ZNF536 encodes a C2H2 zinc-finger transcription factor that functions as a transcriptional repressor. While common noncoding variants at the ZNF536 locus have been reported to be associated with schizophrenia in a genome-wide association study (GWAS), the contribution of rare, protein-altering variants to human disease has not been systematically investigated. Through an international collaboration, we assembled a cohort of 21 affected individuals carrying 18 unique, rare, heterozygous, protein-altering ZNF536 variants. Most variants (15/18) were predicted loss-of-function (LoF) alleles, with the remainder being missense variants. Among families with available inheritance data (17/20), most variants arose de novo (12/17), while others were inherited from mosaic or mildly affected parents (5/17). Clinically, affected individuals presented with developmental delay along with high rates of autism spectrum disorder, intellectual disability, hyperactivity, aggressive behavior, anxiety, and hyperphagia; epilepsy and sleep disturbances were also frequently observed. To assess functional consequences of a proband-associated ZNF536 variant, we generated a Zfp536p.Gln169Ter knock-in mouse model. Homozygous mutants were non-viable, while heterozygotes survived but displayed autism-like behaviors, increased anxiety, and impaired recognition memory. Embryonic brain analysis revealed reduced cortical size, cortical thickness, and decreased deep-layer neuronal density. These features are consistent with phenotypes of a publicly available mouse knockout model and support our clinical cohort findings that rare monoallelic LoF variants in ZNF536 underlie a genetic neurodevelopmental disorder characterized by developmental delay, autism, and behavioral dysregulation. The pathogenicity of missense variants in disease remains to be determined. These results support a role for ZNF536 as a dosage-sensitive regulator of cortical development.
S. Hiatt, Wen-Jing Zhao, Zhong-Qing Wang et al.· American Journal of Human Ge...· 0 citations
Objective. Sensory processing dysfunction (SPD) not only affects most individuals with autism spectrum disorder (ASD), but at least 5% of children without ASD also experience SPD. Our understanding of the relationship between sensory dysfunction and resting state brain activity is still emerging. The objective of this study was to examine group differences and behavioral associations with resting state alpha and beta oscillatory activity in ASD, SPD, and typically developing control (TDC) groups. Approach. This study compared long-range resting state functional connectivity of neural oscillatory behavior in 60 male children aged 8–12 years with (ASD; N = 18), those with (SPD; N = 18) who did not meet ASD criteria, and typically developing control participants (TDC; N = 24) using magnetoencephalography. Functional connectivity analyses were performed in the alpha and beta frequency bands, which are known to be implicated in sensory information processing. Group differences in functional connectivity and associations between sensory abilities and functional connectivity were examined. Main results. Distinct patterns of functional connectivity differences between ASD and SPD groups were found only in the beta band, but not in the alpha band. In both alpha and beta bands, ASD and SPD cohorts differed from the TDC cohort. Distinct patterns of associations between imaginary coherence and performance-based measures of sensory processing and verbal abilities were identified across groups. Significance. These findings demonstrate distinct long-range alpha and beta band phase-lagged neural synchrony alterations in SPD and ASD that are associated with sensory processing abilities in male children. These measures could serve as potential candidate neurophysiological markers for ASD and SPD at the group level, and may provide mechanistic insights relevant to biomarker development.
C. Demopoulos, Xuan Jesson, Molly Gerdes et al.· Journal of Neural Engineerin...· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
