Turner syndrome (TS) is a model for X-chromosome influences on neurodevelopment because it is most commonly caused by absence of one X-chromosome, and associated with altered brain structure and function. However, all prior in vivo magnetic resonance imaging studies of the brain in TS have either used manual approaches or voxel-based-morphometry (VBM) to measure cortical volume (CV). These methods, unlike surface-based-morphometry (SBM), cannot measure the two neurobiologically distinct determinants of CV– cortical thickness (CT) and surface area (SA) – which have differing genetic determinants, and may be independently altered. Therefore, in 24 adults with X-monosomy and 19 healthy female controls, we used SBM to compare (i) lobar CV, CT and SA, (ii) an index of hemispheric gyrification (iii) CT throughout the cortical sheet, and (iv) CT correlation between cortical regions. Compared to controls, females with TS had (i) significantly increased CT and decreased SA in parietal and occipital lobes (resulting in no significant difference in lobar CV), (ii) reduced hemispheric gyrification bilaterally, (iii) foci of significantly increased CT involving inferior-temporal, lateral-occipital, intraparietal sulcus (IPS), cingulate, and orbito-frontal cortices, (iv) significantly reduced CT correlation between the left IPS and cortical regions including supramarginal and lateral-occipital gyri. Our findings suggest that females with TS have complex, sometimes ‘opposing’, abnormalities in SA/gyrification (decreased) and CT (increased); which can result in no overall detectable differences in CV. Thus haploinsufficiency of X-chromosome genes, may differentially impact the distinct mechanisms shaping SA (e.g. cortical folding) and CT (e.g. dendritic arborization/pruning). CT disruptions are maximal within and between cortical regions previously implicated in the TS cognitive phenotype.

Objective

There is overlap between an autistic and hyperactive-inattentive symptomatology when studied cross-sectionally. This study is the first to examine the longitudinal pattern of association between social-communication deficits and hyperactive-inattentive symptoms in the general population, from childhood through adolescence. We explored the interrelationship between trajectories of co-occurring symptoms, and sought evidence for shared prenatal/perinatal risk factors.

Method

Study participants were 5,383 singletons of white ethnicity from the Avon Longitudinal Study of Parents and Children (ALSPAC). Multiple measurements of hyperactive-inattentive traits (Strengths and Difficulties Questionnaire) and autistic social-communication impairment (Social Communication Disorder Checklist) were obtained between 4 and 17 years. Both traits and their trajectories were modeled in parallel using latent class growth analysis (LCGA). Trajectory membership was subsequently investigated with respect to prenatal/perinatal risk factors.

Results

LCGA analysis revealed two distinct social-communication trajectories (persistently impaired versus low-risk) and four hyperactive-inattentive trait trajectories (persistently impaired, intermediate, childhood-limited and low-risk). Autistic symptoms were more stable than those of attention-deficit/hyperactivity disorder (ADHD) behaviors, which showed greater variability. Trajectories for both traits were strongly but not reciprocally interlinked, such that the majority of children with a persistent hyperactive-inattentive symptomatology also showed persistent social-communication deficits but not vice versa. Shared predictors, especially for trajectories of persistent impairment, were maternal smoking during the first trimester, which included familial effects, and a teenage pregnancy.

Conclusions

Our longitudinal study reveals that a complex relationship exists between social-communication and hyperactive-inattentive traits. Patterns of association change over time, with corresponding implications for removing exclusivity criteria for ASD and ADHD, as proposed for DSM-5.

Recognized cases of autism spectrum disorders are on the rise. It is unclear whether this increase is attributable to secular trends in biological susceptibility, or to a change in diagnostic practices and recognition. One hint concerning etiological influences is the universally reported male excess (in the range of 4:1 to 10:1). Evidence suggests that genetic influences from the X chromosome play a crucial role in engendering this male vulnerability. In this review, we discuss three categories of genetic disease that highlight the importance of X-linked genes in the manifestation of an autistic phenotype: aneuploides (Turner syndrome and Klinefelter syndrome), trinucleotide expansions (Fragile X syndrome) and nucleotide mutations (Rett Syndrome, Neuroligins 3 & 4, and SLC6A8). The lessons from these diseases include an understanding of autistic features as a broad phenotype rather than as a single clinical entity, the role of multiple genes either alone or in concert with the manifestation of autistic features, and the role of epigenetic factors such as imprinting and X-inactivation in the expression of disease severity. Better understanding of the clinical phenotypes of social cognition and the molecular neurogenetics of X-linked gene disorders will certainly provide additional tools for understanding autism in the years to come.

Objective

Recent genome-wide analysis identified a genetic variant on 5p14.1 (rs4307059), which is associated with risk for autism spectrum disorder. This study investigated whether rs4307059 also operates as a quantitative trait locus underlying a broader autism phenotype in the general population, focusing specifically on the social communication aspect of the spectrum.

Method

Study participants were 7,313 children from the Avon Longitudinal Study of Parents and Children. Single-trait and joint-trait genotype associations were investigated for 29 measures related to language and communication, verbal intelligence, social interaction, and behavioral adjustment, assessed between ages 3 and 12 years. Analyses were performed in one-sided or directed mode and adjusted for multiple testing, trait interrelatedness, and random genotype dropout.

Results

Single phenotype analyses showed that an increased load of rs4307059 risk allele is associated with stereotyped conversation and lower pragmatic communication skills, as measured by the Children's Communication Checklist (at a mean age of 9.7 years). In addition a trend toward a higher frequency of identification of special educational needs (at a mean age of 11.8 years) was observed. Variation at rs4307059 was also associated with the phenotypic profile of studied traits. This joint signal was fully explained neither by single-trait associations nor by overall behavioral adjustment problems but suggested a combined effect, which manifested through multiple subthreshold social, communicative, and cognitive impairments.

Conclusions

Our results suggest that common variation at 5p14.1 is associated with social communication spectrum phenotypes in the general population and support the role of rs4307059 as a quantitative trait locus for autism spectrum disorder.