Publications by authors named "Hayley Crawford"

37 Publications

Prevalence of anxiety symptomatology and diagnosis in syndromic intellectual disability: A systematic review and meta-analysis.

Neurosci Biobehav Rev 2022 07 2;138:104719. Epub 2022 Jun 2.

The School of Psychology, College of Health and Life Sciences, Aston University, UK. Electronic address:

Individuals with syndromic intellectual disability are at increased risk of experiencing anxiety. Comparing prevalence estimates of anxiety will allow the identification of at-risk groups and inform causal pathways of anxiety. No known study has explored estimates of anxiety symptomatology and diagnosis, including specific anxiety profiles, across groups whilst accounting for methodological quality of studies. This systematic review and meta-analysis aimed to fill this gap. Prior to review completion, methodology and analysis plans were registered and documented in a protocol (CRD42019123561). Data from 83 papers, involving a pooled sample of 13,708 across eight syndromes were synthesised using a random effects model. Anxiety prevalence ranged from 9 % (95 % CI: 4-14) in Down syndrome to 73% in Rett syndrome (95 % CI: 70-77). Anxiety prevalence across syndromic intellectual disability was higher than for intellectual disability of mixed aetiology and general population estimates. Substantial variability between syndromes identified groups at higher risk than others. The identification of high-risk groups is crucial for early intervention, allowing us to refine models of risk and identify divergent profiles.
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http://dx.doi.org/10.1016/j.neubiorev.2022.104719DOI Listing
July 2022

The behavioural phenotype of SATB2-associated syndrome: a within-group and cross-syndrome analysis.

J Neurodev Disord 2022 03 29;14(1):25. Epub 2022 Mar 29.

School of Psychology, University of Birmingham, Edgbaston, Birmingham, UK.

Background: SATB2-associated syndrome (SAS) is a multisystem neurodevelopmental disorder characterised by intellectual disability, speech delay, and craniofacial anomalies. Although the clinical presentation of SAS is well-delineated, behaviours associated with SAS are less well-defined. Given the varied social profile reported in SAS of a 'jovial' predisposition and autistic behaviours, there may be phenotypic overlap with both Angelman syndrome (AS) and non-syndromal autism. This study aimed to describe behaviours in SAS in relation to chronological age and level of ability and contrast aspects of the behavioural phenotype with AS and non-syndromal autism.

Methods: Informant report questionnaire measures of behaviour, emotion, and autism characteristics were completed for 81 individuals with SAS (aged 1-36 years; 43 male). Within-group associations were analysed, and categorical data were compared between pre-school (1-5 years), school-age (6-15 years), and adolescent and adult SAS sub-groups (16 years and over). Cross-syndrome subscale and item-level analyses were conducted for 63 individuals with SAS (aged 1-27 years; 31 male), who were matched according to age and level of ability to 63 individuals with AS (aged 2-25 years; 32 male) and 63 individuals with non-syndromal autism (aged 3-26 years; 53 male).

Results: In SAS, higher rates of overactivity were moderately associated with lower self-help ability, and higher general anxiety scores were reported for males compared with females. Cross-syndrome subscale analyses uncovered several significant differences (p < .01), with comparatively low rates of stereotyped behaviour, overactivity, insistence on sameness and positive affect, and comparatively greater interest and pleasure and compulsive behaviour in individuals with SAS. Item-level analyses revealed a distinct profile of repetitive and autistic behaviours.

Limitations: Developmental analysis was based on a cross-sectional rather than a longitudinal research design, the contribution of pain and sleep to behaviour was not explored, and molecular genetic testing to determine genotype-phenotype behavioural relationships was not possible.

Conclusions: This study highlights the importance of behavioural comparisons to well-delineated groups and the utility of fine-grained item-level analyses to elucidate aspects of behaviour that might be syndrome related or shared across neurodevelopmental disorders. Future research is needed to further describe the distinctive repetitive and autistic behavioural phenotype in SAS.
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http://dx.doi.org/10.1186/s11689-022-09426-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8966214PMC
March 2022

Utilising Interview Methodology to Inform the Development of New Clinical Assessment Tools for Anxiety in Autistic Individuals Who Speak Few or no Words.

J Autism Dev Disord 2022 Mar 18. Epub 2022 Mar 18.

Department of Psychology, College of Health and Life Sciences, Aston University, Birmingham, B4 7ET, UK.

Autistic individuals with intellectual disability who speak few or no words are at high risk of anxiety but are underrepresented in research. This study aimed to describe the presentation of anxiety in this population and discuss implications for the development of assessments. Interviews were conducted with 21 parents/carers of autistic individuals and nine clinicians. Data were analysed using content analysis and interpretative phenomenological analysis. Anxiety behaviours described by parents/carers included increased vocalisation, avoidance and behaviours that challenge. Changes to routine were highlighted as triggering anxiety. Clinicians discussed the importance of identifying an individual's baseline of behaviour, knowing an individual well and ruling out other forms of distress. This study raises considerations for early identification of anxiety and for subsequent support.
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http://dx.doi.org/10.1007/s10803-022-05509-yDOI Listing
March 2022

Executive function, repetitive behaviour and restricted interests in neurodevelopmental disorders.

Res Dev Disabil 2022 Mar 8;122:104166. Epub 2022 Jan 8.

School of Psychology, University of Birmingham, B15 2TT, United Kingdom.

Background: Individuals with genetic syndromes show unique profiles of repetitive behaviours and restricted interests (RRBs). The executive dysfunction account of RRBs suggests that in autistic (AUT) individuals executive function impairments underpin RRBs, but not communication and social interaction autistic characteristics.

