goodale T, Thiruvahindrapuram B, Rickaby J, Gazzellone M, Carson AR, Howe JL, Wang Z, Wei J, Stewart AF, Roberts R, McPherson R, Fiebig A, Franke A, Schreiber S, Zwaigenbaum L, Fernandez BA, Roberts W, Arnold PD, Szatmari P, Marshall CR, Schachar R, Scherer SW (2011) Rare copy number variation discovery and cross-disorder comparisons identify risk genes for ADHD. Sci Transl Med 3:95ra75. doi:10.1126/scitranslmed.3002464

    Article  PubMed  CAS  Google Scholar 

  17. Krawczak M, Nikolaus S, von Eberstein H, Croucher PJ, El Mokhtari NE, Schreiber S (2006) PopGen: population-based recruitment of patients and controls for the analysis of complex genotype-phenotype relationships. Commun Genet 9:55–61

    Article  Google Scholar 

  18. Stewart AF, Dandona S, Chen L, Assogba O, Belanger M, Ewart G, LaRose R, Doelle H, Williams K, Wells GA, McPherson R, Roberts R (2009) Kinesin family member 6 variant Trp719Arg does not associate with angiographically defined coronary artery disease in the Ottawa Heart Genomics Study. J Am Coll Cardiol 53:1471–1472. doi:10.1016/j.jacc.2008.12.051

    Article  PubMed  CAS  Google Scholar 

  19. Pinto D, Darvishi K, Shi X, Rajan D, Rigler D, Fitzgerald T, Lionel AC, Thiruvahindrapuram B, Macdonald JR, Mills R, Prasad A, Noonan K, Gribble S, Prigmore E, Donahoe PK, Smith RS, Park JH, Hurles ME, Carter NP, Lee C, Scherer SW, Feuk L (2011) Comprehensive assessment of array-based platforms and calling algorithms for detection of copy number variants. Nat Biotechnol 29:512–520. doi:10.1038/nbt.1852

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  20. Pinto D, Pagnamenta AT, Klei L, Anney R, Merico D, Regan R, Conroy J, Magalhaes TR, Correia C, Abrahams BS, Almeida J, Bacchelli E, Bader GD, Bailey AJ, Baird G, Battaglia A, Berney T, Bolshakova N, Bölte S, Bolton PF, Bourgeron T, Brennan S, Brian J, Bryson SE, Carson AR, Casallo G, Casey J, Chung BHY, Cochrane L, Corsello C, Crawford EL, Crossett A, Cytrynbaum C, Dawson G, de Jonge M, Delorme R, Drmic I, Duketis E, Duque F, Estes A, Farrar P, Fernandez BA, Folstein SE, Fombonne E, Freitag CM, Gilbert J, Gillberg C, Glessner JT, Goldberg J, Green A, Green J, Guter SJ, Hakonarson H, Heron EA, Hill M, Holt R, Howe JL, Hughes G, Hus V, Igliozzi R, Kim C, Klauck SM, Kolevzon A, Korvatska O, Kustanovich V, Lajonchere CM, Lamb JA, Laskawiec M, Leboyer M, Le Couteur A, Leventhal B, Lionel AC, Liu X-Q, Lord C, Lotspeich L, Lund SC, Maestrini E, Mahoney W, Mantoulan C, Marshall CR, McConachie H, McDougle CJ, McGrath J, McMahon WM, Merikangas A, Migita O, Minshew NJ, Mirza GK, Munson J, Nelson SF, Noakes C, Noor A, Nygren A, Oliveira G, Papanikolaou K, Parr JR, Parrini B, Paton T, Pickles A, Pilorge M, Piven J, Ponting CP, Posey DJ, Poustka A, Poustka F, Prasad A, Ragoussis J, Renshaw K, Rickaby J, Roberts W, Roeder K, Roge B, Rutter ML, Bierut LJ, Rice JP, Salt J, Sansom K, Sato D, Segurado R, Sequeira AF, Senman L, Shah N, Sheffield VC, Soorya L, Sousa I, Stein O, Sykes N, Stoppioni V, Strawbridge C, Tancredi R, Tansey K, Thiruvahindrapduram B, Thompson AP, Thomson S, Tryfon A, Tsiantis J, Van Engeland H, Vincent JB, Volkmar F, Wallace S, Wang K, Wang Z, Wassink TH, Webber C, Weksberg R, Wing K, Wittemeyer K, Wood S, Wu J, Yaspan BL, Zurawiecki D, Zwaigenbaum L, Buxbaum JD, Cantor RM, Cook EH, Coon H, Cuccaro ML, Devlin B, Ennis S, Gallagher L, Geschwind DH, Gill M, Haines JL, Hallmayer J, Miller J, Monaco AP, Nurnberger JI Jr, Paterson AD, Pericak-Vance MA, Schellenberg GD, Szatmari P, Vicente AM, Vieland VJ, Wijsman EM, Scherer SW, Sutcliffe JS, Betancur C, for the AGP (2010) Functional impact of global rare copy number variation in autism spectrum disorders. Nature 466:368–372. doi:10.1038/nature09146

