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Language phenotypes in children with sex chromosome trisomies.

ABSTRACT: Background Sex chromosome trisomies (47,XXX, 47,XXY and 47,XYY) are known to be a risk factor for language disorder, but it is hard to predict outcomes, because many cases are identified only when problems are found. Methods We recruited children aged 5-16 years with all three types of trisomy, and divided them into a High Bias group, identified in the course of investigations for neurodevelopmental problems, and a Low Bias group, identified via prenatal screening or other medical investigations. Children from a twin sample were used to compare pattern and severity of language problems: they were subdivided according to parental concerns about language/history of speech-language therapy into a No Concerns group (N = 118) and a Language Concerns group (N = 57). Children were assessed on a psychometric battery and a standardized parent checklist. After excluding children with intellectual disability, autism or hearing problems, the sample included 28 XXX, 18 XXY and 14 XYY Low Bias cases and 7 XXX, 13 XXY and 17 XYY High Bias cases. Results Variation within each trisomy group was substantial: within the Low Bias group, overall language scores were depressed relative to normative data, but around one third had no evidence of problems. There was no effect of trisomy type, and the test profile was similar to the Language Concerns comparison group. The rate of problems was much greater in the High Bias children with trisomies. Conclusions When advising parents after discovery of a trisomy, it is important to emphasise that, though there is an increased risk of language problems, there is a very wide range of outcomes. Severe language problems are more common in those identified via genetic testing for neurodevelopmental problems but these are not characteristic of children identified on prenatal screening.

SUBMITTER: Bishop DVM

PROVIDER: S-EPMC6376256 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: The presence of an extra sex chromosome is associated with an increased rate of neurodevelopmental difficulties involving language. The 'double hit' hypothesis proposes that the adverse impact of the extra sex chromosome is amplified when genes that are expressed from the sex chromosomes interact with autosomal variants that usually have only mild effects. We predicted that the impact of an additional sex chromosome on neurodevelopment would depend on common autosomal variants involved in synaptic functions. Methods: We analysed data from 130 children with sex chromosome trisomies (SCTs: 42 girls with trisomy X, 43 boys with Klinefelter syndrome, and 45 boys with XYY). Two comparison groups were formed from 370 children from a twin study. Three indicators of phenotype were: (i) Standard score on a test of nonword repetition; (ii). A language factor score derived from a test battery; (iii) A general scale of neurodevelopmental challenges based on all available information. Preselected regions of two genes, CNTNAP2 and NRXN1, were tested for association with neurodevelopmental outcomes using Generalised Structural Component Analysis. Results: There was wide phenotypic variation in the SCT group, as well as overall impairment on all three phenotypic measures. There was no association of phenotype with CNTNAP2 or NRXN1 variants in either the SCT group or the comparison groups. Supplementary analyses found no indication of any impact of trisomy type on the results, and exploratory analyses of individual SNPs confirmed the lack of association. Conclusions: We cannot rule out that a double hit may be implicated in the phenotypic variability in children with SCTs, but our analysis does not find any support for the idea that common variants in CNTNAP2 or NRXN1 are associated with the severity of language and neurodevelopmental impairments that often accompany an extra X or Y chromosome. Stage 1 report: http://dx.doi.org/10.12688/wellcomeopenres.13828.2.

Project description:Background: The presence of an extra sex chromosome is associated with an increased rate of neurodevelopmental difficulties involving language. Group averages, however, obscure a wide range of outcomes. Hypothesis: The 'double hit' hypothesis proposes that the adverse impact of the extra sex chromosome is amplified when genes that are expressed from the sex chromosomes interact with autosomal variants that usually have only mild effects. Neuroligin-4 genes are expressed from X and Y chromosomes; they play an important role in synaptic development and have been implicated in neurodevelopment. We predict that the impact of an additional sex chromosome on neurodevelopment will be correlated with common autosomal variants involved in related synaptic functions. We describe here an analysis plan for testing this hypothesis using existing data. The analysis of genotype-phenotype associations will be conducted after this plan is published and peer-reviewed Methods: Neurodevelopmental data and DNA are available for 130 children with sex chromosome trisomies (SCTs: 42 girls with trisomy X, 43 boys with Klinefelter syndrome, and 45 boys with XYY). Children from a twin study using the same phenotype measures will form two comparison groups (Ns = 184 and 186). Three indicators of a neurodevelopment disorder phenotype will be used: (i) Standard score on a test of nonword repetition; (ii). A language factor score derived from a test battery; (iii) A general scale of neurodevelopmental challenges based on all available information. Autosomal genes were identified by literature search on the basis of prior association with (a) speech/language/reading phenotypes and (b) synaptic function. Preselected regions of two genes scoring high on both criteria, CNTNAP2 and NRXN1, will be tested for association with neurodevelopmental outcomes using Generalised Structural Component Analysis. We predict the association with one or both genes will be detectable in children with SCTs and stronger than in the comparison samples.

Project description:BackgroundSex Chromosome Trisomies (SCTs; XXX, XXY, XYY) are genetic conditions that are associated with increased risk for neurodevelopmental problems and psychopathology. There is a great need for early preventive intervention programs to optimize outcome, especially considering the increase in prenatal diagnoses due to recent advances in non-invasive prenatal screening. This study is the first to evaluate efficacy of a neurocognitive training in children with SCT. As social behavioral problems have been identified as among the key areas of vulnerability, it was targeted at improving a core aspect of social cognition, the understanding of social cues from facial expressions.MethodsParticipants were 24 children with SCT and 18 typically developing children, aged 4-8 years old. Children with SCT were assigned to a training (n = 13) or waiting list (no-training) group (n = 11). Children in the training group completed a neurocognitive training program (The Transporters), aimed to increase understanding of facial emotions. Participants were tested before and after the training on facial emotion recognition and Theory of Mind abilities (NEPSY-II), and on social orienting (eyetracking paradigm). The SCT no-training group and typically developing control group were also assessed twice with the same time interval without any training. Feasibility of the training was evaluated with the Social Validity Questionnaire filled out by the parents and by children's ratings on a Visual Analog Scale.ResultsThe SCT training group improved significantly more than the SCT no-training and TD no-training group on facial emotion recognition (large effect size; ηp2 = 0.28), performing comparable to typical controls after completing the training program. There were no training effects on ToM abilities and social orienting. Both children and parents expressed satisfaction with the feasibility of the training.ConclusionsThe significant improvement in facial emotion recognition, with large effect sizes, suggests that there are opportunities for positively supporting the development of social cognition in children with an extra X- or Y-chromosome, already at a very young age. This evidence based support is of great importance given the need for preventive and early training programs in children with SCT, aimed to minimize neurodevelopmental impact.

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Language phenotypes in children with sex chromosome trisomies.

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