Aims: To 1) describe profiles of behavioural manifestations of executive function (EF behaviours) and 2) explore the relationship between EF behaviours and autistic traits across individuals with Cornelia de Lange (CdLS), fragile X (FXS) and Rubinstein-Taybi syndromes (RTS), and AUT individuals.

Method: Carers completed the Behavior Rating Inventory of Executive Function - Preschool Version and the Social Communication Questionnaire. Data reporting on 25 individuals with CdLS (Mage = 18.60, SD = 8.94), 25 with FXS (Mage = 18.48, SD = 8.80), 25 with RTS (Mage = 18.60, SD = 8.65) and 25 AUT individuals (Mage = 18.52, SD = 8.65) matched on chronological age and adaptive ability were included in analyses.

Results: All groups showed impairments across EF behaviours compared to two-to-three-year-old typically developing normative samples with no differences between groups. Different EF behaviours predicted RRBs in the syndrome groups with no associations found in the AUT group.

Conclusions: Syndrome related differences should be considered when developing targeted interventions that focus on EF behaviours and/or RRBs in these groups.
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http://dx.doi.org/10.1016/j.ridd.2021.104166DOI Listing
March 2022

Executive function, repetitive behaviour and restricted interests in neurodevelopmental disorders.

Res Dev Disabil 2022 Mar 8;122:104166. Epub 2022 Jan 8.

School of Psychology, University of Birmingham, B15 2TT, United Kingdom.

Background: Individuals with genetic syndromes show unique profiles of repetitive behaviours and restricted interests (RRBs). The executive dysfunction account of RRBs suggests that in autistic (AUT) individuals executive function impairments underpin RRBs, but not communication and social interaction autistic characteristics.

Aims: To 1) describe profiles of behavioural manifestations of executive function (EF behaviours) and 2) explore the relationship between EF behaviours and autistic traits across individuals with Cornelia de Lange (CdLS), fragile X (FXS) and Rubinstein-Taybi syndromes (RTS), and AUT individuals.

Method: Carers completed the Behavior Rating Inventory of Executive Function - Preschool Version and the Social Communication Questionnaire. Data reporting on 25 individuals with CdLS (Mage = 18.60, SD = 8.94), 25 with FXS (Mage = 18.48, SD = 8.80), 25 with RTS (Mage = 18.60, SD = 8.65) and 25 AUT individuals (Mage = 18.52, SD = 8.65) matched on chronological age and adaptive ability were included in analyses.

Results: All groups showed impairments across EF behaviours compared to two-to-three-year-old typically developing normative samples with no differences between groups. Different EF behaviours predicted RRBs in the syndrome groups with no associations found in the AUT group.

Conclusions: Syndrome related differences should be considered when developing targeted interventions that focus on EF behaviours and/or RRBs in these groups.
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http://dx.doi.org/10.1016/j.ridd.2021.104166DOI Listing
March 2022

Genetic modifiers in rare disorders: the case of fragile X syndrome.

Eur J Hum Genet 2021 01 29;29(1):173-183. Epub 2020 Aug 29.

Department of Psychology, Saint Joseph's University, Philadelphia, PA, USA.

Methods employed in genome-wide association studies are not feasible ways to explore genotype-phenotype associations in rare disorders due to limited statistical power. An alternative approach is to examine relationships among specific single nucleotide polymorphisms (SNPs), selected a priori, and behavioural characteristics. Here, we adopt this strategy to examine relationships between three SNPs (5-HTTLPR, MAOA, COMT) and specific clinically-relevant behaviours that are phenotypic of fragile X syndrome (FXS) but vary in severity and frequency across individuals. Sixty-four males with FXS participated in the current study. Data from standardised informant measures of challenging behaviour (defined as physical aggression, property destruction, stereotyped behaviour, and self-injury), autism symptomatology, attention-deficit-hyperactivity-disorder characteristics, repetitive behaviour and mood/interest and pleasure were compared between each SNP genotype. No association was observed between behavioural characteristics and either 5-HTTLPR (serotonin) or MAOA (monoamine oxidase) genotypes. However, compared to the COMT (dopamine) AG and GG genotypes, the AA genotype was associated with greater interest and pleasure in the environment, and with reduced risk for property destruction, stereotyped behaviour and compulsive behaviour. The results suggest that common genetic variation in the COMT genotype affecting dopamine levels in the brain may contribute to the variability of challenging and repetitive behaviours and interest and pleasure in this population. This study identifies a role for additional genetic risk in understanding the neural and genetic mechanisms contributing to phenotypic variability in neurodevelopmental disorders, and highlights the merit of investigating SNPs that are selected a priori on a theoretical basis in rare populations.
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http://dx.doi.org/10.1038/s41431-020-00711-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852869PMC
January 2021

Scaling of Early Social Cognitive Skills in Typically Developing Infants and Children with Autism Spectrum Disorder.

J Autism Dev Disord 2020 Nov;50(11):3988-4000

CMHWR and Mental Health and Wellbeing Unit, Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, CV4 7AL, UK.

We delineate the sequence that typically developing infants pass tasks that assess different early social cognitive skills considered precursors to theory-of-mind abilities. We compared this normative sequence to performance on these tasks in a group of autistic (AUT) children. 86 infants were administered seven tasks assessing intention reading and shared intentionality (Study 1). Infants responses followed a consistent developmental sequence, forming a four-stage scale. These tasks were administered to 21 AUT children (Study 2), who passed tasks in the same sequence. However, performance on tasks that required following others' eye gaze and cooperating with others was delayed. Findings indicate that earlier-developing skills provide a foundation for later-developing skills, and difficulties in acquiring some early social cognitive skills in AUT children.
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http://dx.doi.org/10.1007/s10803-020-04449-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557487PMC
November 2020

Scaling of Early Social Cognitive Skills in Typically Developing Infants and Children with Autism Spectrum Disorder.

