Exome Sequencing in an Admixed Isolated Population Indicates Variants Confer a Risk for Specific Language Impairment

English version České info

Children affected by Specific Language Impairment (SLI) have unexpected problems learning to talk and understand language, despite developing normally in all other areas. This disorder runs in families but we do not understand how the genetic contributions work, or which genetic mechanisms might be important. In this paper, we study a Chilean population who are affected by a high incidence of SLI. Such populations may provide increased power to discover contributory genetic factors, under appropriate conditions. We identify a genetic change in the population that causes a change to a protein called NFXL1. This change is usually very rare but is found at a higher frequency than expected in our population, particularly in those people affected by SLI. We then looked at this gene in over 100 individuals from the UK affected by SLI and found four more changes that probably affect the protein. This is a higher number than we would expect by chance. We therefore propose that the NFXL1 gene and the protein it encodes might be important in risk of SLI.

Vyšlo v časopise: Exome Sequencing in an Admixed Isolated Population Indicates Variants Confer a Risk for Specific Language Impairment. PLoS Genet 11(3): e32767. doi:10.1371/journal.pgen.1004925
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004925

Souhrn

Zdroje

1. Harel S, Greenstein Y, Kramer U, Yifat R, Samuel E, et al. (1996) Clinical characteristics of children referred to a child development center for evaluation of speech, language, and communication disorders. Pediatr Neurol 15: 305–311. 8972529

2. American-Psychiatric-Association (2000) Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IVTR). Washington, DC: American Psychiatric Publishing.

3. Law J, Boyle J, Harris F, Harkness A, Nye C (2000) Prevalence and natural history of primary speech and language delay: findings from a review of the literature. Int J Lang Commun Disord 35: 165–188. 10912250

4. Whitehouse AJ (2010) Is there a sex ratio difference in the familial aggregation of specific language impairment? A meta-analysis. J Speech Lang Hear Res 53: 1015–1025. doi: 10.1044/1092-4388(2009/09-0078) 20605945

5. Bishop DV, Laws G, Adams C, Norbury CF (2006) High heritability of speech and language impairments in 6-year-old twins demonstrated using parent and teacher report. Behav Genet 36: 173–184. 16485179

6. Bishop DV (2001) Genetic and environmental risks for specific language impairment in children. Philos Trans R Soc Lond B Biol Sci 356: 369–380. 11316485

7. Newbury DF, Winchester L, Addis L, Paracchini S, Buckingham LL, et al. (2009) CMIP and ATP2C2 modulate phonological short-term memory in language impairment. Am J Hum Genet 85: 264–272. doi: 10.1016/j.ajhg.2009.07.004 19646677

8. Luciano M, Evans DM, Hansell NK, Medland SE, Montgomery GW, et al. (2013) A genome-wide association study for reading and language abilities in two population cohorts. Genes Brain Behav 12: 645–652. doi: 10.1111/gbb.12053 23738518

9. Gialluisi A, Newbury DF, Wilcutt EG, Olson RK, DeFries JC, et al. (2014) Genome-wide screening for DNA variants associated with reading and language traits. Genes Brain Behav 13: 686–701. doi: 10.1111/gbb.12158 25065397

10. St Pourcain B, Cents RA, Whitehouse AJ, Haworth CM, Davis OS, et al. (2014) Common variation near ROBO2 is associated with expressive vocabulary in infancy. Nat Commun 5: 4831. doi: 10.1038/ncomms5831 25226531

11. Eicher JD, Powers NR, Miller LL, Akshoomoff N, Amaral DG, et al. (2013) Genome-wide association study of shared components of reading disability and language impairment. Genes Brain Behav 12: 792–801. doi: 10.1111/gbb.12085 24024963

12. Nudel R, Simpson NH, Baird G, O’Hare A, Conti-Ramsden G, et al. (2014) Genome-wide association analyses of child genotype effects and parent-of-origin effects in specific language impairment (SLI). Genes, Brain, Behavior 13: 418–429. doi: 10.1111/gbb.12127 24571439

13. Ceroni F, Simpson NH, Francks C, Baird G, Conti-Ramsden G, et al. (2014) Homozygous microdeletion of exon 5 in ZNF277 in a girl with specific language impairment. Eur J Hum Genet 22: 1165–1171. doi: 10.1038/ejhg.2014.4 24518835

14. Simpson NH, Addis L, Brandler WM, Slonims V, Clark A, et al. (2013) Increased prevalence of sex chromosome aneuploidies in specific language impairment and dyslexia. Dev Med Child Neurol 56: 346–353. doi: 10.1111/dmcn.12294 24117048

15. Newbury DF, Paracchini S, Scerri TS, Winchester L, Addis L, et al. (2011) Investigation of dyslexia and SLI risk variants in reading—and language-impaired subjects. Behav Genet 41: 90–104. doi: 10.1007/s10519-010-9424-3 21165691

