Background: Children with chromosome 22q11.2 deletion syndrome (22q11.2DS) exhibit nonverbal learning disability that may manifest in part because of working memory (WM) deficits. 22q11.2DS is a complex developmental disorder with serious physical, learning, cognitive, and psychiatric symptoms including a risk of developing schizophrenia 30 times that of the general population. WM impairment likely contributes to and exacerbates learning difficulties, school problems, existing neuropsychological disorders such as attention deficit hyperactivity disorder (ADHD); and a poor WM may be a biological risk marker for future mental illness. WM impairment is established in this population, but less is known about its neurological origins. Frontoparietal cortical development and function are key to WM processing. In the neurotypical developing brain, studies indicate activation associated with WM shifts from parietal to frontal regions with age. However, in children with 22q11.2DS, activation is restricted to the frontal cortex, and volumes are reduced in parietal regions where abnormal tractography abides. The overarching aim of this study was to determine the neural origins of WM impairment in people with 22q11.2DS. Methods: We measured WM in children and adolescents with (n = 29) and without (n = 27) 22q11.2DS using the WISC-IV and a computer-based spatial working memory task (SWMT) task. Participants’ brains were scanned using high-resolution magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). Focusing on brain morphometry and structural connectivity within frontoparietal networks, we investigated neural underpinnings of WM processing in 22 children with 22q11.2DS and 19 typically developing (TD) controls ages 7 to 16 (M = 12.13 ± 2.41). A connectome mapping network involved in WM processing was constructed by superimposing cortical segmentations on white-matter tractography. Results: Children with 22q11.2DS had impaired working memory performance. Individuals’ performance on our SWMT moderated the association between diagnosis and gray and white matter macro and microstructure. Children with 22q11.2DS with better working memory had larger lateral orbitofrontal volumes, greater axial diffusivity in the left superior frontal to superior parietal tract, and smaller volume in the right superior frontal to lateral orbitofrontal tract. Poorer performance in children with 22q11.2DS was associated with smaller right superior parietal and superior frontal cortical volumes. Conclusions: Children with 22q11.2DS performed worse on measures of working memory. Their performance was related to regional cortical volume differences and white matter microstructure abnormalities in the frontal and parietal lobes. These are brain regions consistently implicated in WM processing.

22q11.2 Deletion Syndrome (22q) is the most common microdeletion known in humans. Studies have hypothesized that larger nasopharyngeal proportions lead to velopharyngeal dysfunction (VPD) in individuals in 22q.22q patients that undergo the pharyngeal flap surgery to correct their velopharyngeal insufficiency have been reported to experience an increased rate of surgical complications due to their complex anatomical differences.Treatment of velopharyngeal insufficiency among patients with 22q therefore requires quantitative anatomical data of the nasopharyngeal area for surgical planning. No studies to date have analyzed the nasopharyngeal volume in a non-sedated pediatric population with 22q. The aim of this study was to investigate the volumetric and linear characteristics of the nasopharyngeal port among children with 22q using a novel, non-sedated 3D imaging protocol. MRI data were obtained on 20 participants, 10 with a confirmed diagnosis of 22q and 10 control subjects. All participants were between 4-12 years of age. 3D MRI data were collected while the velum was relaxed as the participants lay in the supine position. The 3D scan involved a 0.8 in-plane isotropic resolution with an acquisition time of less than 5 minutes.MRI data were transferred into Amira 6 Visualization Volume Modeling software (Visage Imaging GmbH, Berlin, Germany). Both volumetric and linear measurements of the nasopharyngeal port were taken. The measures were selected based on relevance to speech resonance features and comparable studies in the literature. Linear measurements were taken of the velopharyngeal (VP) width, anterior cranial base angle (ACBA), pharyngeal depth, osseous pharyngeal depth, and adenoid-nasopharyngeal ratio (ANR). Volumetric measurements included adenoid volume (AV), nasopharyngeal volume (NPV), and oronasopharyngeal volume (ONV) . Independent samples t-tests were used to assess differences between the control and clinical groups. The total volume of the nasopharynx was found to be significantly larger in the 22q group (2890.70 mm3) compared to the control group (1542.10 mm3). Significant differences were additionally noted among linear measures, including a more obtuse angle of the ACBA in the 22q group. These results support our initial hypothesis regarding larger nasopharyngeal airways in patients with 22q compared to the control group. Quantitative anatomical data of nasopharyngeal proportions in children with 22q can be used to tailor surgery to provide a more personalized treatment approach to enhance speech and surgical outcomes in the 22q population.

