Deficiency of the Heterogeneous Nuclear Ribonucleoprotein U locus leads to delayed hindbrain neurogenesis.

Genetic variants affecting Heterogeneous Nuclear Ribonucleoprotein U (HNRNPU) have been identified in several neurodevelopmental disorders (NDDs). HNRNPU is widely expressed in the human brain and shows the highest postnatal expression in the cerebellum. Recent studies have investigated the role of HNRNPU in cerebral cortical development, but the effects of HNRNPU deficiency on cerebellar development remain unknown. Here, we describe the molecular and cellular outcomes of HNRNPU locus deficiency during in vitro neural differentiation of patient-derived and isogenic neuroepithelial stem cells with a hindbrain profile. We demonstrate that HNRNPU deficiency leads to chromatin remodeling of A/B compartments, and transcriptional rewiring, partly by impacting exon inclusion during mRNA processing. Genomic regions affected by the chromatin restructuring and host genes of exon usage differences show a strong enrichment for genes implicated in epilepsies, intellectual disability, and autism. Lastly, we show that at the cellular level HNRNPU downregulation leads to an increased fraction of neural progenitors in the maturing neuronal population. We conclude that the HNRNPU locus is involved in delayed commitment of neural progenitors to differentiate in cell types with hindbrain profile.

Presynaptic dysfunction in CASK-related neurodevelopmental disorders.

CASK-related disorders are genetically defined neurodevelopmental syndromes. There is limited information about the effects of CASK mutations in human neurons. Therefore, we sought to delineate CASK-mutation consequences and neuronal effects using induced pluripotent stem cell-derived neurons from two mutation carriers. One male case with autism spectrum disorder carried a novel splice-site mutation and a female case with intellectual disability carried an intragenic tandem duplication. We show reduction of CASK protein in maturing neurons from the mutation carriers, which leads to significant downregulation of genes involved in presynaptic development and of CASK protein interactors. Furthermore, CASK-deficient neurons showed decreased inhibitory presynapse size as indicated by VGAT staining, which may alter the excitatory-inhibitory (E/I) balance in developing neural circuitries. Using in vivo magnetic resonance spectroscopy quantification of GABA in the male mutation carrier, we further highlight the possibility to validate in vitro cellular data in the brain. Our data show that future pharmacological and clinical studies on targeting presynapses and E/I imbalance could lead to specific treatments for CASK-related disorders.

Association between Copy Number Variation and Response to Social Skills Training in Autism Spectrum Disorder.

Challenges in social communication and interaction are core features of autism spectrum disorder (ASD) for which social skills group training (SSGT) is a commonly used intervention. SSGT has shown modest and heterogeneous effects. One of the major genetic risk factors in ASD is rare copy number variation (CNV). However, limited information exists whether CNV profiles could be used to aid intervention decisions. Here, we analyzed the rare genic CNV carrier status for 207 children, of which 105 received SSGT and 102 standard care as part of a randomized clinical trial for SSGT. We found that being a carrier of rare genic CNV did not have an impact on the SSGT outcome measured by the parent-report Social Responsiveness Scale (SRS). However, when stratifying by pathogenicity and size of the CNVs, we identified that carriers of clinically significant and large genic CNVs (>500 kb) showed inferior SRS outcomes at post-intervention (P = 0.047 and P = 0.036, respectively) and follow-up (P = 0.008 and P = 0.072, respectively) when adjusting for standard care effects. Our study provides preliminary evidence that carriers of clinically significant and large genic CNVs might not benefit as much from SSGT as non-carriers. Our results indicate that genetic information might help guide the modifications of interventions in ASD.