J Autism Dev Disord 2020 Nov;50(11):3988-4000

CMHWR and Mental Health and Wellbeing Unit, Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, CV4 7AL, UK.

We delineate the sequence that typically developing infants pass tasks that assess different early social cognitive skills considered precursors to theory-of-mind abilities. We compared this normative sequence to performance on these tasks in a group of autistic (AUT) children. 86 infants were administered seven tasks assessing intention reading and shared intentionality (Study 1). Infants responses followed a consistent developmental sequence, forming a four-stage scale. These tasks were administered to 21 AUT children (Study 2), who passed tasks in the same sequence. However, performance on tasks that required following others' eye gaze and cooperating with others was delayed. Findings indicate that earlier-developing skills provide a foundation for later-developing skills, and difficulties in acquiring some early social cognitive skills in AUT children.
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http://dx.doi.org/10.1007/s10803-020-04449-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557487PMC
November 2020

A Behavioural Assessment of Social Anxiety and Social Motivation in Fragile X, Cornelia de Lange and Rubinstein-Taybi Syndromes.

J Autism Dev Disord 2020 Jan;50(1):127-144

Cerebra Centre for Neurodevelopmental Disorders, School of Psychology, University of Birmingham, Edgbaston, B15 2TT, UK.

Unique socio-behavioural phenotypes are reported for individuals with different neurodevelopmental disorders. Here, the effects of adult familiarity and nature of interaction on social anxiety and social motivation were investigated in individuals with fragile X (FXS; n = 20), Cornelia de Lange (CdLS; n = 20) and Rubinstein-Taybi (RTS; n = 20) syndromes, compared to individuals with Down syndrome (DS; n = 20). The Social Anxiety and Motivation Rating Scale was employed whilst participants completed four social tasks, each administered separately by a familiar adult, and also by an unfamiliar adult. Compared to participants with DS, those with FXS and RTS exhibited high levels of social anxiety but similar levels of social motivation. Participants with CdLS showed heightened social anxiety and reduced social motivation only during interactions with an unfamiliar adult when active participation was voluntary.
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http://dx.doi.org/10.1007/s10803-019-04232-5DOI Listing
January 2020

Lifespan trajectory of affect in Cornelia de Lange syndrome: towards a neurobiological hypothesis.

J Neurodev Disord 2019 06 7;11(1). Epub 2019 Jun 7.

Cerebra Centre for Neurodevelopmental Disorders, School of Psychology, University of Birmingham, Edgbaston, B15 2TT, UK.

Background: Depressive symptomology and low affect are comparatively common in individuals with genetic disorders such as Cornelia de Lange syndrome. However, lifespan trajectories and associated person characteristics have not been examined. In this study, the trajectories for affect and associated behavioural characteristics were investigated in individuals with Cornelia de Lange syndrome with individuals with fragile X syndrome (FXS) comparable for chronological age and total number of behavioural indicators of ASD included for the purpose of contrast.

Methods: A 7-year longitudinal study of affect (mood, interest and pleasure) was conducted in individuals with CdLS (n = 44) and FXS (n = 95). The trajectories of low affect were explored, as well as associations between Time 1 behavioural characteristics and affect at Time 1 and Time 3 (7 years later).

Results: The CdLS group were lower in mood than the FXS group overall (p < .001). Interest and pleasure scores showed a significant decline over the lifespan for individuals with CdLS (p < .001) but not the FXS group. Lower level of ability at Time 1 was associated with lower mood at Time 1 and Time 3 in the FXS group only. Higher levels of ASD symptomology at Time 1 were associated with low mood and interest and pleasure in both syndrome groups at Time 1 and Time 3. Greater insistence on sameness at Time 1 was associated with lower mood at Time 1 in the FXS group and lower interest and pleasure at Time 1 and Time 3 in the CdLS group.

Conclusions: Low affect in specific genetic syndromes may be associated with differing lifespan trajectories and behavioural profiles. Specifically, individuals with CdLS appear at risk for experiencing declines in levels of interest and pleasure whereas individuals with FXS show no significant change in the level of affect with age.
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http://dx.doi.org/10.1186/s11689-019-9269-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555708PMC
June 2019

Social Avoidance Emerges in Infancy and Persists into Adulthood in Fragile X Syndrome.

J Autism Dev Disord 2019 Sep;49(9):3753-3766

Department of Psychiatry and Behavioral Sciences and MIND Institute, University of California-Davis, Sacramento, CA, USA.

Fragile X syndrome (FXS) is characterized by both social approach and social avoidance. However, the age of emergence and developmental trajectory of social avoidance has not been examined. This study investigates the longitudinal developmental trajectory and dynamic nature of social avoidance in males with FXS from infancy through young adulthood (n = 191). Multiple facets of social avoidance were collected using the Social Avoidance Scale (Roberts et al. 2007, 2009). Overall, 81% of males with FXS displayed social avoidance, which emerged during infancy, increased in severity across childhood, and stabilized through adolescence and early adulthood. An exaggerated "warm up" effect was also observed in FXS. This study delineates the complex profile of social avoidance, a common and impairing behavioral feature of FXS.
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http://dx.doi.org/10.1007/s10803-019-04051-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698894PMC
September 2019

Temper outbursts in Lowe syndrome: Characteristics, sequence, environmental context and comparison to Prader-Willi syndrome.

J Appl Res Intellect Disabil 2019 Sep 29;32(5):1216-1227. Epub 2019 May 29.

School of Life and Health Sciences, Aston University, Birmingham, UK.

