The effect of an extra sex chromosome on language development
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The effect of an extra sex chromosome on language development



Slides from a talk given to the Klinefelter's syndrome association, Derby, 22nd June 2013

Slides from a talk given to the Klinefelter's syndrome association, Derby, 22nd June 2013



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    The effect of an extra sex chromosome on language development The effect of an extra sex chromosome on language development Presentation Transcript

    • 1 The effect of an extra sex chromosome on language development Dorothy V. M. Bishop University of Oxford
    • 2 Developmental language disorders • Family/twin studies indicate genes are important • Nearly always have normal number of chromosomes • Unusual to find any genetic mutation • Likely to be like height: lots of common genetic variants, each with small effect Specific language impairment Dyslexia Autism Bishop, D. V. M. (2008). Specific language impairment, dyslexia, and autism: Using genetics to unravel their relationship. In C. F. Norbury, J. B. Tomblin & D. V. M. Bishop (Eds.), Understanding developmental language disorders: from theory to practice (pp. 67-78). Hove: Psychology Press.
    • 3 Human chromosomes One of each pair inherited from mother, one from father
    • 4 Sex chromosome trisomies • 1960s: Newborn screening studies done to look at unbiased samples • Most children attend mainstream school • But increased educational difficulties, especially affecting language, in all three trisomies, though with some differences in cognitive profile. • Trisomy effects relatively mild: – few genes on Y – for most genes on X, all but one inactivated Leggett, V., Jacobs, P., Nation, K., Scerif, G., & Bishop, D. V. M. (2010). Neurocognitive outcomes of individuals with a sex chromosome trisomy: XXX, XYY, or XXY: a systematic review. Developmental Medicine and Child Neurology, 52(2), 119-129. doi: 10.1111/j.1469-8749.2009.03545.x
    • 5Patricia Jacobs
    • 6 Prenatal screening • Prenatal screening for sex chromosome trisomies (SCTs) offered via National Health Service in the UK for older mothers, and those with other risk factors
    • 7 Autism, language and communication in children with sex chromosome trisomies Archives of Disease in Childhood 2011 Dorothy V. M. Bishop, Angela Barnicoat, Patricia Boyd, Debbie Shears, Alan Fryer, Katherine Lachlan, Diana Wellesley, Patricia Jacobs, Prisca Middlemiss, Sarah Smithson, Victoria Leggett, Kate Nation, & Gaia Scerif.
    • 8 Measures •Standardized parental interview :Vineland Adaptive Behaviour Scales •Questionnaires completed by parent, including Children’s Communication Checklist – 2 •Demographic/schooling information NB. Children may not have been told about the SCT – direct testing not possible
    • 9 N children according to chromosomes and method of ascertainment Group I: Recruited via prenatal screening OR joined support group when child less than one year old (N = 10) Group II: Joined support group, Unique, when child > 1 yr [NB no XXY from support group] Group I N Mean (SD) age (yr) Range XXX 30 9.2 (3.88) 4-15 yr XXY 19 9.4 (4.10) 4-15 yr XYY 21 8.7 (3.48) 4-15 yr Group II XXX 28 10.4 (4.25) 4-17 yr XYY 37 10.0 (3.36) 4-16 yr Siblings female 26 11.0 (3.38) 4-16 yr male 42 11.4 (3.24) 4-16 yr
    • 10 Statement of special educational needs XXX 30 5 (14%) XXY 19 6 (32%) XYY 21 10 (48%) XXX 28 14 (50%) XYY 37 29 (78%) Siblings XX 26 0 (0%) XY 41 4 (10%) National data N SEN Group I Group II Girls 3992857 199150 (5%) Boys 3992857 456350 (11%) Substantial individual variation
    • 11 Received speech and language therapy N SALT XXX 30 7 (24%) XXY 19 9 (47%) XYY 21 15 (71%) XXX 28 17 (61%) XYY 37 27 (73%) Siblings XX 26 1 (4%) XY 41 7 (18%) Group I Group II
    • 12 Diagnosed with Autistic Spectrum Disorder XXX 30 0 (0%) XXY 19 2 (11%) XYY 21 4 (20%) XXX 28 0 (0%) XYY 37 7 (19%) Siblings XX 26 0 (0%) XY 41 0 (0%) National data N ASD Group I Group II Girls 3992857 6680 (0.2%) Boys 3992857 23760 (0.6%)
    • 13 Combinations of diagnoses (Groups I and II combined) XXX XXY XYY language 21 (36%) 7 (36%) 30 (52%) ASD 0 (0%) 0 (0%) 1 (1%) ADHD 1 (1%) 0 (0%) 1 (1%) lang+ASD 0 (0%) 2 (10%) 6 (10%) lang+motor 4 (7%) 0 (0%) 1 (1%) lang+ASD+ADHD 0 (0%) 0 (0%) 2 (3%) lang+ASD+motor 0 (0%) 0 (0%) 2 (3%) none 31 (54%) 10 (52%) 14 (24%)