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  21. Piton A, Gauthier J, Hamdan FF, Lafrenière RG, Yang Y, Henrion E, Laurent S, Noreau A, Thibodeau P, Karemera L, Spiegelman D, Kuku F, Duguay J, Destroismaisons L, Jolivet P, Côté M, Lachapelle K, Diallo O, Raymond A, Marineau C, Champagne N, Xiong L, Gaspar C, Rivière JB, Tarabeux J, Cossette P, Krebs MO, Rapoport JL, Addington A, Delisi LE, Mottron L, Joober R, Fombonne E, Drapeau P, Rouleau GA (2011) Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia. Mol Psychiatry 16:867–880. doi:10.1038/mp.2010.54

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  22. Sultana R, Yu C-E, Yu J, Munson J, Chen D, Hua W, Estes A, Cortes F, de la Barra F, Yu D, Haider ST, Trask BJ, Green ED, Raskind WH, Disteche CM, Wijsman E, Dawson G, Storm DR, Schellenberg GD, Villacres EC (2002) Identification of a novel gene on chromosome 7q11.2 interrupted by a translocation breakpoint in a pair of autistic twins. Genomics 80:129–134

    Article  PubMed  CAS  Google Scholar 

  23. Nagamani SC, Erez A, Ben-Zeev B, Frydman M, Winter S, Zeller R, El-Khechen D, Escobar L, Stankiewicz P, Patel A, Cheung SW (2013) Detection of copy-number variation in AUTS2 gene by targeted exonic array CGH in patients with developmental delay and autistic spectrum disorders. Eur J Hum Genet 21:343–346. doi:10.1038/ejhg.2012.157

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  24. Beunders G, Voorhoeve E, Golzio C, Pardo LM, Rosenfeld JA, Talkowski ME, Simonic I, Lionel AC, Vergult S, Pyatt RE, van de Kamp J, Nieuwint A, Weiss MM, Rizzu P, Verwer LE, van Spaendonk RM, Shen Y, Wu BL, Yu T, Yu Y, Chiang C, Gusella JF, Lindgren AM, Morton CC, van Binsbergen E, Bulk S, van Rossem E, Vanakker O, Armstrong R, Park SM, Greenhalgh L, Maye U, Neill NJ, Abbott KM, Sell S, Ladda R, Farber DM, Bader PI, Cushing T, Drautz JM, Konczal L, Nash P, De Los Reyes E, Carter MT, Hopkins E, Marshall CR, Osborne LR, Gripp KW, Thrush DL, Hashimoto S, Gastier-Foster JM, Astbury C, Ylstra B, Meijers-Heijboer H, Posthuma D, Menten B, Mortier G, Scherer SW, Eichler EE, Girirajan S, Katsanis N, Groffen AJ, Sistermans EA (2013) Exonic deletions in AUTS2 cause a syndromic form of intellectual disability and suggest a critical role for the C terminus. Am J Hum Genet 92:210–220. doi:10.1016/j.ajhg.2012.12.011

