Language impairment in a case of a complex chromosomal rearrangement with a breakpoint downstream of FOXP2

Molecular Cytogenetics

Paloma García-Bellido¹  Dianne F. Newbury³  Antonio Benítez-Burraco²  Emanuela V. Volpi⁴  Catherine M. Green³  May T. M. Chan⁵  Ron Nudel³  Daniela Moralli³ 

[1] Faculty of Modern languages, University of Oxford, 47 Wellington Square, Oxford OX1 2JF, UK;Department of Spanish Philology and its Didactics, University of Huelva, Huelva, Spain;Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Headington, Oxford OX3 7BN, UK;Department of Biomedical Sciences, University of Westminster, 115 New Cavendish Street, London W1W 6UW, UK;Worcester College, University of Oxford, OX1 2HBOxford, UK

关键词: Spanish;    Non-coding elements;    FOXP2 regulation;    Chromosomal rearrangement;    Language impairment;   

Others  :  1221618
DOI  :  10.1186/s13039-015-0148-1

 received in 2015-03-24, accepted in 2015-05-20,  发布年份 2015

【 摘 要 】

Background

We report on a young female, who presents with a severe speech and language disorder and a balanced de novo complex chromosomal rearrangement, likely to have resulted from a chromosome 7 pericentromeric inversion, followed by a chromosome 7 and 11 translocation.

Results

Using molecular cytogenetics, we mapped the four breakpoints to 7p21.1-15.3 (chromosome position: 20,954,043-21,001,537, hg19), 7q31 (chromosome position: 114,528,369-114,556,605, hg19), 7q21.3 (chromosome position: 93,884,065-93,933,453, hg19) and 11p12 (chromosome position: 38,601,145-38,621,572, hg19). These regions contain only non-coding transcripts (ENSG00000232790 on 7p21.1 and TCONS_00013886, TCONS_00013887, TCONS_00014353, TCONS_00013888 on 7q21) indicating that no coding sequences are directly disrupted. The breakpoint on 7q31 mapped 200 kb downstream of FOXP2, a well-known language gene. No splice site or non-synonymous coding variants were found in the FOXP2 coding sequence. We were unable to detect any changes in the expression level of FOXP2 in fibroblast cells derived from the proband, although this may be the result of the low expression level of FOXP2 in these cells.

Conclusions

We conclude that the phenotype observed in this patient either arises from a subtle change in FOXP2 regulation due to the disruption of a downstream element controlling its expression, or from the direct disruption of non-coding RNAs.

【 授权许可】

   
2015 Moralli et al.

【 图 表 】

Fig. 1.

