1

The effect of an extra sex chromosome on language

development

Dorothy V. M. BishopUniversity 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

Specificlanguage

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 Childhood2011

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) RangeXXX 30 9.2 (3.88) 4-15 yrXXY 19 9.4 (4.10) 4-15 yrXYY 21 8.7 (3.48) 4-15 yrGroup IIXXX 28 10.4 (4.25) 4-17 yrXYY 37 10.0 (3.36) 4-16 yrSiblingsfemale 26 11.0 (3.38) 4-16 yrmale 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%)SiblingsXX 26 0 (0%)XY 41 4 (10%)National data

N SEN

Group I

Group II

Girls 3992857 199150 (5%)

Boys 3992857 456350 (11%)

Substantial individualvariation

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%)SiblingsXX 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%)SiblingsXX 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 XYYlanguage 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 itemsscales 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 itemsscales 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 itemsscales 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

Languagestructure Pragmatics

Mean CCC-2 subscales,

nonASD only

A. speechB. syntaxC. semanticsD. coherenceE. inappropriate initiationF. stereotyped languageG. use of contextH. nonverbal communicationI. social relationsJ. 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 BishopWellcome Trust Principal Research Fellow,Oxford Study of Children’s Communication Impairments,Department of Experimental Psychology,South Parks Road,Oxford,OX1 3UD.

http://oscci.psy.ox.ac.uk/get-involved-1/take-part