16. Scerri TS, Morris AP, Buckingham LL, Newbury DF, Miller LL, et al. (2011) DCDC2, KIAA0319 and CMIP are associated with reading-related traits. Biological Psychiatry 70: 237–245. doi: 10.1016/j.biopsych.2011.02.005 21457949

17. Shu W, Yang H, Zhang L, Lu MM, Morrisey EE (2001) Characterization of a new subfamily of winged-helix/forkhead (Fox) genes that are expressed in the lung and act as transcriptional repressors. J Biol Chem 276: 27488–27497. 11358962

18. 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. 11586359

19. Feuk L, Kalervo A, Lipsanen-Nyman M, Skaug J, Nakabayashi K, et al. (2006) Absence of a paternally inherited FOXP2 gene in developmental verbal dyspraxia. Am J Hum Genet 79: 965–972. 17033973

20. 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. 15877281

21. Shriberg LD, Ballard KJ, Tomblin JB, Duffy JR, Odell KH, et al. (2006) Speech, prosody, and voice characteristics of a mother and daughter with a 7;13 translocation affecting FOXP2. J Speech Lang Hear Res 49: 500–525. 16787893

22. 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. 16470794

23. Fisher SE (2006) Tangled webs: tracing the connections between genes and cognition. Cognition 101: 270–297. 16764847

24. Spiteri E, Konopka G, Coppola G, Bomar J, Oldham M, et al. (2007) Identification of the transcriptional targets of FOXP2, a gene linked to speech and language, in developing human brain. Am J Hum Genet 81: 1144–1157. 17999357

25. Vernes SC, Spiteri E, Nicod J, Groszer M, Taylor JM, et al. (2007) High-throughput analysis of promoter occupancy reveals direct neural targets of FOXP2, a gene mutated in speech & language disorders. Am J Hum Genet 81: 1232–1250. 17999362

26. Rodenas-Cuadrado P, Ho J, Vernes SC (2014) Shining a light on CNTNAP2: complex functions to complex disorders. Eur J Hum Genet 22: 171–178. doi: 10.1038/ejhg.2013.100 23714751

27. Stein MB, Yang BZ, Chavira DA, Hitchcock CA, Sung SC, et al. (2011) A common genetic variant in the neurexin superfamily member CNTNAP2 is associated with increased risk for selective mutism and social anxiety-related traits. Biol Psychiatry 69: 825–831. doi: 10.1016/j.biopsych.2010.11.008 21193173

28. 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

29. Peter B, Raskind WH, Matsushita M, Lisowski M, Vu T, et al. (2011) Replication of CNTNAP2 association with nonword repetition and support for FOXP2 association with timed reading and motor activities in a dyslexia family sample. J Neurodev Disord 3: 39–49. doi: 10.1007/s11689-010-9065-0 21484596

30. Whitehouse AJ, Bishop DV, Ang QW, Pennell CE, Fisher SE (2011) CNTNAP2 variants affect early language development in the general population. Genes Brain Behav 10: 451–456. doi: 10.1111/j.1601-183X.2011.00684.x 21310003

31. Whalley HC, O’Connell G, Sussmann JE, Peel A, Stanfield AC, et al. (2011) Genetic variation in CNTNAP2 alters brain function during linguistic processing in healthy individuals. Am J Med Genet B Neuropsychiatr Genet 156B: 941–948. doi: 10.1002/ajmg.b.31241 21987501

32. Kos M, van den Brink D, Snijders TM, Rijpkema M, Franke B, et al. (2012) CNTNAP2 and language processing in healthy individuals as measured with ERPs. PLoS One 7: e46995. doi: 10.1371/journal.pone.0046995 23115634

33. Villanueva P, de Barbieri Z, Palomino HM, Palomino H (2008) [High prevalence of specific language impairment in Robinson Crusoe Island. A possible founder effect]. Rev Med Chil 136: 186–192. 18483672

34. Villanueva P, Fernandez MA, Z DEB, Palomino H (2013) Consanguinity on Robinson Crusoe Island, an Isolated Chilean Population. J Biosoc Sci: 1–10. 23931260

35. Villanueva P, Newbury DF, Jara L, De Barbieri Z, Mirza G, et al. (2011) Genome-wide analysis of genetic susceptibility to language impairment in an isolated Chilean population. Eur J Hum Genet 19: 687–695. doi: 10.1038/ejhg.2010.251 21248734

36. Thornton T, McPeek MS (2007) Case-control association testing with related individuals: a more powerful quasi-likelihood score test. Am J Hum Genet 81: 321–337. 17668381

37. SLIC (2002) A genomewide scan identifies two novel loci involved in Specific Language Impairment. Am J Hum Genet 70: 384–398. 11791209

38. SLIC (2004) Highly significant linkage to the SLI1 locus in an expanded sample of individuals affected by specific language impairment. Am J Hum Genet 74: 1225–1238. 15133743

39. Falcaro M, Pickles A, Newbury DF, Addis L, Banfield E, et al. (2008) Genetic and phenotypic effects of phonological short-term memory and grammatical morphology in specific language impairment. Genes Brain Behav 7: 393–402. 18005161

40. Durbin RM, Abecasis GR, Altshuler DL, Auton A, Brooks LD, et al. (2010) A map of human genome variation from population-scale sequencing. Nature 467: 1061–1073.