Background: There is limited research into the nature and aetiology of temper outbursts in people with intellectual disabilities. In this study, we describe the phenomenology and environmental context of temper outbursts in Lowe syndrome, a rare genetic syndrome in which outbursts are purportedly frequent.

Method: A temper outburst interview (TOI) was conducted with caregivers of seventeen individuals with Lowe syndrome to generate an account of the behavioural sequence, common antecedents and consequences of temper outbursts, and to enable comparisons with similar work on Prader-Willi syndrome.

Results: Outbursts in Lowe syndrome were frequently triggered by thwarted goal-directed behaviour and were associated with high levels of physical aggression and property destruction.

Conclusions: Form and sequence of outbursts showed similarities to Prader-Willi syndrome and to behaviours reported in literature on typically developing children. The results highlight the importance of considering shared aetiology as well as syndrome-specific pathways in the development of outbursts.
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http://dx.doi.org/10.1111/jar.12613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851695PMC
September 2019

Infant Social Avoidance Predicts Autism but Not Anxiety in Fragile X Syndrome.

Front Psychiatry 2019 7;10:199. Epub 2019 May 7.

Department of Psychology, University of South Carolina, Columbia, SC, United States.

Autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and anxiety are three of the most common childhood psychiatric disorders. Early trajectories of social avoidance have been linked with these psychiatric disorders in previous studies, but it remains unclear how social avoidance differentially predicts comorbid disorders in a high-risk genetic subgroup. Here, we delineate the association between trajectories of social avoidance from infancy and subsequent ASD, ADHD, and anxiety outcomes at preschool in children with fragile X syndrome (FXS), a well-characterized single-gene disorder highly associated with social avoidance as well as elevated rates of ASD, ADHD, and anxiety. Males with FXS ( = 78) aged 4-62 months participated in a longitudinal study resulting in 201 assessments. The Social Avoidance Scale (SAS) documented socially avoidant behaviors from infancy in three domains-physical movement, facial expression, and eye contact during both the first minute and the last hour of an interaction. ASD, ADHD, and anxiety symptom outcomes at preschool were measured via parent-report questionnaires. Increased social avoidance across infancy and preschool predicted elevated ASD symptom severity but reduced ADHD and anxiety symptom severity in males with FXS. ASD, ADHD, and anxiety symptoms relate inconsistently to social avoidance behaviors, providing new insight toward the debate of independence or overlap among these disorders in FXS and other disorders (i.e., ASD). The results suggest that the nuanced profile of the developmental and temporal aspects of social avoidance may inform more the accuracy of differential diagnoses of comorbid psychiatric disorders in FXS.
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http://dx.doi.org/10.3389/fpsyt.2019.00199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6514151PMC
May 2019

The Persistence of Self-injurious and Aggressive Behavior in Males with Fragile X Syndrome Over 8 Years: A Longitudinal Study of Prevalence and Predictive Risk Markers.

J Autism Dev Disord 2019 Jul;49(7):2913-2922

Cerebra Centre for Neurodevelopmental Disorders, School of Psychology, University of Birmingham, 52 Pritchatts Road, Birmingham, B15 2TT, UK.

Self-injurious and aggressive behaviors are common in fragile X syndrome (FXS). However, little is known about the persistence of these behaviors and associated risk markers. We established the prevalence and persistence of self-injurious and aggressive behaviors over eight years in males with FXS, and associations with risk markers. Results showed 77% and 69% persistence rates for self-injurious and aggressive behavior, respectively. Baseline levels of repetitive behavior predicted persistent self-injurious behavior. Chronological age, impulsivity and overactivity were associated with persistent aggressive behavior but only impulsivity predicted persistence. This is the first study to document the persistence of self-injurious and aggressive behavior in FXS over the medium to long term and to identify behavioral risk markers that might facilitate targeted early intervention.
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http://dx.doi.org/10.1007/s10803-019-04002-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6606661PMC
July 2019

Differential effects of anxiety and autism on social scene scanning in males with fragile X syndrome.

J Neurodev Disord 2017 09 25;9(1). Epub 2017 Sep 25.

Department of Psychology, Durham University, Durham, DH1 3LE, UK.

Background: Existing literature draws links between social attention and socio-behavioural profiles in neurodevelopmental disorders. Fragile X syndrome (FXS) is associated with a known socio-behavioural phenotype of social anxiety and social communication difficulties alongside high social motivation. However, studies investigating social attention in males with FXS are scarce. Using eye tracking, this study investigates social attention and its relationship with both anxiety and autism symptomatology in males with FXS.

Methods: We compared dwell times to the background, body, and face regions of naturalistic social scenes in 11 males with FXS (M  = 26.29) and 11 typically developing (TD) children who were matched on gender and receptive language ability (M  = 6.28). Using informant-report measures, we then investigated the relationships between social scene scanning and anxiety, and social scene scanning and social communicative impairments.

Results: Males with FXS did not differ to TD children on overall dwell time to the background, body, or face regions of the naturalistic social scenes. Whilst males with FXS displayed developmentally 'typical' social attention, increased looking at faces was associated with both heightened anxiety and fewer social communication impairments in this group.

Conclusions: These results offer novel insights into the mechanisms associated with social attention in FXS and provide evidence to suggest that anxiety and autism symptomatology, which are both heightened in FXS, have differential effects on social attention.
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http://dx.doi.org/10.1186/s11689-017-9189-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389139PMC
September 2017

An experimental study of executive function and social impairment in Cornelia de Lange syndrome.

J Neurodev Disord 2017 Sep 11;9(1):33. Epub 2017 Sep 11.

Cerebra Centre for Neurodevelopmental Disorders, School of Psychology, University of Birmingham, B15 2TT, Edgbaston, UK.