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  25. Anney R, Klei L, Pinto D, Regan R, Conroy J, Magalhaes TR, Correia C, Abrahams BS, Sykes N, Pagnamenta AT, Almeida J, Bacchelli E, Bailey AJ, Baird G, Battaglia A, Berney T, Bolshakova N, Bölte S, Bolton PF, Bourgeron T, Brennan S, Brian J, Carson AR, Casallo G, Casey J, Chu SH, Cochrane L, Corsello C, Crawford EL, Crossett A, Dawson G, de Jonge M, Delorme R, Drmic I, Duketis E, Duque F, Estes A, Farrar P, Fernandez BA, Folstein SE, Fombonne E, Freitag CM, Gilbert J, Gillberg C, Glessner JT, Goldberg J, Green J, Guter SJ, Hakonarson H, Heron EA, Hill M, Holt R, Howe JL, Hughes G, Hus V, Igliozzi R, Kim C, Klauck SM, Kolevzon A, Korvatska O, Kustanovich V, Lajonchere CM, Lamb JA, Laskawiec M, Leboyer M, Le Couteur A, Leventhal BL, Lionel AC, Liu XQ, Lord C, Lotspeich L, Lund SC, Maestrini E, Mahoney W, Mantoulan C, Marshall CR, McConachie H, McDougle CJ, McGrath J, McMahon WM, Melhem NM, Merikangas A, Migita O, Minshew NJ, Mirza GK, Munson J, Nelson SF, Noakes C, Noor A, Nygren G, Oliveira G, Papanikolaou K, Parr JR, Parrini B, Paton T, Pickles A, Piven J, Posey DJ, Poustka A, Poustka F, Prasad A, Ragoussis J, Renshaw K, Rickaby J, Roberts W, Roeder K, Roge B, Rutter ML, Bierut LJ, Rice JP, Salt J, Sansom K, Sato D, Segurado R, Senman L, Shah N, Sheffield VC, Soorya L, Sousa I, Stoppioni V, Strawbridge C, Tancredi R, Tansey K, Thiruvahindrapduram B, Thompson AP, Thomson S, Tryfon A, Tsiantis J, Van Engeland H, Vincent JB, Volkmar F, Wallace S, Wang K, Wang Z, Wassink TH, Wing K, Wittemeyer K, Wood S, Yaspan BL, Zurawiecki D, Zwaigenbaum L, Betancur C, Buxbaum JD, Cantor RM, Cook EH, Coon H, Cuccaro ML, Gallagher L, Geschwind DH, Gill M, Haines JL, Miller J, Monaco AP, Nurnberger JI Jr, Paterson AD, Pericak-Vance MA, Schellenberg GD, Scherer SW, Sutcliffe JS, Szatmari P, Vicente AM, Vieland VJ, Wijsman EM, Devlin B, Ennis S, Hallmayer J (2010) A genome-wide scan for common alleles affecting risk for autism. Hum Mol Genet 19:4072–4082. doi:10.1093/hmg/ddq307

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  26. Chapman NH, Estes A, Munson J, Bernier R, Webb SJ, Rothstein JH, Minshew NJ, Dawson G, Schellenberg GD, Wijsman EM (2011) Genome-scan for IQ discrepancy in autism: evidence for loci on chromosomes 10 and 16. Hum Genet 129:59–70. doi:10.1007/s00439-010-0899-z

