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We identified individuals with variations in ACTL6B, a component of the chromatin remodeling machinery including the BAF complex. Ten individuals harbored bi-allelic mutations and presented with global developmental delay, epileptic encephalopathy, and spasticity, and ten individuals with de novo heterozygous mutations displayed intellectual disability, ambulation deficits, severe language impairment, hypotonia, Rett-like stereotypies, and minor facial dysmorphisms (wide mouth, diastema, bulbous nose). Nine of these ten unrelated individuals had the identical de novo c.1027G>A (p.Gly343Arg) mutation. Human-derived neurons were generated that recaptured ACTL6B expression patterns in development from progenitor cell to post-mitotic neuron, validating the use of this model. Engineered knock-out of ACTL6B in wild-type human neurons resulted in profound deficits in dendrite development, a result recapitulated in two individuals with different bi-allelic mutations, and reversed on clonal genetic repair or exogenous expression of ACTL6B. Whole-transcriptome analyses and whole-genomic profiling of the BAF complex in wild-type and bi-allelic mutant ACTL6B neural progenitor cells and neurons revealed increased genomic binding of the BAF complex in ACTL6B mutants, with corresponding transcriptional changes in several genes including TPPP and FSCN1, suggesting that altered regulation of some cytoskeletal genes contribute to altered dendrite development. Assessment of bi-alleic and heterozygous ACTL6B mutations on an ACTL6B knock-out human background demonstrated that bi-allelic mutations mimic engineered deletion deficits while heterozygous mutations do not, suggesting that the former are loss of function and the latter are gain of function. These results reveal a role for ACTL6B in neurodevelopment and implicate another component of chromatin remodeling machinery in brain disease.

Background: The self-reported KIDSCREEN questionnaires are ideal for capturing children’s and adolescents’ health-related quality of life (HRQoL) and have gained worldwide popularity. Responding to demands for the concise nature of KIDSCREEN among Chinese Mainland researchers and practitioners, this study aimed to evaluate the psychometric properties of the Mandarin Chinese self-reported KIDSCREEN-27 (KS-27) and KIDSCREEN-10 index (KS-10), which are short versions of the self-reported KIDSCREEN-52 (KS-52). Methods: This study reanalyzed the validation dataset of the Mandarin Chinese self-reported KS-52. The dataset originated from a cross-sectional survey conducted in Weifang City, the Chinese Mainland, from October to November 2016. Adolescents aged 11–17 years (N = 4385) were surveyed, and sub-samples (N = 841) were retested. Statistical analyses were conducted on the feasibility, item and dimension properties, reliability, and validity of the Mandarin Chinese self-reported KS-27 and KS-10. Results: Indirect evidence from the Small Group Pilot Survey indicated that the Mandarin Chinese self-reported KS-27 and KS-10 can be completed on average in less than 12.33 mins. Their response rate exceeded 90% regardless of the unit- and item (dimension)-level. The psychometric properties of items and dimensions were likewise found to be satisfactory. Internal consistency was robust with inter-item and item-total correlations (0.173–0.873, 0.422–0.786), Cronbach’s alpha (0.786–0.881), Guttman’s lambda-2 and - 6 (0.807–0.889, 0.829–0.896), and McDonald’s omega (0.725–0.886). Test–retest reliability at both item- and dimension-level was excellent, with intraclass correlation coefficients (ICCs) of (0.590–0.696, 0.785–0.842); standard error of measurements (SEMs) of (0.352–0.635, 0.949–1.949). Confirmatory factor analysis (CFA) confirmed their five- and one-dimensional structures, albeit with slight modifications. Moreover, the multi-group confirmatory factor analysis (MG-CFA) substantiated their configural and metric invariance across gender and grade groups. Convergent validity was robust, with stronger correlations observed with comparable dimensions of the Mandarin Chinese self-reported PedsQL™ 4.0, while discriminant validity was evident with low correlations observed with less comparable dimensions. The known-group validity was mainly supported by medium to large effect sizes concerning differences in socioeconomic status (η2 = 0.07–0.17, Cohen’s d = 0.55–1.03) and mental health status (η2 = 0.09–0.40, Cohen’s d = 0.73–1.83). The Mandarin Chinese self-reported KS-52 served as the criterion; the ICCs between the Mandarin Chinese self-reported KS-27 and KS-10 and their comparable dimensions were stronger, indicating robust criterion validity. Conclusions: The Mandarin Chinese self-reported KS-27 and KS-10 demonstrated excellent psychometric properties, indicating their good potential for measuring HRQoL for children and adolescents in the Chinese Mainland. [ABSTRACT FROM AUTHOR]

Many genes in the human genome encode proteins that are dosage sensitive, meaning they require protein levels within a narrow range to properly execute function. To investigate if clinically relevant variation in protein levels impacts the same downstream pathways in human disease, we generated cell models of two SETBP1 syndromes: Schinzel-Giedion Syndrome (SGS) and SETBP1 haploinsufficiency disease (SHD), where SGS is caused by too much protein, and SHD is caused by not enough SETBP1. Using patient and sex-matched healthy first-degree relatives from both SGS and SHD SETBP1 cases, we assessed how SETBP1 protein dosage affects downstream pathways in human forebrain progenitor cells. We find that extremes of SETBP1 protein dose reciprocally influence important signalling molecules such as AKT, suggesting that the SETBP1 protein operates within a narrow dosage range and that extreme doses are detrimental. We identified SETBP1 nuclear bodies as interacting with the nuclear lamina and suggest that SETBP1 may organize higher order chromatin structure via links to the nuclear envelope. SETBP1 protein doses may exert significant influence on global gene expression patterns via these SETBP1 nuclear bodies. This work provides evidence for the importance of SETBP1 protein dose in human brain development, with implications for two neurodevelopmental disorders., (© The Author(s) 2025. Published by Oxford University Press.)

In order to study whether patients with schizophrenia have cerebral injury, neuron-specific enolase (NSE) and myelin basic protein (MBP)in cerebrospinal fluid (CSF) of 33 patients with first episode schizophrenia and 9 from the control group were determined by double antibody sandwich enzyme immunoassay method. The results showed that there was significant difference in the NSE contents between the experimental group and control group (P<0.01). The NSE contents in CSF in the experimental group were positively correlated with MBP in schizophrenia patients (P< 0. 05). These findings suggested that patients with schizophrenia had cerebral injury.