【 参考文献 】

• [1]Benítez-Burraco A. Genes y lenguaje: aspectos ontogeniticos, filogeneticos y cognitivos. Reverte, Barcelona; 2009.
• [2]Newbury DF, Fisher SE, Monaco AP. Recent advances in the genetics of language impairment. Genomic Med. 2010; 2:6. BioMed Central Full Text
• [3]Graham SA, Fisher SE. Decoding the genetics of speech and language. Curr Opin Neurobiol. 2013; 23(1):43-51.
• [4]Gopnik M, Crago MB. Familial aggregation of a developmental language disorder. Cognition. 1991; 39(1):1-50.
• [5]Vargha-Khadem F, Watkins K, Alcock K, Fletcher P, Passingham R. Praxic and nonverbal cognitive deficits in a large family with a genetically transmitted speech and language disorder. Proc Natl Acad Sci U S A. 1995; 92(3):930-3.
• [6]Watkins KE, Dronkers NF, Vargha-Khadem F. Behavioural analysis of an inherited speech and language disorder: comparison with acquired aphasia. Brain. 2002; 125(Pt 3):452-64.
• [7]Lai CS, Fisher SE, Hurst JA, Vargha-Khadem F, Monaco AP. A forkhead-domain gene is mutated in a severe speech and language disorder. Nature. 2001; 413(6855):519-23.
• [8]Shriberg LD, Ballard KJ, Tomblin JB, Duffy JR, Odell KH, Williams CA. Speech, prosody, and voice characteristics of a mother and daughter with a 7;13 translocation affecting FOXP2. J Speech Lang Hear Res. 2006; 49(3):500-25.
• [9]Kosho T, Sakazume S, Kawame H, Wakui K, Wada T, Okoshi Y et al.. De-novo balanced translocation between 7q31 and 10p14 in a girl with central precocious puberty, moderate mental retardation, and severe speech impairment. Clin Dysmorphol. 2008; 17(1):31-4.
• [10]Tomblin JB, O’Brien M, Shriberg LD, Williams C, Murray J, Patil S et al.. Language features in a mother and daughter of a chromosome 7;13 translocation involving FOXP2. J Speech Lang Hear Res. 2009; 52(5):1157-74.
• [11]Wassink TH, Piven J, Vieland VJ, Pietila J, Goedken RJ, Folstein SE et al.. Evaluation of FOXP2 as an autism susceptibility gene. Am J Med Genet. 2002; 114(5):566-9.
• [12]MacDermot KD, Bonora E, Sykes N, Coupe AM, Lai CS, Vernes SC et al.. Identification of FOXP2 truncation as a novel cause of developmental speech and language deficits. Am J Hum Genet. 2005; 76(6):1074-80.
• [13]Roll P, Vernes SC, Bruneau N, Cillario J, Ponsole-Lenfant M, Massacrier A et al.. Molecular networks implicated in speech-related disorders: FOXP2 regulates the SRPX2/uPAR complex. Hum Mol Genet. 2010; 19(24):4848-60.
• [14]García-Bellido P, Benítez-Burraco A, Roselló M, Monfort S, Martínez F, Oltra S et al.. A case of Spanish language disorders with a rare genetic cause. In: Linguistics: The Challenge of Clinical Application. Marrero V, Pineda I, editors. UNED-Euphonia Ediciones, Madrid; 2009: p.365-70.
• [15]Kirk SA, J.J. M, Kirk WK. Test Illinois de Aptitudes Psicolingüísticas. Manual. 2a Ed. Adaptación Española. TEA Ediciones, Madrid; 1989.
• [16]Wechsler D. WISC-R. Escala de Inteligencia de Wechsler para Niños - Revisada. Manual. TEA Ediciones, Madrid; 2001.
• [17]Lopez-Bendito G, Flames N, Ma L, Fouquet C, Di Meglio T, Chedotal A et al.. Robo1 and Robo2 cooperate to control the guidance of major axonal tracts in the mammalian forebrain. J Neurosci. 2007; 27(13):3395-407.
• [18]Suda S, Iwata K, Shimmura C, Kameno Y, Anitha A, Thanseem I et al.. Decreased expression of axon-guidance receptors in the anterior cingulate cortex in autism. Mol Autism. 2011; 2(1):14. BioMed Central Full Text
• [19]St Pourcain B, Cents RA, Whitehouse AJ, Haworth CM, Davis OS, O’Reilly PF et al.. Common variation near ROBO2 is associated with expressive vocabulary in infancy. Nat Commun. 2014; 5:4831.
• [20]Edelstein SB, Breakefield XO, Hanin, Koslow SH. Human fibroblast cultures. In: Physicochemical Methodoloyies and Psychiatric Research. Raven, New York; 1980: p.199-243.
• [21]Barry G. Integrating the roles of long and small non-coding RNA in brain function and disease. Mol Psychiatry. 2014; 19(4):410-6.
• [22]van de Vondervoort II, Gordebeke PM, Khoshab N, Tiesinga PH, Buitelaar JK, Kozicz T et al.. Long non-coding RNAs in neurodevelopmental disorders. Front Mol Neurosci. 2013; 6:53.
• [23]Talkowski ME, Maussion G, Crapper L, Rosenfeld JA, Blumenthal I, Hanscom C et al.. Disruption of a large intergenic noncoding RNA in subjects with neurodevelopmental disabilities. Am J Hum Genet. 2012; 91(6):1128-34.
• [24]Rooney DE, Czepulkowski BH. Human cytogenetics: a practical approach. 2nd ed ed. IRL Press at Oxford University Press, Oxford; 1992.
• [25]Garimberti E, Tosi S. Fluorescence in situ hybridization (FISH), basic principles and methodology. Methods Mol Biol. 2010; 659:3-20.
• [26]Rozen S, Skaletsky H. Primer3 on the WWW for general users and for biologist programmers. Methods Mol Biol. 2000; 132:365-86.
• [27]Life Technologies. Taqman Gene Expression Protocol. https://tools. lifetechnologies.com/content/sfs/manuals/cms_041280.pdf webcite
• [28]Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods. 2001; 25(4):402-8.