    Article  PubMed Central  PubMed  Google Scholar 

  27. Casey JP, Magalhaes T, Conroy JM, Regan R, Shah N, Anney R, Shields DC, Abrahams BS, Almeida J, Bacchelli E, Bailey AJ, Baird G, Battaglia A, Berney T, Bolshakova N, Bolton PF, Bourgeron T, Brennan S, Cali P, Correia C, Corsello C, Coutanche M, Dawson G, de Jonge M, Delorme R, Duketis E, Duque F, Estes A, Farrar P, Fernandez BA, Folstein SE, Foley S, Fombonne E, Freitag CM, Gilbert J, Gillberg C, Glessner JT, Green J, Guter SJ, Hakonarson H, Holt R, Hughes G, Hus V, Igliozzi R, Kim C, Klauck SM, Kolevzon A, Lamb JA, Leboyer M, Le Couteur A, Leventhal BL, Lord C, Lund SC, Maestrini E, Mantoulan C, Marshall CR, McConachie H, McDougle CJ, McGrath J, McMahon WM, Merikangas A, Miller J, Minopoli F, Mirza GK, Munson J, Nelson SF, Nygren G, Oliveira G, Pagnamenta AT, Papanikolaou K, Parr JR, Parrini B, Pickles A, Pinto D, Piven J, Posey DJ, Poustka A, Poustka F, Ragoussis J, Roge B, Rutter ML, Sequeira AF, Soorya L, Sousa I, Sykes N, Stoppioni V, Tancredi R, Tauber M, Thompson AP, Thomson S, Tsiantis J, Van Engeland H, Vincent JB, Volkmar F, Vorstman JA, Wallace S, Wang K, Wassink TH, White K, Wing K, Wittemeyer K, Yaspan BL, Zwaigenbaum L, Betancur C, Buxbaum JD, Cantor RM, Cook EH, Coon H, Cuccaro ML, Geschwind DH, Haines JL, Hallmayer J, Monaco AP, Nurnberger JI Jr, Pericak-Vance MA, Schellenberg GD, Scherer SW, Sutcliffe JS, Szatmari P, Vieland VJ, Wijsman EM, Green A, Gill M, Gallagher L, Vicente A, Ennis S (2012) A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder. Hum Genet 131:565–579. doi:10.1007/s00439-011-1094-6

    Article  PubMed Central  PubMed  Google Scholar 

  28. Miller DT, Shen Y, Weiss LA, Korn J, Anselm I, Bridgemohan C, Cox GF, Dickinson H, Gentile J, Harris DJ, Hegde V, Hundley R, Khwaja O, Kothare S, Luedke C, Nasir R, Poduri A, Prasad K, Raffalli P, Reinhard A, Smith SE, Sobeih MM, Soul JS, Stoler J, Takeoka M, Tan WH, Thakuria J, Wolff R, Yusupov R, Gusella JF, Daly MJ, Wu BL (2009) Microdeletion/duplication at 15q13.2q13.3 among individuals with features of autism and other neuropsychiatric disorders. J Med Genet 46:242–248. doi:10.1136/jmg.2008.059907

    Article  PubMed  CAS  Google Scholar 

  29. Griggs BL, Ladd S, Saul RA, DuPont BR, Srivastava AK (2008) Dedicator of cytokinesis 8 is disrupted in two patients with mental retardation and developmental disabilities. Genomics 91:195–202

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  30. Noor A, Gianakopoulos PJ, Fernandez B, Marshall CR, Szatmari P, Roberts W, Scherer SW, Vincent JB (2009) Copy number variation analysis and sequencing of the X-linked mental retardation gene TSPAN7/TM4SF2 in patients with autism spectrum disorder. Psychiatr Genet 19:154–155. doi:10.1097/YPG.0b013e32832a4fe5

    Article  PubMed  Google Scholar 

  31. Bochukova EG, Huang N, Keogh J, Henning E, Purmann C, Blaszczyk K, Saeed S, Hamilton-Shield J, Clayton-Smith J, O'Rahilly S, Hurles ME, Farooqi IS (2010) Large, rare chromosomal deletions associated with severe early-onset obesity. Nature 463:666–670. doi:10.1038/nature08689

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  32. Bachmann-Gagescu R, Mefford HC, Cowan C, Glew GM, Hing AV, Wallace S, Bader PI, Hamati A, Reitnauer PJ, Smith R, Stockton DW, Muhle H, Helbig I, Eichler EE, Ballif BC, Rosenfeld J, Tsuchiya KD (2010) Recurrent 200-kb deletions of 16p11.2 that include the SH2B1 gene are associated with developmental delay and obesity. Genet Med 12:641–647. doi:10.1097/GIM.0b013e3181ef4286

    Article  PubMed  Google Scholar 

  33. Amici M, Doherty A, Jo J, Jane D, Cho K, Collingridge G, Dargan S (2009) Neuronal calcium sensors and synaptic plasticity. Biochem Soc Trans 37:1359–1363. doi:10.1042/BST0371359

