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RAD21 encodes a key component of the cohesin complex, and variants in RAD21 have been associated with Cornelia de Lange Syndrome (CdLS). Limited information on phenotypes attributable to RAD21 variants and genotype-phenotype relationships is currently published. We gathered a series of 49 individuals from 33 families with RAD21 alterations [24 different intragenic sequence variants (2 recurrent), 7 unique microdeletions], including 24 hitherto unpublished cases. We evaluated consequences of 12 intragenic variants by protein modelling and molecular dynamic studies. Full clinical information was available for 29 individuals. Their phenotype is an attenuated CdLS phenotype compared to that caused by variants in NIPBL or SMC1A for facial morphology, limb anomalies, and especially for cognition and behavior. In the 20 individuals with limited clinical information, additional phenotypes include Mungan syndrome (in patients with biallelic variants) and holoprosencephaly, with or without CdLS characteristics. We describe several additional cases with phenotypes including sclerocornea, in which involvement of the RAD21 variant is uncertain. Variants were frequently familial, and genotype-phenotype analyses demonstrated striking interfamilial and intrafamilial variability. Careful phenotyping is essential in interpreting consequences of RAD21 variants, and protein modeling and dynamics can be helpful in determining pathogenicity. The current study should be helpful when counseling families with a RAD21 variation.

To assess emotional and behavioral problems in children and adolescents with neurofibromatosis type 1,parents of 183 individuals aged 10.8 ± 3.1 years (range 6-17) completed the Child Behavior Checklist (CBCL). Also, 173 teachers completed the Teacher's Report Form (TRF), and 88 adolescents (children from 11 to 17 years) completed the Youth Self-Report (YSR). According to parental ratings, 32% scored in the clinical range (above the 90th percentile). This percentage was much lower when rated by teachers or adolescents themselves. Scores from all informants on scales for Somatic complaints, Social problems, and Attention problems were significantly different from normative scores. Attentional problems were associated with lower verbal IQ, male gender, younger age, and ADHD-symptoms. Disease-related factors did not predict behavioral problems scores. Substantial emotional and behavioral problems were reported by parents, teachers, and to a lesser extent by adolescents with NF1 themselves. Possibly, a positive illusory bias affects the observation of behavioral problems by adolescents with NF1., (© 2017 Wiley Periodicals, Inc.)

Background: Recent studies have suggested that deregulated AKT1 signaling is associated with schizophrenia. We hypothesized that if this is indeed the case, we should observe both decreased AKT1 expression as well as deregulation of AKT1 regulated pathways in Peripheral Blood Mononuclear Cells (PBMCs) of schizophrenia patients., Objectives: To examine PBMC expression levels of AKT1 in schizophrenia patients versus controls, and to examine whether functional biological processes in which AKT1 plays an important role are deregulated in schizophrenia patients., Methods/results: A case-control study, investigating whole-genome PBMC gene expression in male, recent onset (<5 years) schizophrenia patients (N = 41) as compared to controls (N = 29). Genes, differentially expressed between patients and controls were identified using ANOVA with Benjamini-Hochberg correction (false discovery rate (FDR) = 0.05). Functional aspects of the deregulated set of genes were investigated with the Ingenuity Pathway Analysis (IPA) Software Tool. We found significantly decreased PBMC expression of AKT1 (p<0.001, t = -4.25) in the patients. AKT1 expression was decreased in antipsychotic-free or -naive patients (N = 11), in florid psychotic (N = 20) and in remitted (N = 21) patients. A total of 1224 genes were differentially expressed between patients and controls (FDR = 0.05). Functional analysis of the entire deregulated gene set indicated deregulated canonical pathways involved in a large number of cellular processes: immune system, cell adhesion and neuronal guidance, neurotrophins and (neural) growth factors, oxidative stress and glucose metabolism, and apoptosis and cell-cycle regulation. Many of these processes are associated with AKT1., Conclusions: We show significantly decreased PBMC gene expression of AKT1 in male, recent-onset schizophrenia patients. Our observations suggest that decreased PBMC AKT1 expression is a stable trait in recent onset, male schizophrenia patients. We identified several AKT related cellular processes which are potentially affected in these patients, a majority of which play a prominent role in current schizophrenia hypotheses.

22q11 Deletion Syndrome (22q11DS) is associated with dysmorphology and a high prevalence of schizophrenia-like symptoms. Several genes located on chromosome 22q11 have been linked to schizophrenia. The deletion is thought to disrupt the expression of multiple genes involved in maturation and development of neurons and neuronal circuits, and neurotransmission. We investigated whole-genome gene expression of Peripheral Blood Mononuclear Cells (PBMC's) of 8 22q11DS patients and 8 age- and gender-matched controls, to (1) investigate the expression levels of 22q11 genes and (2) to investigate whether 22q11 genes participate in functional genetic networks relevant to schizophrenia. Functional relationships between genes differentially expressed in patients (as identified by Locally Adaptive Statistical procedure (LAP) or satisfying p<0.05 and fold-change >1.5) were investigated with the Ingenuity Pathways Analysis (IPA). 14 samples (7 patients, 7 controls) passed quality controls. LAP identified 29 deregulated genes. Pathway analysis showed 262 transcripts differentially expressed between patients and controls. Functional pathways most disturbed were cell death, cell morphology, cellular assembly and organization, and cell-to-cell signaling. In addition, 10 canonical pathways were identified, among which the signal pathways for Natural Killer-cells, neurotrophin/Trk, neuregulin, axonal guidance, and Huntington's disease. Our findings support the use of 22q11DS as a research model for schizophrenia. We identified decreased expression of several genes (among which COMT, Ufd1L, PCQAP, and GNB1L) previously linked to schizophrenia as well as involvement of signaling pathways relevant to schizophrenia, of which Neurotrophin/Trk and neuregulin signaling seems to be especially notable.