Background: Extreme shyness and social anxiety is reported to be characteristic of adolescents and adults with Cornelia de Lange syndrome (CdLS); however, the nature of these characteristics is not well documented. In this study, we develop and apply an experimental assessment of social anxiety in a group of adolescents and adults with CdLS to determine the nature of the social difficulties and whether they are related to impairments in executive functioning.

Methods: A familiar and unfamiliar examiner separately engaged in socially demanding tasks comprising three experimental conditions with a group of individuals with CdLS (n = 25; % male = 44; mean age = 22.16; SD = 8.81) and a comparable group of individuals with Down syndrome (DS; n = 20; % male = 35; mean age = 24.35; SD = 5.97). Behaviours indicative of social anxiety were coded. The Behavior Rating Inventory of Executive Function-Preschool version, an informant measure of executive function, was completed by participants' caregivers.

Results: Significantly less verbalisation was observed in the CdLS group than the DS group in conditions requiring the initiation of speech. In the CdLS group, impairments in verbalisation were not associated with a greater degree of intellectual disability but were significantly correlated with impairments in both planning and working memory. This association was not evident in the DS group.

Conclusions: Adolescents and adults with CdLS have a specific difficulty with the initiation of speech when social demands are placed upon them. This impairment in verbalisation may be underpinned by specific cognitive deficits, although further research is needed to investigate this fully.
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http://dx.doi.org/10.1186/s11689-017-9213-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5592717PMC
September 2017

Diverse Profiles of Anxiety Related Disorders in Fragile X, Cornelia de Lange and Rubinstein-Taybi Syndromes.

J Autism Dev Disord 2017 Dec;47(12):3728-3740

Cerebra Centre for Neurodevelopmental Disorders, School of Psychology, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.

Anxiety disorders are heightened in specific genetic syndromes in comparison to intellectual disability of heterogeneous aetiology. In this study, we described and contrasted anxiety symptomatology in fragile X (FXS), Cornelia de Lange (CdLS) and Rubinstein-Taybi syndromes (RTS), and compared the symptomatology to normative data for typically-developing children and children diagnosed with an anxiety disorder. Scores did not differ between children diagnosed with an anxiety disorder and (a) participants with FXS on social phobia, panic/agoraphobia, physical injury fears, and obsessive-compulsive subscales (b) participants with CdLS on separation anxiety, generalized anxiety, panic/agoraphobia, physical injury fears and obsessive-compulsive subscales, and (c) participants with RTS on panic/agoraphobia and obsessive-compulsive subscales. The results highlight divergent profiles of anxiety symptomatology between these groups.
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http://dx.doi.org/10.1007/s10803-016-3015-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5676833PMC
December 2017

Visual preference for social stimuli in individuals with autism or neurodevelopmental disorders: an eye-tracking study.

Mol Autism 2016 5;7:24. Epub 2016 Apr 5.

School of Psychology, University of Birmingham, Birmingham, UK ; Center for Autism Research, Children's Hospital of Philadelphia, Philadelphia, PA USA.

Background: Recent research has identified differences in relative attention to competing social versus non-social video stimuli in individuals with autism spectrum disorder (ASD). Whether attentional allocation is influenced by the potential threat of stimuli has yet to be investigated. This is manipulated in the current study by the extent to which the stimuli are moving towards or moving past the viewer. Furthermore, little is known about whether such differences exist across other neurodevelopmental disorders. This study aims to determine if adolescents with ASD demonstrate differences in attentional allocation to competing pairs of social and non-social video stimuli, where the actor or object either moves towards or moves past the viewer, in comparison to individuals without ASD, and to determine if individuals with three genetic syndromes associated with differing social phenotypes demonstrate differences in attentional allocation to the same stimuli.

Methods: In study 1, adolescents with ASD and control participants were presented with social and non-social video stimuli in two formats (moving towards or moving past the viewer) whilst their eye movements were recorded. This paradigm was then employed with groups of individuals with fragile X, Cornelia de Lange, and Rubinstein-Taybi syndromes who were matched with one another on chronological age, global adaptive behaviour, and verbal adaptive behaviour (study 2).

Results: Adolescents with ASD demonstrated reduced looking-time to social versus non-social videos only when stimuli were moving towards them. Individuals in the three genetic syndrome groups showed similar looking-time but differences in fixation latency for social stimuli moving towards them. Across both studies, we observed within- and between-group differences in attention to social stimuli that were moving towards versus moving past the viewer.

Conclusions: Taken together, these results provide strong evidence to suggest differential visual attention to competing social versus non-social video stimuli in populations with clinically relevant, genetically mediated differences in socio-behavioural phenotypes.
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http://dx.doi.org/10.1186/s13229-016-0084-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4822328PMC
December 2016

Face scanning and spontaneous emotion preference in Cornelia de Lange syndrome and Rubinstein-Taybi syndrome.

J Neurodev Disord 2015 30;7(1):22. Epub 2015 Jul 30.

Cerebra Centre for Neurodevelopmental Disorders, School of Psychology, University of Birmingham, Edgbaston, B15 2TT UK.

Background: Existing literature suggests differences in face scanning in individuals with different socio-behavioural characteristics. Cornelia de Lange syndrome (CdLS) and Rubinstein-Taybi syndrome (RTS) are two genetically defined neurodevelopmental disorders with unique profiles of social behaviour.

Methods: Here, we examine eye gaze to the eye and mouth regions of neutrally expressive faces, as well as the spontaneous visual preference for happy and disgusted facial expressions compared to neutral faces, in individuals with CdLS versus RTS.

Results: Results indicate that the amount of time spent looking at the eye and mouth regions of faces was similar in 15 individuals with CdLS and 17 individuals with RTS. Both participant groups also showed a similar pattern of spontaneous visual preference for emotions.

