Influences of RASopathies on Neuroanatomical Variation in Children.

BACKGROUND: RASopathies are a group of disorders characterized by pathogenic mutations in the Ras/mitogen-activated protein kinase (Ras/MAPK) signaling pathway. Distinct pathogenic variants in genes encoding proteins in the Ras/MAPK pathway cause Noonan syndrome (NS) and neurofibromatosis type 1 (NF1), which are associated with increased risk for autism spectrum disorder and attention-deficit/hyperactivity disorder. METHODS: This study examined the effect of RASopathies (NS and NF1) on human neuroanatomy, specifically on surface area (SA), cortical thickness (CT), and subcortical volumes. Using vertex-based analysis for cortical measures and Desikan region of interest parcellation for subcortical volumes, we compared structural T1-weighted images of children with RASopathies (n = 91, mean age = 8.81 years, SD = 2.12) to those of sex- and age-matched typically developing children (n = 74, mean age = 9.07 years, SD = 1.77). RESULTS: Compared with typically developing children, RASopathies had convergent effects on SA and CT, exhibiting increased SA in the precentral gyrus, decreased SA in occipital regions, and thinner CT in the precentral gyrus. RASopathies exhibited divergent effects on subcortical volumes, with syndrome-specific influences from NS and NF1. Overall, children with NS showed decreased volumes in striatal and thalamic structures, and children with NF1 displayed increased volumes in the hippocampus, amygdala, and thalamus. CONCLUSIONS: Our study reveals the converging and diverging neuroanatomical effects of RASopathies on human neurodevelopment. The convergence of cortical effects on SA and CT indicates a shared influence of Ras/MAPK hyperactivation on the human brain. Therefore, considering these measures as objective outcome indicators for targeted treatments is imperative.

Novel effects of Ras-MAPK pathogenic variants on the developing human brain and their link to gene expression and inhibition abilities.

The RASopathies are genetic syndromes associated with pathogenic variants causing dysregulation of the Ras/mitogen-activated protein kinase (Ras-MAPK) pathway, essential for brain development, and increased risk for neurodevelopmental disorders. Yet, the effects of most pathogenic variants on the human brain are unknown. We examined: (1) How Ras-MAPK activating variants of PTPN11/SOS1 protein-coding genes affect brain anatomy. (2) The relationship between PTPN11 gene expression levels and brain anatomy, and (3) The relevance of subcortical anatomy to attention and memory skills affected in the RASopathies. We collected structural brain MRI and cognitive-behavioral data from 40 pre-pubertal children with Noonan syndrome (NS), caused by PTPN11 (n = 30) or SOS1 (n = 10) variants (age 8.53 ± 2.15, 25 females), and compared them to 40 age- and sex-matched typically developing controls (9.24 ± 1.62, 27 females). We identified widespread effects of NS on cortical and subcortical volumes and on determinants of cortical gray matter volume, surface area (SA), and cortical thickness (CT). In NS, we observed smaller volumes of bilateral striatum, precentral gyri, and primary visual area (d's < -0.8), and extensive effects on SA (d's > |0.8|) and CT (d's > |0.5|) relative to controls. Further, SA effects were associated with increasing PTPN11 gene expression, most prominently in the temporal lobe. Lastly, PTPN11 variants disrupted normative relationships between the striatum and inhibition functioning. We provide evidence for the effects of Ras-MAPK pathogenic variants on striatal and cortical anatomy as well as links between PTPN11 gene expression and cortical SA increases, and striatal volume and inhibition skills. These findings provide essential translational information on the Ras-MAPK pathway's effect on human brain development and function.

Preferential looking to eyes versus mouth in early infancy: heritability and link to concurrent and later development.

