No Evidence for Association of Autism with Rare Heterozygous Point Mutations in Contactin-Associated Protein-Like 2 (), or in Other Contactin-Associated Proteins or Contactins

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Contactins and Contactin-Associated Proteins, and Contactin-Associated Protein-Like 2 (CNTNAP2) in particular, have been widely cited as autism risk genes based on findings from homozygosity mapping, molecular cytogenetics, copy number variation analyses, and both common and rare single nucleotide association studies. However, data specifically with regard to the contribution of heterozygous single nucleotide variants (SNVs) have been inconsistent. In an effort to clarify the role of rare point mutations in CNTNAP2 and related gene families, we have conducted targeted next-generation sequencing and evaluated existing sequence data in cohorts totaling 2704 cases and 2747 controls. We find no evidence for statistically significant association of rare heterozygous mutations in any of the CNTN or CNTNAP genes, including CNTNAP2, placing marked limits on the scale of their plausible contribution to risk.

Vyšlo v časopise: No Evidence for Association of Autism with Rare Heterozygous Point Mutations in Contactin-Associated Protein-Like 2 (), or in Other Contactin-Associated Proteins or Contactins. PLoS Genet 11(1): e32767. doi:10.1371/journal.pgen.1004852
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004852

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1. Strauss KA, Puffenberger EG, Huentelman MJ, Gottlieb S, Dobrin SE, et al. (2006) Recessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2. N Engl J Med 354: 1370–1377. doi: 10.1056/NEJMoa052773 16571880

2. Bakkaloglu B, O’Roak BJ, Louvi A, Gupta AR, Abelson JF, et al. (2008) Molecular cytogenetic analysis and resequencing of contactin associated protein-like 2 in autism spectrum disorders. Am J Hum Genet 82: 165–173. doi: 10.1016/j.ajhg.2007.09.017 18179895

3. Alarcon M, Abrahams BS, Stone JL, Duvall JA, Perederiy JV, et al. (2008) Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene. Am J Hum Genet 82: 150–159. doi: 10.1016/j.ajhg.2007.09.005 18179893

4. Arking DE, Cutler DJ, Brune CW, Teslovich TM, West K, et al. (2008) A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism. Am J Hum Genet 82: 160–164. doi: 10.1016/j.ajhg.2007.09.015 18179894

5. Penagarikano O, Abrahams BS, Herman EI, Winden KD, Gdalyahu A, et al. (2011) Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits. Cell 147: 235–246. doi: 10.1016/j.cell.2011.08.040 21962519

6. Vernes SC, Newbury DF, Abrahams BS, Winchester L, Nicod J, et al. (2008) A functional genetic link between distinct developmental language disorders. N Engl J Med 359: 2337–2345. doi: 10.1056/NEJMoa0802828 18987363

7. Poot M, Beyer V, Schwaab I, Damatova N, Van’t Slot R, et al. (2010) Disruption of CNTNAP2 and additional structural genome changes in a boy with speech delay and autism spectrum disorder. Neurogenetics 11: 81–89. doi: 10.1007/s10048-009-0205-1 19582487

8. Zweier C, de Jong EK, Zweier M, Orrico A, Ousager LB, et al. (2009) CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Hopkins-like mental retardation and determine the level of a common synaptic protein in Drosophila. Am J Hum Genet 85: 655–666. doi: 10.1016/j.ajhg.2009.10.004 19896112

9. Zweier C (2012) Severe Intellectual Disability Associated with Recessive Defects in CNTNAP2 and NRXN1. Mol Syndromol 2: 181–185. doi: 10.1159/000331270 22670139

10. Jackman C, Horn ND, Molleston JP, Sokol DK (2009) Gene associated with seizures, autism, and hepatomegaly in an Amish girl. Pediatr Neurol 40: 310–313. doi: 10.1016/j.pediatrneurol.2008.10.013 19302947

11. Anney R, Klei L, Pinto D, Regan R, Conroy J, et al. (2010) A genome-wide scan for common alleles affecting risk for autism. Hum Mol Genet 19: 4072–4082. doi: 10.1093/hmg/ddq307 20663923

12. Wang K, Zhang H, Ma D, Bucan M, Glessner JT, et al. (2009) Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature 459: 528–533. doi: 10.1038/nature07999 19404256

13. Weiss LA, Arking DE, Daly MJ, Chakravarti A (2009) A genome-wide linkage and association scan reveals novel loci for autism. Nature 461: 802–808. doi: 10.1038/nature08490 19812673

14. Anney R, Klei L, Pinto D, Almeida J, Bacchelli E, et al. (2012) Individual common variants exert weak effects on the risk for autism spectrum disorderspi. Hum Mol Genet 21: 4781–4792. doi: 10.1093/hmg/dds301 22843504

15. Sampath S, Bhat S, Gupta S, O’Connor A, West AB, et al. (2013) Defining the contribution of CNTNAP2 to autism susceptibility. PLoS One 8: e77906. doi: 10.1371/journal.pone.0077906 24147096

16. Compton AG, Albrecht DE, Seto JT, Cooper ST, Ilkovski B, et al. (2008) Mutations in contactin-1, a neural adhesion and neuromuscular junction protein, cause a familial form of lethal congenital myopathy. Am J Hum Genet 83: 714–724. doi: 10.1016/j.ajhg.2008.10.022 19026398

17. Fernandez T, Morgan T, Davis N, Klin A, Morris A, et al. (2004) Disruption of contactin 4 (CNTN4) results in developmental delay and other features of 3p deletion syndrome. Am J Hum Genet 74: 1286–1293. doi: 10.1086/421474 15106122

