BAZ2B haploinsufficiency as a cause of developmental delay, intellectual disability, and autism spectrum disorder.

The bromodomain adjacent to zinc finger 2B gene (BAZ2B) encodes a protein involved in chromatin remodeling. Loss of BAZ2B function has been postulated to cause neurodevelopmental disorders. To determine whether BAZ2B deficiency is likely to contribute to the pathogenesis of these disorders, we performed bioinformatics analyses that demonstrated a high level of functional convergence during fetal cortical development between BAZ2B and genes known to cause autism spectrum disorder (ASD) and neurodevelopmental disorder. We also found an excess of de novo BAZ2B loss-of-function variants in exome sequencing data from previously published cohorts of individuals with neurodevelopmental disorders. We subsequently identified seven additional individuals with heterozygous deletions, stop-gain, or de novo missense variants affecting BAZ2B. All of these individuals have developmental delay (DD), intellectual disability (ID), and/or ASD. Taken together, our findings suggest that haploinsufficiency of BAZ2B causes a neurodevelopmental disorder, whose cardinal features include DD, ID, and ASD.

RNA-based translation activators for targeted gene upregulation.

Technologies capable of programmable translation activation offer strategies to develop therapeutics for diseases caused by insufficient gene expression. Here, we present "translation-activating RNAs" (taRNAs), a bifunctional RNA-based molecular technology that binds to a specific mRNA of interest and directly upregulates its translation. taRNAs are constructed from a variety of viral or mammalian RNA internal ribosome entry sites (IRESs) and upregulate translation for a suite of target mRNAs. We minimize the taRNA scaffold to 94 nucleotides, identify two translation initiation factor proteins responsible for taRNA activity, and validate the technology by amplifying SYNGAP1 expression, a haploinsufficiency disease target, in patient-derived cells. Finally, taRNAs are suitable for delivery as RNA molecules by lipid nanoparticles (LNPs) to cell lines, primary neurons, and mouse liver in vivo. taRNAs provide a general and compact nucleic acid-based technology to upregulate protein production from endogenous mRNAs, and may open up possibilities for therapeutic RNA research.

Sensory Processing Phenotypes in Phelan-McDermid Syndrome and SYNGAP1-Related Intellectual Disability.

Sensory processing differences are an established feature of both syndromic and non-syndromic Autism Spectrum Disorders (ASDs). Significant work has been carried out to characterize and classify specific sensory profiles in non-syndromic autism. However, it is not known if syndromic autism disorders, such as Phelan-McDermid Syndrome (PMD) or SYNGAP1-related Intellectual Disability (SYNGAP1-ID), have unique sensory phenotypes. Understanding the sensory features of these disorders is important for providing appropriate care and for understanding their underlying mechanisms. Our objective in this work was to determine the sensory processing abnormalities present in two syndromic ASDs: Phelan-McDermid Syndrome and SYNGAP1-related Intellectual Disability. Using a standardized instrument, the Short Sensory Profile-2, we characterized sensory features in 41 patients with PMD and 24 patients with SYNGAP1-ID, and sub-scores were then calculated for seeking, avoiding, sensitivity and registration, as well as overall sensory and behavior scores. We found both patient groups exhibited atypical sensory features, including high scores in the areas of avoiding and seeking. Thus, we discovered significant sensory processing abnormalities are common in these syndromic ASDs. Measurements of sensory processing could serve as useful clinical endpoints for trials of novel therapeutics for these populations.

Comparison of Treadmill Gait Between a Pediatric-Aged Individual With SYNGAP1-Related Intellectual Disability and a Fraternal Twin.

SYNGAP1-related Intellectual Disability (SYNGAP1-ID) is a rare neurodevelopmental condition characterized by profound intellectual disability, gross motor delays, and behavioral issues. Ataxia and gait difficulties are often observed but have not yet been characterized by laboratory-based kinematic analyses. This investigation identified gait characteristics of an individual with SYNGAP1-ID and compared these with a neurotypical fraternal twin. Lower limb kinematics were collected with a 12-camera motion capture system while both participants walked on a motorized treadmill. Kinematic data were separated into strides, and stride times calculated. Sagittal plane hip, knee, and ankle joints were filtered and temporally normalized to 100 samples. Minimum and maximum joint angles, range of motion (ROM) and angular velocities were obtained for each joint by stride and averaged for each participant. ROM symmetry between left and right joints was also calculated. Discrete relative phase (DRP) was used to assess coordination and variability between joints within a single limb and compared across limbs. Phase portraits were calculated by joint, and their areas were computed with a MATLAB script. Statistical parametric mapping (SPM) was used to assess differences in joint angle waveforms between participants. P1, the individual with SYNGAP1-ID, displayed significantly reduced stride times relative to the fraternal twin, i.e., P2. A majority of minimum, maximum angles, ROMs, and angular velocities were significantly different between P1 and P2. Phase portrait areas were consistently less in P1 relative to P2 and there were differences in knee and ankle symmetries. DRP showed no differences between individuals, suggesting that P1's coordinative events remained similar to those observed during neurotypical gait (P2). SPM revealed significant differences between the left and right legs at the knee and ankle joints of P1 while P2 joint left and right waveforms were nearly identical for all joints. Additionally, SPM revealed there were significant differences between P1 and P2 for all joints. This investigation identified several major gait features of an individual with SYNGAP1-ID and provided a comprehensive characterization of these features by utilizing both linear and non-linear analyses. While limited in generalizability, this report provides a strong quantitative appraisal of gait in an individual with SYNGAP1-ID as well as an analysis pathway for future investigations.

The transcriptional repressor DEC2 regulates sleep length in mammals.

Sleep deprivation can impair human health and performance. Habitual total sleep time and homeostatic sleep response to sleep deprivation are quantitative traits in humans. Genetic loci for these traits have been identified in model organisms, but none of these potential animal models have a corresponding human genotype and phenotype. We have identified a mutation in a transcriptional repressor (hDEC2-P385R) that is associated with a human short sleep phenotype. Activity profiles and sleep recordings of transgenic mice carrying this mutation showed increased vigilance time and less sleep time than control mice in a zeitgeber time- and sleep deprivation-dependent manner. These mice represent a model of human sleep homeostasis that provides an opportunity to probe the effect of sleep on human physical and mental health.