BACKGROUND: From birth, infants orient preferentially to faces, and when looking at the face, they attend primarily to eyes and mouth. These areas convey different types of information, and earlier research suggests that genetic factors influence the preference for one or the other in young children. METHODS: In a sample of 535 5-month-old infant twins, we assessed eye (relative to mouth) preference in early infancy, i.e., before neural systems for social communication and language are fully developed. We investigated the contribution of genetic and environmental factors to the preference for looking at eyes, and the association with concurrent traits and follow-up measures. RESULTS: Eye preference was independent from all other concurrent traits measured, and had a moderate-to-high contribution from genetic influences (A = 0.57; 95% CI: 0.45, 0.66). Preference for eyes at 5 months was associated with higher parent ratings of receptive vocabulary at 14 months. No statistically significant association with later autistic traits was found. Preference for eyes was strikingly stable across different stimulus types (e.g., dynamic vs. still), suggesting that infants' preference at this age does not reflect sensitivity to low-level visual cues. CONCLUSIONS: These results suggest that individual differences in infants' preferential looking to eyes versus mouth to a substantial degree reflect genetic variation. The findings provide new leads on both the perceptual basis and the developmental consequences of these attentional biases.

Brain structure in autoimmune Addison's disease.

Long-term disturbances in cortisol levels might affect brain structure in individuals with autoimmune Addison's disease (AAD). This study investigated gray and white matter brain structure in a cohort of young adults with AAD. T1- and diffusion-weighted images were acquired for 52 individuals with AAD and 70 healthy controls, aged 19-43 years, using magnetic resonance imaging. Groups were compared on cortical thickness, surface area, cortical gray matter volume, subcortical volume (FreeSurfer), and white matter microstructure (FSL tract-based spatial statistics). Individuals with AAD had 4.3% smaller total brain volume. Correcting for head size, we did not find any regional structural differences, apart from reduced volume of the right superior parietal cortex in males with AAD. Within the patient group, a higher glucocorticoid (GC) replacement dose was associated with smaller total brain volume and smaller volume of the left lingual gyrus, left rostral anterior cingulate cortex, and right supramarginal gyrus. With the exception of smaller total brain volume and potential sensitivity of the parietal cortex to GC disturbances in men, brain structure seems relatively unaffected in young adults with AAD. However, the association between GC replacement dose and reduced brain volume may be reason for concern and requires follow-up study.

Syndrome-Specific Neuroanatomical Phenotypes in Girls With Turner and Noonan Syndromes.

BACKGROUND: Turner syndrome (TS) and Noonan syndrome (NS) are distinct genetic conditions with highly similar physical and neurodevelopmental phenotypes. TS is caused by X chromosome absence, whereas NS results from genetic mutations activating the Ras-mitogen-activated protein kinase signaling pathway. Previous neuroimaging studies in individuals with TS and NS have shown neuroanatomical variations relative to typically developing individuals, a standard comparison group when initially examining a clinical group of interest. However, none of these studies included a second clinical comparison group, limiting their ability to identify syndrome-specific neuroanatomical phenotypes. METHODS: In this study, we compared the behavioral and brain phenotypes of 37 girls with TS, 26 girls with NS, and 37 typically developing girls, all ages 5 to 12 years, using univariate and multivariate data-driven analyses. RESULTS: We found divergent neuroanatomical phenotypes between groups, despite high behavioral similarities. Relative to the typically developing group, TS was associated with smaller whole-brain cortical surface area (p ≤ .0001), whereas NS was associated with smaller whole-brain cortical thickness (p = .013). TS was associated with larger subcortical volumes (left amygdala, p = .002; right hippocampus, p = .002), whereas NS was associated with smaller subcortical volumes (bilateral caudate, p ≤ .003; putamen, p < .001; pallidum, p < .001; right hippocampus, p = .015). Multivariate analyses also showed diverging brain phenotypes in terms of surface area and cortical thickness, with surface area outperforming cortical thickness at group separation. CONCLUSIONS: TS and NS have syndrome-specific brain phenotypes, despite their behavioral similarities. Our observations suggest that neuroanatomical phenotypes better reflect the different genetic etiologies of TS and NS and may be superior biomarkers relative to behavioral phenotypes.

Visual disengagement in young infants in relation to age, sex, SES, developmental level and adaptive functioning.

