Five autism-associated transcriptional regulators target shared loci proximal to brain-expressed genes.

Many autism spectrum disorder (ASD)-associated genes act as transcriptional regulators (TRs). Chromatin immunoprecipitation sequencing (ChIP-seq) was used to identify the regulatory targets of ARID1B, BCL11A, FOXP1, TBR1, and TCF7L2, ASD-associated TRs in the developing human and mouse cortex. These TRs shared substantial overlap in the binding sites, especially within open chromatin. The overlap within a promoter region, 1-2,000 bp upstream of the transcription start site, was highly predictive of brain-expressed genes. This signature was observed in 96 out of 102 ASD-associated genes. In vitro CRISPRi against ARID1B and TBR1 delineated downstream convergent biology in mouse cortical cultures. After 8 days, NeuN+ and CALB+ cells were decreased, GFAP+ cells were increased, and transcriptomic signatures correlated with the postmortem brain samples from individuals with ASD. We suggest that functional convergence across five ASD-associated TRs leads to shared neurodevelopmental outcomes of haploinsufficient disruption.

Massively parallel reporter assays and mouse transgenic assays provide complementary information about neuronal enhancer activity.

Genetic studies find hundreds of thousands of noncoding variants associated with psychiatric disorders. Massively parallel reporter assays (MPRAs) and in vivo transgenic mouse assays can be used to assay the impact of these variants. However, the relevance of MPRAs to in vivo function is unknown and transgenic assays suffer from low throughput. Here, we studied the utility of combining the two assays to study the impact of non-coding variants. We carried out an MPRA on over 50,000 sequences derived from enhancers validated in transgenic mouse assays and from multiple fetal neuronal ATAC-seq datasets. We also tested over 20,000 variants, including synthetic mutations in highly active neuronal enhancers and 177 common variants associated with psychiatric disorders. Variants with a high impact on MPRA activity were further tested in mice. We found a strong and specific correlation between MPRA and mouse neuronal enhancer activity including changes in neuronal enhancer activity in mouse embryos for variants with strong MPRA effects. Mouse assays also revealed pleiotropic variant effects that could not be observed in MPRA. Our work provides a large catalog of functional neuronal enhancers and variant effects and highlights the effectiveness of combining MPRAs and mouse transgenic assays.

Access to MRI in Patients With Cardiac Implantable Electronic Devices is Variable and an Issue in Australia.

AIMS: This study aimed to characterise the level of access to magnetic resonance imaging (MRI) in Australian hospitals for patients with MR-conditional and non-MR-conditional cardiac implantable electronic devices (CIED), and to identify any barriers impeding this access. METHODS: All Australian Tertiary Referral Public Hospitals (n=38) were surveyed with a mixed qualitative and quantitative questionnaire. Provision of MRI to patients with MR-conditional and non-MR-conditional CIEDs; patient monitoring strategies during scan and personnel in attendance; barriers impeding MRI access. RESULTS: Of the 35 (92%) hospitals that completed the survey, a majority (85.7%) scan MR-conditional CIEDs, while a minority (8.6%) scan non-MR-conditional CIEDs. MR-conditional device scanning is often limited to non-pacing dependent patients, excluding implantable cardioverter-defibrillators. In total, 21% of sites exclude thoracic MR scans for CIED patients. Although most centres scan on 1.5 Tesla (T) machines (59%), 10% scan at 3T and 31% scan at both strengths. Sites vary in patient monitoring strategies and personnel in attendance; 80% require staff with Advanced Cardiac Life Support to be present. Barriers to service expansion include an absence of national guidelines, formal training, and logistical device support. CONCLUSIONS: Most surveyed Australian hospitals offer MRI for patients with MR-conditional CIEDs, however many still have exclusions for particular patient groups or scan requests. Only three surveyed sites offer MRI for patients with non-MR-conditional CIEDs in Australia. A national effort is needed to address the identified barriers including the development of national guidelines, formal training, and logistical support.