    Article  PubMed  CAS  Google Scholar 

  34. 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 Genet 5:e1000536. doi:10.1371/journal.pgen.1000536

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  35. Ernst C, Marshall CR, Shen Y, Metcalfe K, Rosenfeld J, Hodge JC, Torres A, Blumenthal I, Chiang C, Pillalamarri V, Crapper L, Diallo AB, Ruderfer D, Pereira S, Sklar P, Purcell S, Wildin RS, Spencer AC, Quade BF, Harris DJ, Lemyre E, Wu BL, Stavropoulos DJ, Geraghty MT, Shaffer LG, Morton CC, Scherer SW, Gusella JF, Talkowski ME (2012) Highly penetrant alterations of a critical region including BDNF in human psychopathology and obesity. Arch Gen Psychiatry 69:1238–1246. doi:10.1001/archgenpsychiatry.2012.660

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  36. Lionel AC, Vaags AK, Sato D, Gazzellone MJ, Mitchell EB, Chen HY, Costain G, Walker S, Egger G, Thiruvahindrapuram B, Merico D, Prasad A, Anagnostou E, Fombonne E, Zwaigenbaum L, Roberts W, Szatmari P, Fernandez BA, Georgieva L, Brzustowicz LM, Roetzer K, Kaschnitz W, Vincent JB, Windpassinger C, Marshall CR, Trifiletti RR, Kirmani S, Kirov G, Petek E, Hodge JC, Bassett AS, Scherer SW (2013) Rare exonic deletions implicate the synaptic organizer Gephyrin (GPHN) in risk for autism, schizophrenia and seizures. Hum Mol Genet 22:2055–2066. doi:10.1093/hmg/ddt056

    Article  PubMed  CAS  Google Scholar 

  37. Bylund GO, Wipemo LC, Lundberg LA, Wikström PM (1998) RimM and RbfA are essential for efficient processing of 16S rRNA in Escherichia coli. J Bacteriol 180:73–82

    PubMed Central  PubMed  CAS  Google Scholar 

  38. Sherr EH (2003) The ARX story (epilepsy, mental retardation, autism, and cerebral malformations): one gene leads to many phenotypes. Curr Opin Pediatr 15:567–571

    Article  PubMed  Google Scholar 

  39. Thorson L, Bryke C, Rice G, Artzer A, Schilz C, Israel J, Huber S, Laffin J, Raca G (2010) Clinical and molecular characterization of overlapping interstitial Xp21-p22 duplications in two unrelated individuals. Am J Med Genet A 152A:904–915. doi:10.1002/ajmg.a.33340

    Article  PubMed  Google Scholar 

  40. Piccione M, Sanfilippo C, Cavani S, Salatiello P, Malacarne M, Pierluigi M, Fichera M, Luciano D, Corsello G (2011) Molecular and clinical characterization of a small duplication Xp in a human female with psychiatric disorders. J Genet 90:473–477

    Article  PubMed  Google Scholar 

  41. Carrié A, Jun L, Bienvenu T, Vinet MC, McDonell N, Couvert P, Zemni R, Cardona A, Van Buggenhout G, Frints S, Hamel B, Moraine C, Ropers HH, Strom T, Howell GR, Whittaker A, Ross MT, Kahn A, Fryns JP, Beldjord C, Marynen P, Chelly J (1999) A new member of the IL-1 receptor family highly expressed in hippocampus and involved in X-linked mental retardation. Nat Genet 23:25–31

    PubMed  Google Scholar 

  42. Piton A, Michaud JL, Peng H, Aradhya S, Gauthier J, Mottron L, Champagne N, Lafrenière RG, Hamdan FF, S2D team, Joober R, Fombonne E, Marineau C, Cossette P, Dubé MP, Haghighi P, Drapeau P, Barker PA, Carbonetto S, Rouleau GA (2008) Mutations in the calcium-related gene IL1RAPL1 are associated with autism. Hum Mol Genet 17:3965–3974. doi:10.1093/hmg/ddn300