The aim of this study was to quantify the frequently observed problems in motor control in Neurofibromatosis type 1 (NF1) using three tasks on motor performance and motor learning. A group of 70 children with NF1 was compared to age-matched controls. As expected, NF1 children showed substantial problems in visuo-motor integration (Beery VMI). Prism-induced hand movement adaptation seemed to be mildly affected. However, no significant impairments in the accuracy of simple eye or hand movements were observed. Also, saccadic eye movement adaptation, a cerebellum dependent task, appeared normal. These results suggest that the motor problems of children with NF1 in daily life are unlikely to originate solely from impairments in motor learning. Our findings, therefore, do not support a general dysfunction of the cerebellum in children with NF1.

Objective: To investigate health-related quality of life (HR-QOL) in children with neurofibromatosis type 1 (NF1) with parental reports and children's self-reports, and to investigate the potential contribution of demographic factors, disease-specific factors, and problems in school performance or behavior., Study Design: In a prospective observational study, parents of 58 children with NF1 (32 boys, 26 girls, age 12.2 +/- 2.5 years) visiting a university clinic, and their 43 children 10 years or older were assessed with the Child Health Questionnaire (CHQ). Potential determinants of domain scores were assessed in 3 explorative regression models., Results: Parents reported a significant impact of NF1 on 9/13 CHQ scales, with moderate effect sizes on 8 (general health perceptions, physical functioning, general behavior, mental health, self esteem, family activities, role functioning emotional/behavioral, and parent emotional impact). Children report an impact on bodily pain, and an above average general behavior. Multiple CHQ scales were sensitive to demographic factors and behavioral problems, and 1 to NF1 severity. NF1 visibility and school problems did not influence HR-QOL., Conclusions: Parents, but not the children with NF1, report a profound impact of NF1 on physical, social, behavioral, and emotional aspects of HR-QOL. Multiple HR-QOL domains were most sensitive to behavioral problems, which points to an exciting potential opportunity to improve HR-QOL in children with NF1 by addressing these behavioral problems.

Defects in rat sarcoma viral oncogene homolog (RAS)-extracellular signal regulated kinase (ERK) and phosphatidylinositol 3-kinase (PI3K)-mammalian target of rapamycin (MTOR) signaling pathways have recently been shown to cause several genetic disorders classified as neuro-cardio-facial-cutaneous (NCFC) and Hamartoma syndromes. Although these pathways are well-known players in cell proliferation and cancer, their role in cognitive function is less appreciated. Here, we focus on the cognitive problems associated with mutations in the RAS-ERK and PI3K-MTOR signaling pathways and on the underlying mechanisms revealed by recent animal studies. Cancer drugs have been shown to reverse the cognitive deficits in mouse models of NCFC and Hamartoma syndromes, raising hopes for clinical trials.

School functioning of 86 Dutch neurofibromatosis type 1 children (7-17 years) using teacher questionnaires was analyzed to determine the impact of neurofibromatosis type 1 on school performance. In all, 75% of the neurofibromatosis type 1 children performed more than 1 standard deviation below grade peers in at least one of the domains of spelling, mathematics, technical reading or comprehensive reading. Furthermore, neurofibromatosis type 1 children had a 4-fold increased risk for attending special education and a 6-fold increased risk for receiving remedial teaching for learning, behavior, speech, or motor problems. Children without apparent learning disabilities still frequently displayed neuropsychological deficits. Only 10% of the children did not show any school-functioning problems. Finally, it was found that the clinical severity of neurofibromatosis type 1 correlated with the cognitive deficits. Taken together, it was shown that neurofibromatosis type 1 has profound impact on school performance. Awareness of these problems may facilitate timely recognition and appropriate support.

Background and Purpose: Hyperintensities on T2-weighted images are seen in the brains of most patients with neurofibromatosis type I (NF-1), but the origin of these unidentified bright objects (UBOs) remains obscure. In the current study, we examined the diffusion characteristics of brain tissue in children with NF-1 to test the hypothesis that a microstructural abnormality is present in NF-1., Materials and Methods: Diffusion tensor imaging (DTI) was performed in 50 children with NF-1 and 8 controls. Circular regions of interest were manually placed in 7 standardized locations in both hemispheres, including UBO sites. Apparent diffusion coefficients (ADC), fractional anisotropy (FA), and axial anisotropy (A(m)) were used to differentiate quantitatively between healthy and disordered brain matter. Differences in eigenvalues (lambda(1), lambda(2), lambda(3)) were determined to examine parenchymal integrity., Results: We found higher ADC values for UBOs than for normal-appearing sites (P < .01) and higher ADC values for normal-appearing sites than for controls (P < .04 in 5 of 7 regions). In most regions, we found no differences in FA or A(m). Eigenvalues lambda(2) and lambda(3) were higher at UBO sites than in normal-appearing sites (P < .04)., Conclusion: With ADC, it was possible to differentiate quantitatively between normal- and abnormal-appearing brain matter in NF-1 and also between normal-appearing brain matter in NF-1 and healthy brain matter in controls, indicating subtle pathologic damage disrupting the tissue microstructure in the NF-1 brain. Higher diffusivity for lambda(1), lambda(2), and lambda(3) indicates that this disturbance of microstructure is caused by accumulation of fluid or vacuolation.