    • CCC-2: instructions • This checklist contains a series of statements describing how children communicate. For each statement, you are asked to give information about the child whose name (or code number) appears below. You are asked to judge whether you have observed that behaviour: • less than once a week (or never) • at least once a week, but not every day • once or twice a day • several times (more than twice) a day (or always) Norbury, C. F., Nash, M., Bishop, D. V. M., & Baird, G. (2004). Using parental checklists to identify diagnostic groups in children with communication impairment: A validation of the Children's Communication Checklist - 2. International Journal of Language and Communication Disorders, 39, 345-364.
    • CCC-2: sample items scales A-D, language form/content A: Speech. Simplifies words by leaving out some sounds, e.g. “crocodile” pronounced as “cockodile”, or “stranger” as “staynger” B: Syntax. (+) Produces long and complicated sentences such as: "When we went to the park I had a go on the swings"; "I saw this man standing on the corner" C: Semantics. Is vague in choice of words, making it unclear what s/he is talking about, e.g. saying “that thing” rather than “kettle” D: Coherence. (+) Talks clearly about what s/he plans to do in the future (e.g. what s/he will do tomorrow, or plans for going on holiday)
    • CCC-2: sample items scales E-H, pragmatics E: Inappropriate initiation. Talks repetitively about things that no-one is interested in F: Stereotyped language. Repeats back what others have just said. For instance, if you ask, “what did you eat?” might say, “what did I eat?” G: Use of context. Gets confused when a word is used with a different meaning from usual: e.g. might fail to understand if an unfriendly person was described as ‘cold’ (and would assume they were shivering!) H: Nonverbal communication. Ignores conversational overtures from others (e.g. if asked, "what are you making?" does not look up and just continues working)
    • CCC-2: sample items scales I-J, autistic-like features I: Social relations. (+) Talks about his/her friends; shows interest in what they do and say J: Interests. Shows interest in things or activities that most people would find unusual, such as traffic lights, washing machines, lamp-posts
    • 18 Non- verbal Language structure Pragmatics Mean CCC-2 subscales, nonASD only A. speech B. syntax C. semantics D. coherence E. inappropriate initiation F. stereotyped language G. use of context H. nonverbal communication I. social relations J. interests
    • 19 Why wasn’t ASD noticed in previous studies? • More common in prenatal than neonatal samples? Could relate to parental age • Children who previously would be diagnosed as language impaired, now diagnosed with ASD: ‘diagnostic substitution’ Bishop, D. V. M., Whitehouse, A. J. O., Watt, H. J., & Line, E. A. (2008). Autism and diagnostic substitution: Evidence from a study of adults with a history of developmental language disorder. Developmental Medicine and Child Neurology, 50, 341-345. doi: 10.1111/j.1469-8749.2008.02057.x
    • 20 Why are communication problems seen in all three trisomies? Some speculations about mechanism
    • 21 Similarities: role for neuroligins? • Neuroligins – genes that are important for communication between brain cells • Currently lots of interest in possible role of neuroligins in autism • One neuroligin on the X chromosome, NLGN4X, is usually NOT inactivated • And there is a similar gene on the Y chromosome • Extra dose of gene product in XXX, XXY and XYY
    • 22 Why is there such variation within each genotype?
    • 23 Neuroligins as multipliers? • One possibility: extra dose of neuroligin could increase the impact of genetic risk variants on other chromosomes • For instance, in those with 46 chromosomes, a common form of a gene called CNTNAP2 is associated with slight difference in language. • Current study: We are testing whether this effect is enhanced in those with extra X or Y Bishop, D. V. M., & Scerif, G. (2011). Klinefelter syndrome as a window on the etiology of language and communication impairments in children. Acta Paediatrica, 100(6), 903- 907. doi: DOI: 10.1111/j.1651-2227.2011.02150.x
    • 24 Professor Dorothy Bishop Wellcome Trust Principal Research Fellow, Oxford Study of Children’s Communication Impairments, Department of Experimental Psychology, South Parks Road, Oxford, OX1 3UD.