Conclusions: These results provide insight into two rare, genetically defined neurodevelopmental disorders that have been reported to exhibit contrasting socio-behavioural characteristics and suggest that differences in social behaviour may not be sufficient to predict attention to the eye region of faces. These results also suggest that differences in the social behaviours of these two groups may be cognitively mediated rather than subcortically mediated.
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http://dx.doi.org/10.1186/s11689-015-9119-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4520195PMC
August 2015

BDNF Val(66)Met and 5-HTTLPR Genotype are Each Associated with Visual Scanning Patterns of Faces in Young Children.

Front Behav Neurosci 2015 13;9:175. Epub 2015 Jul 13.

School of Psychology, University of Birmingham , Birmingham , UK ; Center for Autism Research, Children's Hospital of Philadelphia , Philadelphia, PA , USA.

Previous studies have documented both neuroplasticity-related BDNF Val(66)Met and emotion regulation-related 5-HTTLPR polymorphisms as genetic variants that contribute to the processing of emotions from faces. More specifically, research has shown the BDNF Met allele and the 5-HTTLPR Short allele to be associated with mechanisms of negative affectivity that relate to susceptibility for psychopathology. We examined visual scanning pathways in response to angry, happy, and neutral faces in relation to BDNF Val(66)Met and 5-HTTLPR genotyping in 49 children aged 4-7 years. Analyses revealed that variations in the visual processing of facial expressions of anger interacted with BDNF Val(66)Met genotype, such that children who carried at least one low neuroplasticity Met allele exhibited a vigilance-avoidance pattern of visual scanning compared to homozygotes for the high neuroplasticity Val allele. In a separate investigation of eye gaze towards the eye versus mouth regions of neutral faces, we observed that short allele 5-HTTLPR carriers exhibited reduced looking at the eye region compared with those with the higher serotonin uptake Long allele. Together, these findings suggest that genetic mechanisms early in life may influence the establishment of patterns of visual scanning of environmental stressors, which in conjunction with other factors such as negative life events, may lead to psychological difficulties and disorders in the later adolescent and adult years.
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http://dx.doi.org/10.3389/fnbeh.2015.00175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4500100PMC
July 2015

Implicit Discrimination of Basic Facial Expressions of Positive/Negative Emotion in Fragile X Syndrome and Autism Spectrum Disorder.

Am J Intellect Dev Disabil 2015 Jul;120(4):328-45

Fragile X syndrome (FXS) and autism spectrum disorders (ASD) are characterized by impaired social functioning. We examined the spontaneous discrimination of happy and disgusted facial expressions, from neutral faces, in individuals with FXS (n  =  13, Mage  =  19.70) and ASD (n  =  15, Mage  =  11.00) matched on adaptive behavior and verbal abilities measured by the Vineland Adaptive Behavior Scale. Eye gaze to the eyes and mouth of neutral faces was also measured. Results suggest individuals with FXS and ASD distinguish facial expressions spontaneously in the same way. Individuals with FXS looked significantly less at the eye region of neutral faces than individuals with ASD. These results provide insight into similarities and differences in face processing in two neurodevelopmental disorders noted for their similarities in social behavior.
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http://dx.doi.org/10.1352/1944-7558-120.4.328DOI Listing
July 2015

HIV-1 adaptation to antigen processing results in population-level immune evasion and affects subtype diversification.

Cell Rep 2014 Apr 13;7(2):448-463. Epub 2014 Apr 13.

Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, Oxford University, John Radcliffe Hospital, Headley Way, Oxford OX3 9DS, UK; Division of Clinical Neurology, Nuffield Department of Clinical Neurosciences, Weatherall Institute of Molecular Medicine, Oxford University, John Radcliffe Hospital, Headley Way, Oxford OX3 9DS, UK. Electronic address:

The recent HIV-1 vaccine failures highlight the need to better understand virus-host interactions. One key question is why CD8(+) T cell responses to two HIV-Gag regions are uniquely associated with delayed disease progression only in patients expressing a few rare HLA class I variants when these regions encode epitopes presented by ~30 more common HLA variants. By combining epitope processing and computational analyses of the two HIV subtypes responsible for ~60% of worldwide infections, we identified a hitherto unrecognized adaptation to the antigen-processing machinery through substitutions at subtype-specific motifs. Multiple HLA variants presenting epitopes situated next to a given subtype-specific motif drive selection at this subtype-specific position, and epitope abundances correlate inversely with the HLA frequency distribution in affected populations. This adaptation reflects the sum of intrapatient adaptations, is predictable, facilitates viral subtype diversification, and increases global HIV diversity. Because low epitope abundance is associated with infrequent and weak T cell responses, this most likely results in both population-level immune evasion and inadequate responses in most people vaccinated with natural HIV-1 sequence constructs. Our results suggest that artificial sequence modifications at subtype-specific positions in vitro could refocus and reverse the poor immunogenicity of HIV proteins.
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http://dx.doi.org/10.1016/j.celrep.2014.03.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4005910PMC
April 2014

The hypervariable HIV-1 capsid protein residues comprise HLA-driven CD8+ T-cell escape mutations and covarying HLA-independent polymorphisms.

J Virol 2011 Feb 24;85(3):1384-90. Epub 2010 Nov 24.

Department of Paediatrics, University of Oxford, Peter Medawar Building for Pathogen Research, South Parks Rd, Oxford OX1 3SY, United Kingdom.