18. Pagnamenta AT, Bacchelli E, de Jonge MV, Mirza G, Scerri TS, et al. (2010) Characterization of a family with rare deletions in CNTNAP5 and DOCK4 suggests novel risk loci for autism and dyslexia. Biol Psychiatry 68: 320–328. doi: 10.1016/j.biopsych.2010.02.002 20346443

19. Ng PC, Henikoff S (2001) Predicting deleterious amino acid substitutions. Genome Res 11: 863–874. doi: 10.1101/gr.176601 11337480

20. Ng PC, Henikoff S (2003) SIFT: Predicting amino acid changes that affect protein function. Nucleic Acids Res 31: 3812–3814. doi: 10.1093/nar/gkg509 12824425

21. Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, et al. (2010) A method and server for predicting damaging missense mutations. Nat Methods 7: 248–249. doi: 10.1038/nmeth0410-248 20354512

22. Purcell S, Cherny SS, Sham PC (2003) Genetic Power Calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics 19: 149–150. doi: 10.1093/bioinformatics/19.1.149 12499305

23. Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ, et al. (2012) De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485: 237–241. doi: 10.1038/nature10945 22495306

24. Neale BM, Kou Y, Liu L, Ma’ayan A, Samocha KE, et al. (2012) Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 485: 242–245. doi: 10.1038/nature11011 22495311

25. O’Roak BJ, Vives L, Girirajan S, Karakoc E, Krumm N, et al. (2012) Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485: 246–250. doi: 10.1038/nature10989 22495309

26. Iossifov I, Ronemus M, Levy D, Wang Z, Hakker I, et al. (2012) De novo gene disruptions in children on the autistic spectrum. Neuron 74: 285–299. doi: 10.1016/j.neuron.2012.04.009 22542183

27. Lim ET, Raychaudhuri S, Sanders SJ, Stevens C, Sabo A, et al. (2013) Rare complete knockouts in humans: population distribution and significant role in autism spectrum disorders. Neuron 77: 235–242. doi: 10.1016/j.neuron.2012.12.029 23352160

28. Lai CS, Fisher SE, Hurst JA, Vargha-Khadem F, Monaco AP (2001) A forkhead-domain gene is mutated in a severe speech and language disorder. Nature 413: 519–523. doi: 10.1038/35097076 11586359

29. MacDermot KD, Bonora E, Sykes N, Coupe AM, Lai CS, et al. (2005) Identification of FOXP2 truncation as a novel cause of developmental speech and language deficits. Am J Hum Genet 76: 1074–1080. doi: 10.1086/430841 15877281

30. Zeesman S, Nowaczyk MJ, Teshima I, Roberts W, Cardy JO, et al. (2006) Speech and language impairment and oromotor dyspraxia due to deletion of 7q31 that involves FOXP2. Am J Med Genet A 140: 509–514. doi: 10.1002/ajmg.a.31110 16470794

31. Petrin AL, Giacheti CM, Maximino LP, Abramides DV, Zanchetta S, et al. (2010) Identification of a microdeletion at the 7q33-q35 disrupting the CNTNAP2 gene in a Brazilian stuttering case. Am J Med Genet A 152A: 3164–3172. doi: 10.1002/ajmg.a.33749 21108403

32. Roohi J, Montagna C, Tegay DH, Palmer LE, DeVincent C, et al. (2009) Disruption of contactin 4 in three subjects with autism spectrum disorder. J Med Genet 46: 176–182. doi: 10.1136/jmg.2008.057505 18349135

33. Glessner JT, Wang K, Cai G, Korvatska O, Kim CE, et al. (2009) Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature 459: 569–573. doi: 10.1038/nature07953 19404257

34. Chahrour MH, Yu TW, Lim ET, Ataman B, Coulter ME, et al. (2012) Whole-exome sequencing and homozygosity analysis implicate depolarization-regulated neuronal genes in autism. PLoS Genet 8: e1002635. doi: 10.1371/journal.pgen.1002635 22511880

35. Yu TW, Chahrour MH, Coulter ME, Jiralerspong S, Okamura-Ikeda K, et al. (2013) Using whole-exome sequencing to identify inherited causes of autism. Neuron 77: 259–273. doi: 10.1016/j.neuron.2012.11.002 23352163

36. Fischbach GD, Lord C (2010) The Simons Simplex Collection: a resource for identification of autism genetic risk factors. Neuron 68: 192–195. doi: 10.1016/j.neuron.2010.10.006 20955926

37. Liu L, Sabo A, Neale BM, Nagaswamy U, Stevens C, et al. (2013) Analysis of rare, exonic variation amongst subjects with autism spectrum disorders and population controls. PLoS Genet 9: e1003443. doi: 10.1371/journal.pgen.1003443 23593035

38. Exome Variant Server, NHLBI GO Exome Sequencing Project (ESP), Seattle, WA (URL: http://evs.gs.washington.edu/EVS/), [December 2012].

39. SeattleSNPs, NHLBI Program for Genomic Applications, SeattleSNPs, Seattle, WA (URL: http://pga.gs.washington.edu) [August 2012].

40. Sanders SJ, Ercan-Sencicek AG, Hus V, Luo R, Murtha MT, et al. (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 21658581

41. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira M, et al. (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81: 559–575. doi: 10.1086/519795 17701901

42. Fernandez TV, Sanders SJ, Yurkiewicz IR, Ercan-Sencicek AG, Kim YS, et al. (2012) Rare copy number variants in tourette syndrome disrupt genes in histaminergic pathways and overlap with autism. Biol Psychiatry 71: 392–402. doi: 10.1016/j.biopsych.2011.09.034 22169095