41. O’Roak BJ, Deriziotis P, Lee C, Vives L, Schwartz JJ, et al. (2011) Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nat Genet 43: 585–589. doi: 10.1038/ng.835 21572417

42. Leblond CS, Jutta H, Delorme R, Proepper C, Betancur C, et al. (2012) Genetic and Functional Analyses of SHANK2 Mutations Suggest a Multiple Hit Model of Autism Spectrum Disorders. Plos Genetics 8: e1002521. doi: 10.1371/journal.pgen.1002521 22346768

43. 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

44. Horn D, Kapeller J, Rivera-Brugues N, Moog U, Lorenz-Depiereux B, et al. (2010) Identification of FOXP1 deletions in three unrelated patients with mental retardation and significant speech and language deficits. Hum Mutat 31: E1851–1860. doi: 10.1002/humu.21362 20848658

45. Girirajan S, Brkanac Z, Coe BP, Baker C, Vives L, et al. (2011) Relative Burden of Large CNVs on a Range of Neurodevelopmental Phenotypes. PLoS Genet 7: e1002334. doi: 10.1371/journal.pgen.1002334 22102821

46. Gilissen C, Hoischen A, Brunner HG, Veltman JA (2012) Disease gene identification strategies for exome sequencing. European Journal of Human Genetics 20: 490–497. 22258526

47. Tang W, Yuan J, Chen X, Shan Y, Luo K, et al. (2005) Cloning and characterization of the CDZFP gene which encodes a putative zinc finger protein. DNA Seq 16: 391–396. 16323267

48. Mussig C, Schroder F, Usadel B, Lisso J (2010) Structure and putative function of NFX1-like proteins in plants. Plant Biol (Stuttg) 12: 381–394. doi: 10.1111/j.1438-8677.2009.00303.x 20522174

49. Chaerkady R, Letzen B, Renuse S, Sahasrabuddhe NA, Kumar P, et al. (2011) Quantitative temporal proteomic analysis of human embryonic stem cell differentiation into oligodendrocyte progenitor cells. Proteomics 11: 4007–4020. doi: 10.1002/pmic.201100107 21770034

50. Song Z, Krishna S, Thanos D, Strominger JL, Ono SJ (1994) A novel cysteine-rich sequence-specific DNA-binding protein interacts with the conserved X-box motif of the human major histocompatibility complex class II genes via a repeated Cys-His domain and functions as a transcriptional repressor. J Exp Med 180: 1763–1774. 7964459

51. Nudel R, Simpson NH, Baird G, O’Hare A, Conti-Ramsden G, et al. (2014) Associations of HLA alleles with specific language impairment. J Neurodev Disord 6: 1. doi: 10.1186/1866-1955-6-1 24433325

52. Xu M, Katzenellenbogen RA, Grandori C, Galloway DA (2010) NFX1 plays a role in human papillomavirus type 16 E6 activation of NFkappaB activity. J Virol 84: 11461–11469. doi: 10.1128/JVI.00538-10 20739528

53. Kamal M, Valanciute A, Dahan K, Ory V, Pawlak A, et al. (2009) C-mip interacts physically with RelA and inhibits nuclear factor kappa B activity. Mol Immunol 46: 991–998. doi: 10.1016/j.molimm.2008.09.034 19019440

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

55. Cummings AC, Lee SL, McCauley JL, Jiang L, Crunk A, et al. (2011) A genome-wide linkage screen in the Amish with Parkinson disease points to chromosome 6. Ann Hum Genet 75: 351–358. doi: 10.1111/j.1469-1809.2011.00643.x 21488853

56. Cummings AC, Torstenson E, Davis MF, D’Aoust LN, Scott WK, et al. (2013) Evaluating power and type 1 error in large pedigree analyses of binary traits. PLoS One 8: e62615. doi: 10.1371/journal.pone.0062615 23658753

57. Nyholt D (2008) Principles of linkage analysis. In: Neale B, Ferreira M, Medland SE, Posthuma D, editors. Statistical genetics: gene mapping through linkage and association. New York; Abingdon: Taylor & Francis. pp. 113–134.