One proposed HIV vaccine strategy is to induce Gag-specific CD8(+) T-cell responses that can corner the virus, through fitness cost of viral escape and unavailability of compensatory mutations. We show here that the most variable capsid residues principally comprise escape mutants driven by protective alleles HLA-B*57, -5801, and -8101 and covarying HLA-independent polymorphisms that arise in conjunction with these escape mutations. These covarying polymorphisms are potentially compensatory and are concentrated around three tropism-determining loops of p24, suggesting structural interdependencies. Our results demonstrate complex patterns of adaptation of HIV under immune selection pressure, the understanding of which should aid vaccine design.
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http://dx.doi.org/10.1128/JVI.01879-10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3020512PMC
February 2011

Impact of HLA in mother and child on disease progression of pediatric human immunodeficiency virus type 1 infection.

J Virol 2009 Oct 15;83(19):10234-44. Epub 2009 Jul 15.

HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa.

A broad Gag-specific CD8(+) T-cell response is associated with effective control of adult human immunodeficiency virus (HIV) infection. The association of certain HLA class I molecules, such as HLA-B*57, -B*5801, and -B*8101, with immune control is linked to mutations within Gag epitopes presented by these alleles that allow HIV to evade the immune response but that also reduce viral replicative capacity. Transmission of such viruses containing mutations within Gag epitopes results in lower viral loads in adult recipients. In this study of pediatric infection, we tested the hypothesis that children may tend to progress relatively slowly if either they themselves possess one of the protective HLA-B alleles or the mother possesses one of these alleles, thereby transmitting a low-fitness virus to the child. We analyzed HLA type, CD8(+) T-cell responses, and viral sequence changes for 61 mother-child pairs from Durban, South Africa, who were monitored from birth. Slow progression was significantly associated with the mother or child possessing one of the protective HLA-B alleles, and more significantly so when the protective allele was not shared by mother and child (P = 0.007). Slow progressors tended to make CD8(+) T-cell responses to Gag epitopes presented by the protective HLA-B alleles, in contrast to progressors expressing the same alleles (P = 0.07; Fisher's exact test). Mothers expressing the protective alleles were significantly more likely to transmit escape variants within the Gag epitopes presented by those alleles than mothers not expressing those alleles (75% versus 21%; P = 0.001). Reversion of transmitted escape mutations was observed in all slow-progressing children whose mothers possessed protective HLA-B alleles. These data show that HLA class I alleles influence disease progression in pediatric as well as adult infection, both as a result of the CD8(+) T-cell responses generated in the child and through the transmission of low-fitness viruses by the mother.
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http://dx.doi.org/10.1128/JVI.00921-09DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2748050PMC
October 2009

Evolution of HLA-B*5703 HIV-1 escape mutations in HLA-B*5703-positive individuals and their transmission recipients.

J Exp Med 2009 Apr 23;206(4):909-21. Epub 2009 Mar 23.

Department of Pediatrics, University of Oxford, England, UK.

HLA-B*57 is the class I allele most consistently associated with control of human immunodeficiency virus (HIV) replication, which may be linked to the specific HIV peptides that this allele presents to cytotoxic T lymphocytes (CTLs), and the resulting efficacy of these cellular immune responses. In two HIV C clade-infected populations in South Africa and Zambia, we sought to elucidate the role of HLA-B*5703 in HIV disease outcome. HLA-B*5703-restricted CTL responses select for escape mutations in three Gag p24 epitopes, in a predictable order. We show that the accumulation of these mutations sequentially reduces viral replicative capacity in vitro. Despite this, in vivo data demonstrate that there is ultimately an increase in viral load concomitant with evasion of all three HLA-B*5703-restricted CTL responses. In HLA-B*5703-mismatched recipients, the previously described early benefit of transmitted HLA-B*5703-associated escape mutations is abrogated by the increase in viral load coincident with reversion. Rapid disease progression is observed in HLA-matched recipients to whom mutated virus is transmitted. These data demonstrate that, although costly escape from CTL responses can progressively attenuate the virus, high viral loads develop in the absence of adequate, continued CTL responses. These data underline the need for a CTL vaccine against multiple conserved epitopes.
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http://dx.doi.org/10.1084/jem.20081984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2715113PMC
April 2009

HLA footprints on human immunodeficiency virus type 1 are associated with interclade polymorphisms and intraclade phylogenetic clustering.

J Virol 2009 May 25;83(9):4605-15. Epub 2009 Feb 25.

Department of Paediatrics, Nuffield Department of Medicine, Peter Medawar Building for Pathogen Research, Oxford, United Kingdom.

The selection of escape mutations has a major impact on immune control of infections with viruses such as human immunodeficiency virus (HIV). Viral evasion of CD8(+) T-cell responses leaves predictable combinations of escape mutations, termed HLA "footprints." The most clearly defined footprints are those associated with HLA alleles that are linked with successful control of HIV, such as HLA-B*57. Here we investigated the extent to which HLA footprint sites in HIV type 1 (HIV-1) are associated with viral evolution among and within clades. First, we examined the extent to which amino acid differences between HIV-1 clades share identity with sites of HLA-mediated selection pressure and observed a strong association, in particular with respect to sites of HLA-B selection (P < 10(-6)). Similarly, the sites of amino acid variability within a clade were found to overlap with sites of HLA-selected mutation. Second, we studied the impact of HLA selection on interclade phylogeny. Removing the sites of amino acid variability did not significantly affect clade-specific clustering, reflecting the central role of founder effects in establishing distinct clades. However, HLA footprints may underpin founder strains, and we show that amino acid substitutions between clades alter phylogeny, underlining a potentially substantial role for HLA in driving ongoing viral evolution. Finally, we investigated the impact of HLA selection on within-clade phylogeny and demonstrate that even a single HLA allele footprint can result in significant phylogenetic clustering of sequences. In conclusion, these data highlight the fact that HLA can be a strong selection force for both intra- and interclade HIV evolution at a population level.
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http://dx.doi.org/10.1128/JVI.02017-08DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2668443PMC
May 2009

Adaptation of HIV-1 to human leukocyte antigen class I.