    Article  PubMed  CAS  Google Scholar 

  43. Mastrangelo M, Leuzzi V (2012) Genes of early-onset epileptic encephalopathies: from genotype to phenotype. Pediatr Neurol 46:24–31. doi:10.1016/j.pediatrneurol.2011.11.003

    Article  PubMed  Google Scholar 

  44. Correia CT, Coutinho AM, Sequeira AF, Sousa IG, Lourenço Venda L, Almeida JP, Abreu RL, Lobo C, Miguel TS, Conroy J, Cochrane L, Gallagher L, Gill M, Ennis S, Oliveira GG, Vicente AM (2010) Increased BDNF levels and NTRK2 gene association suggest a disruption of BDNF/TrkB signaling in autism. Genes Brain Behav 9:841–848. doi:10.1111/j.1601-183X.2010.00627.x

    Article  PubMed  CAS  Google Scholar 

  45. Garcia KL, Yu G, Nicolini C, Michalski B, Garzon DJ, Chiu VS, Tongiorgi E, Szatmari P, Fahnestock M (2012) Altered balance of proteolytic isoforms of pro-brain-derived neurotrophic factor in autism. J Neuropathol Exp Neurol 71:289–297. doi:10.1097/NEN.0b013e31824b27e4

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  46. Chettouh Z, Croquette MF, Delobel B, Gilgenkrants S, Leonard C, Maunoury C, Prieur M, Rethoré MO, Sinet PM, Chery M, Delabar J-M (1995) Molecular mapping of 21 features associated with partial monosomy 21: involvement of the APP-SOD1 region. Am J Hum Genet 57:62–71

    PubMed Central  PubMed  CAS  Google Scholar 

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Acknowledgments

We thank the patients and their families for participating in this study. This work was supported by grants from Genome Canada and the Ontario Genomics Institute, and ÖNB Jubiläumsfonds (Project Number 13226). A.C.L. holds a NeuroDevNet doctoral fellowship. S.W.S. holds the GlaxoSmithKline-CIHR Chair in Genome Sciences at the University of Toronto and The Hospital for Sick Children. This study makes use of data generated by the DECIPHER and ISCA (www.iscaconsortium.org) consortia. A full list of centers contributing to the generation of the DECIPHER data is available from http://decipher.sanger.ac.uk and via email from decipher@sanger.ac.uk. Funding for the DECIPHER project was provided by the Wellcome Trust.

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Authors and Affiliations

  1. Neurogenetics Section, R-30, The Campbell Family Brain Research Institute, The Centre for Addiction & Mental Health (CAMH), 250 College Street, Toronto, ON, M5T 1R8, Canada

    Gerald Egger, Abdul Noor, Huda Mahmood, Oliver Boright, Anna Mikhailov & John B. Vincent

  2. Institute of Human Genetics, Medical University of Graz, Graz, Austria

    Gerald Egger, Katharina M. Roetzer, Thomas Schwarzbraun, Christian Windpassinger & Erwin Petek

  3. Department of Pediatric and Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada

    Abdul Noor

  4. The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada

    Anath C. Lionel, Christian R. Marshall & Stephen W. Scherer

  5. Department of Molecular Genetics and McLaughlin Centre, University of Toronto, Toronto, Ontario, Canada

    Anath C. Lionel, Christian R. Marshall & Stephen W. Scherer

  6. University Clinic for Child and Adolescent Medicine, Medical University of Graz, Graz, Austria

    Wolfgang Kaschnitz

  7. Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada

    John B. Vincent

  8. Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada

    John B. Vincent

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  1. Gerald Egger
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  2. Katharina M. Roetzer
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Corresponding author

Correspondence to John B. Vincent.

Additional information

Gerald Egger and Katharina M. Roetzer contributed equally to this work.

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Egger, G., Roetzer, K.M., Noor, A. et al. Identification of risk genes for autism spectrum disorder through copy number variation analysis in Austrian families. Neurogenetics 15, 117–127 (2014). https://doi.org/10.1007/s10048-014-0394-0

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