58. Pavez M (2003) Test exploratorio de Gramática española de A. Toronto. Aplicación en Chile. Santiago: Ediciones Universidad católica de Chile.

59. Pavez MM, Maggiolo M (2000) Test para evaluar los procesos fonologicos de simplificacion TEPROSIF; De Barbieri Z, editor. Santiago, Chile: Ediciones Escuela de Fonoaudiologia. v. p.

60. Burgemeister B, Blue L, Lorge I (1998) Escala de madurez mental. Columbia: Ed. TEA, Madrid.

61. Villanueva P (2000) Pauta de Examen en Habla y motricidad Orofacial. Santiago: Escuela de Fonoaudiología, Facultad de Medicina, Universidad de Chile.

62. Peña-Casanova J (1991) Programa integrado de exploración Neuropsicológica. Test de Barcelona. Masson, Barcelona.

63. De Renzi E, Vignolo L (1962) The Token Test: a sensitive tests to detect receptive disturbances in aphasics. Brain 85: 665–678. 14026018

64. Tallal P, Hirsch LS, Realpe-Bonilla T, Miller S, Brzustowicz LM, et al. (2001) Familial aggregation in specific language impairment. J Speech Lang Hear Res 44: 1172–1182. 11708534

65. Marth GT, Korf I, Yandell MD, Yeh RT, Gu Z, et al. (1999) A general approach to single-nucleotide polymorphism discovery. Nat Genet 23: 452–456. 10581034

66. Rozen S, Skaletsky H (2000) Primer3 on the WWW for general users and for biologist programmers. Methods Mol Biol 132: 365–386. 10547847

67. Thornton T, Zhang Q, Cai X, Ober C, McPeek MS (2012) XM: association testing on the X-chromosome in case-control samples with related individuals. Genet Epidemiol 36: 438–450. doi: 10.1002/gepi.21638 22552845

68. Bourgain C, Hoffjan S, Nicolae R, Newman D, Steiner L, et al. (2003) Novel case-control test in a founder population identifies P-selectin as an atopy-susceptibility locus. Am J Hum Genet 73: 612–626. 12929084

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

70. Abecasis GR, Cherny SS, Cookson WO, Cardon LR (2002) Merlin—rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 30: 97–101. 11731797

71. Kong A, Cox NJ (1997) Allele-sharing models: LOD scores and accurate linkage tests. Am J Hum Genet 61: 1179–1188. 9345087

72. Schwarz JM, Rodelsperger C, Schuelke M, Seelow D (2010) MutationTaster evaluates disease-causing potential of sequence alterations. Nat Methods 7: 575–576. doi: 10.1038/nmeth0810-575 20676075

73. Dollaghan CA (2011) Taxometric analyses of specific language impairment in 6-year-old children. J Speech Lang Hear Res 54: 1361–1371. doi: 10.1044/1092-4388(2011/10-0187) 21646422

74. Bedore LM, Leonard LB (2001) Grammatical morphology deficits in Spanish-speaking children with specific language impairment. J Speech Lang Hear Res 44: 905–924. 11521782

75. Burden V, Stott CM, Forge J, Goodyer I (1996) The Cambridge Language and Speech Project (CLASP). I. Detection of language difficulties at 36 to 39 months. Dev Med Child Neurol 38: 613–631. 8674912

76. Clark A, O’Hare A, Watson J, Cohen W, Cowie H, et al. (2007) Severe receptive language disorder in childhood—familial aspects and long-term outcomes: results from a Scottish study. Arch Dis Child 92: 614–619. 17405857

77. Conti-Ramsden G, Botting N (1999) Characteristics of children attending language units in England: a national study of 7-year-olds. Int J Lang Commun Disord 34: 359–366. 10884906

78. Semel EM, Wiig EH, Secord W (1992) Clinical Evaluation of Language Fundamentals—Revised. San Antonio: Phychological Corporation.

79. Wechsler D (1992) Wechsler Intelligence Scale for Children - Third UK Edition. London: Psychological Corporation.

80. Lunter G, Goodson M (2011) Stampy: a statistical algorithm for sensitive and fast mapping of Illumina sequence reads. Genome Research 21: 936–939. doi: 10.1101/gr.111120.110 20980556

81. Rivas MA, Beaudoin M, Gardet A, Stevens C, Sharma Y, et al. (2011) Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease. Nat Genet 43: 1066–1073. 21983784

82. Cingolani P, Platts A, Wang le L, Coon M, Nguyen T, et al. (2012) A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. Fly (Austin) 6: 80–92. doi: 10.4161/fly.19695 22728672

83. Mathieson I, McVean G (2012) Differential confounding of rare and common variants in spatially structured populations. Nat Genet 44: 243–246. doi: 10.1038/ng.1074 22306651