Nature 2009 Apr 25;458(7238):641-5. Epub 2009 Feb 25.

Division of Viral Immunology, Center for AIDS Research, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811, Japan.

The rapid and extensive spread of the human immunodeficiency virus (HIV) epidemic provides a rare opportunity to witness host-pathogen co-evolution involving humans. A focal point is the interaction between genes encoding human leukocyte antigen (HLA) and those encoding HIV proteins. HLA molecules present fragments (epitopes) of HIV proteins on the surface of infected cells to enable immune recognition and killing by CD8(+) T cells; particular HLA molecules, such as HLA-B*57, HLA-B*27 and HLA-B*51, are more likely to mediate successful control of HIV infection. Mutation within these epitopes can allow viral escape from CD8(+) T-cell recognition. Here we analysed viral sequences and HLA alleles from >2,800 subjects, drawn from 9 distinct study cohorts spanning 5 continents. Initial analysis of the HLA-B*51-restricted epitope, TAFTIPSI (reverse transcriptase residues 128-135), showed a strong correlation between the frequency of the escape mutation I135X and HLA-B*51 prevalence in the 9 study cohorts (P = 0.0001). Extending these analyses to incorporate other well-defined CD8(+) T-cell epitopes, including those restricted by HLA-B*57 and HLA-B*27, showed that the frequency of these epitope variants (n = 14) was consistently correlated with the prevalence of the restricting HLA allele in the different cohorts (together, P < 0.0001), demonstrating strong evidence of HIV adaptation to HLA at a population level. This process of viral adaptation may dismantle the well-established HLA associations with control of HIV infection that are linked to the availability of key epitopes, and highlights the challenge for a vaccine to keep pace with the changing immunological landscape presented by HIV.
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http://dx.doi.org/10.1038/nature07746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3148020PMC
April 2009

Central role of reverting mutations in HLA associations with human immunodeficiency virus set point.

J Virol 2008 Sep 2;82(17):8548-59. Epub 2008 Jul 2.

Department of Paediatrics, Peter Medawar Building for Pathogen Research, United Kingdom.

Much uncertainty still exists over what T-cell responses need to be induced by an effective human immunodeficiency virus (HIV) vaccine. Previous studies have hypothesized that the effective CD8(+) T-cell responses are those driving the selection of escape mutations that reduce viral fitness and therefore revert post-transmission. In this study, we adopted a novel approach to define better the role of reverting escape mutations in immune control of HIV infection. This analysis of sequences from 710 study subjects with chronic C-clade HIV type 1 infection demonstrates the importance of mutations that impose a fitness cost in the control of viremia. Consistent with previous studies, the viral set points associated with each HLA-B allele are strongly correlated with the number of Gag-specific polymorphisms associated with the relevant HLA-B allele (r = -0.56, P = 0.0034). The viral set points associated with each HLA-C allele were also strongly correlated with the number of Pol-specific polymorphisms associated with the relevant HLA-C allele (r = -0.67, P = 0.0047). However, critically, both these correlations were dependent solely on the polymorphisms identified as reverting. Therefore, despite the inevitable evolution of viral escape, viremia can be controlled through the selection of mutations that are detrimental to viral fitness. The significance of these results is in highlighting the rationale for an HIV vaccine that can induce these broad responses.
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http://dx.doi.org/10.1128/JVI.00580-08DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2519667PMC
September 2008

HLA class I-driven evolution of human immunodeficiency virus type 1 subtype c proteome: immune escape and viral load.

J Virol 2008 Jul 23;82(13):6434-46. Epub 2008 Apr 23.

Department of Microbiology, University of Washington, 1959 NE Pacific Street, Box 358070, Seattle, WA 98195-8070, USA.

Human immunodeficiency virus type 1 (HIV-1) mutations that confer escape from cytotoxic T-lymphocyte (CTL) recognition can sometimes result in lower viral fitness. These mutations can then revert upon transmission to a new host in the absence of CTL-mediated immune selection pressure restricted by the HLA alleles of the prior host. To identify these potentially critical recognition points on the virus, we assessed HLA-driven viral evolution using three phylogenetic correction methods across full HIV-1 subtype C proteomes from a cohort of 261 South Africans and identified amino acids conferring either susceptibility or resistance to CTLs. A total of 558 CTL-susceptible and -resistant HLA-amino acid associations were identified and organized into 310 immunological sets (groups of individual associations related to a single HLA/epitope combination). Mutations away from seven susceptible residues, including four in Gag, were associated with lower plasma viral-RNA loads (q < 0.2 [where q is the expected false-discovery rate]) in individuals with the corresponding HLA alleles. The ratio of susceptible to resistant residues among those without the corresponding HLA alleles varied in the order Vpr > Gag > Rev > Pol > Nef > Vif > Tat > Env > Vpu (Fisher's exact test; P < or = 0.0009 for each comparison), suggesting the same ranking of fitness costs by genes associated with CTL escape. Significantly more HLA-B (chi(2); P = 3.59 x 10(-5)) and HLA-C (chi(2); P = 4.71 x 10(-6)) alleles were associated with amino acid changes than HLA-A, highlighting their importance in driving viral evolution. In conclusion, specific HIV-1 residues (enriched in Vpr, Gag, and Rev) and HLA alleles (particularly B and C) confer susceptibility to the CTL response and are likely to be important in the development of vaccines targeted to decrease the viral load.
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http://dx.doi.org/10.1128/JVI.02455-07DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2447109PMC
July 2008
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