Le syndrome de DiGeorge ou microdélétion 22q11.2, est la délétion chromosomique la plus fréquente chez les êtres humains. Cette délétion est liée à la recombinaison homologue non-allélique au cours de la méiose induisant la perte d’en moyenne 40 gènes. Les études de corrélation génotype/phénotype chez les patients ont révélé des différences phénotypiques entre individus et cela indépendamment de la taille des microdélétions. L’hypothèse de l’implication des mécanismes épigénétiques dans la variabilité phénotypique observée a été soulevée mais reste encore inexplorée. C’est dans ce contexte que nous nous intéressons à l’étude des mécanismes épigénétiques au cours du développement, dans cette pathologie à travers l’utilisation d’un modèle de cellules souches pluripotentes induites humaines (hiPSs). En particulier, nous avons ciblé nos travaux sur le rôle de la chaperonne d’histone HIRA dont le gène est localisé dans la région délétée. HIRA est impliquée dans la déposition du variant d’histone H3.3, une histone majeure dans le cerveau. Afin de comprendre l’implication de HIRA dans les manifestations neurologique du syndrome de DiGeorge et en particulier dans la schizophrénie, nous avons développé et optimisé un nouveau protocole pour la différenciation de cellules hiPSCs en progéniteurs neuronaux, neurones corticaux et neurones dopaminergiques. L’ensemble de ces travaux ouvre donc de nouvelles perspectives pour la modélisation d’un grand nombre de pathologies, et dans le contexte du laboratoire, pour l’exploration des mécanismes épigénétiques associés à la variabilité phénotypique dans différentes maladies génétiques. / The DiGeorge syndrome also known as 22q11.2 microdeletion syndrome, is the most common deletion in humans. This deletion is linked to a non-allelic homologous recombination that occurs during meiosis and involves sequences called LCRs for "Low Copy Repeats". Depending on the LCRs involved, different deletions are observed, inducing the loss of approximately 40 genes. The absence of genotype/phenotype correlation in patients and the phenotypical differences regardless of the size of the microdeletion suggests the involvement of additional parameter. The hypothesis of epigenetic changes associated with the onset or variability of symptoms has been suggested but never investigated. In order to tackle this question, we decided to focus our attention of the role of the HIRA histone chaperone encoded by a gene located in the 22q11.2-deleted region. HIRA is involved in the deposition of the H3.3 histone variant, one of the main histone in the brain. In order to determine whether HIRA is implicated in the neurological manifestations in DiGeorge patients and particularly in schizophrenia, we developed and optimized a new protocol for the direct differentiation of human induced pluripotent stem cell (hiPSCs) into neural progenitors, cortical and dopaminergic neurons. In parallel, we developed a new protocol for hiPSCs differentiation toward the skeletal muscle lineage and the production of multinucleated muscle fibers. Altogether, these results open new perspectives for the modeling of a large number of pathologies, and in the context of our laboratory, the exploration of epigenetic mechanisms associated with phenotypic variability in different genetic diseases.

Children with chromosome 22q11.2 deletion syndrome (22q11.2DS) have serious medical, psychological, and behavioral symptoms that are stressful to their parents. Higher general intelligence quotients (IQ) and emotional intelligence (EI) in children could allay parental stress. Self-reported stress, anxiety, and depression were measured in parents of children with 22q11.2DS (n=42) and a healthy control group (n=20) in relation to children’s IQ and EI. Children with 22q1.2DS had lower IQ and EI scores. Parental groups did not differ in their reported stress, anxiety, or depression. Children’s IQ and EI levels did not relate to parental measures of affect even in the 22q11.2DS group. Based on these families at this measurement point, it appears that parents are coping well with the challenges of raising a child with a complex neurodevelopmental disorder and that IQ and EI do not play a significant role in parental affect. Further interpretation and future directions are discussed.

Neurological abnormalities are associated with emotion processing deficits seen in children with neurodevelopmental disorders. Research suggests that inflammatory mechanisms can negatively impact brain structure and function and are thought to play a role in these processing atypicalities. Children with chromosome 22q11.2 deletion syndrome (22q11.2DS) exhibit emotion processing impairments and associated neural abnormalities. We investigated the roles of inflammatory factors and structural connectivity in relation to emotion processing deficits in 28 children with 22q11.2DS and 33 typically developing children (M = 11.12 years old; SD = 2.17). Results indicate poorer social skills and significantly lower emotion recognition scores in children with 22q11.2DS compared to controls. Additionally, children with 22q11.2DS had higher anisotropic diffusion in right amygdala to fusiform gyrus white matter pathways and lower serum IL-3 concentrations than their typically developing peers. Right amygdala to fusiform gyrus FA values partially mediated the relationship between 22q11.2DS and social skills, as well as the relationship between 22q11.2DS and emotion recognition accuracy. However, there was no indication that IL-3 mediated the relationship between diagnosis and abnormal connectivity. Future studies should employ longitudinal methods to characterize how these connectivity patterns influence social-emotional development as the child ages.

Activation of brain regions that make up the mirror neuron system (MNS) is thought to reflect processing and perceiving behavior, action, and intentionality of other organisms. Sensing and perceiving motor behavior in others is an important component of understanding and participating in social interactions. Children with chromosome 22q11.2 deletion syndrome (22q11.2DS) are diagnosed with serious medical, cognitive, and socio-emotional symptoms. Atypical development and function of the MNS may underpin some aspects of socio-emotional impairment and autism spectrum disorder (ASD)-like symptomology reported. This study of the MNS investigates differences in activation in the operculum, sensorimotor areas, and basal ganglia (BG) in children with 22q11.2DS compared to typically-developing (TD) controls. Twenty-nine children (22q11.2DS: n=15; TD: n=16) between ages 7-16 viewed videos of a human hand manipulating various household objects during a functional magnetic resonance imaging (fMRI) scan. In Analysis 1, children with 22q11.2DS had less extensive brain activation than TD children in the operculum, sensorimotor areas, and BG. In Analysis 2, children with 22q11.2DS had the same results as Analysis 1 with the exception of sensorimotor areas not being highly active in either group. In both analyses, fMRI signal change from baseline to video did not differ significantly between groups. Processing efficiency in children with 22q11.2DS may be lower or more variable when compared to TD peers. This is the first study comparing children with 22q11.2DS to TD peers specifically looking at MNS activation within the operculum region to assess higher cognitive functioning, somatosensory cortex for sensory interpretation, and basal ganglia for gross motor activity. Future studies should compare brain activation between children with ASD and those with 22q11.2DS during an MNS task as the next step to further clarify the origin of ASD symptoms reported in this population.