Visual attention plays a key role in infants' interaction with the environment, and shapes their behavioral and brain development. As such, early problems with flexibly switching gaze from one stimulus to another (visual disengagement) have been hypothesized to lead to developmental difficulties (e.g. joint attention and social skills) over time. This study aimed to identify cross-sectional associations between performance in the Gap task (gaze shift latencies and visual attention disengagement) and measures of development and adaptive behavior in conjunction to any sex or socioeconomic status effects in infancy. We measured visual attention disengagement in 436 5-month-old infants and calculated its association with cognitive developmental level, adaptive behaviours, socioeconomic status (SES) and biological sex. In the Gap task, participants must redirect their gaze from a central stimulus to an appearing peripheral stimulus. The three experimental conditions of the task (Gap, Baseline and Overlap) differ on the timepoint when the central stimuli disappears in relation to the appearance of the peripheral stimulus: 200 ms before the peripheral stimulus appears (Gap), simultaneously to its appearance (Baseline), or with peripheral stimulus offset (Overlap). The data from the experimental conditions showed the expected pattern, with average latencies being the shortest in the Gap and longest in the Overlap condition. Females were faster (p = .004) than males in the Gap condition, which could indicate that arousal-related effects differ as a function of biological sex. Infants from higher SES were slower (p = .031) in the Overlap condition compared to lower SES infants. This suggests that basic visual attention may differ by socio-cultural background, and should be considered when studying visual attention and its developmental correlates. We observed no significant association to concurrent developmental level or adaptive function. Given its large sample size, this study provides a useful reference for future studies of visual disengagement in early infancy.

Volitional eye movement control and ADHD traits: a twin study.

BACKGROUND: Top-down volitional command of eye movements may serve as a candidate endophenotype of ADHD, an important function underlying goal-directed action in everyday life. In this twin study, we examined the relation between performance on a response inhibition eye-tracking paradigm and parent-rated ADHD traits in a population-based twin sample. We hypothesized that altered eye movement control is associated with the severity of ADHD traits and that this association is attributable to genetic factors. METHODS: A total of 640 twins (320 pairs, 50% monozygotic) aged 9-14 years) from the Child and Adolescent Twin Study in Sweden (CATSS) participated. Twins performed the antisaccade task indexing inhibitory alterations as either direction errors (following exogenous cues rather than instructions) or premature anticipatory eye movements (failure to wait for cues). We calculated the associations of eye movement control and ADHD traits using linear regression mixed-effects models and genetic and environmental influences with multivariate twin models. RESULTS: Premature anticipatory eye movements were positively associated with inattentive traits (ß = .17; 95% CI: 0.04, 0.31), while controlling for hyperactive behaviors and other covariates. Both premature anticipatory eye movements and inattention were heritable (h2  = 0.40, 95% CI: 0.22, 0.56; h2  = 0.55; 95% CI: 0.42, 0.65; respectively), and their genetic correlation was small but statistically significant (r = .19, 95% CI: 0.02, 0.36). However, the genetic correlation did not remain significant after adjusting for covariates (age, sex, hyperactivity traits, IQ). No link was found between direction errors and ADHD traits. CONCLUSIONS: This study indicates that there is a specific, genetically influenced, relation between top-down eye movement control and the inattentive traits typical of ADHD.

Visual Disengagement: Genetic Architecture and Relation to Autistic Traits in the General Population.

Visual disengagement has been hypothesized as an endophenotype for autism. In this study we used twin modelling to assess the role of genetics in basic measures of visual disengagement, and tested their putative association to autistic traits in the general population. We used the Gap Overlap task in a sample of 492 twins. Results showed that most of the covariance among eye movement latencies across conditions was shared and primarily genetic. Further, there were unique genetic contributions to the Gap condition, but not to the Overlap condition-i.e. the one theorized to capture visual disengagement. We found no phenotypic association between autistic traits and disengagement, thus not supporting the hypothesis of visual disengagement as an endophenotype for autistic traits.