IMPACT

Neurodevelopmental disorders (NDDs) represent a large and heterogeneous group of rare disorders. Individual types of NDDs with a known genetic etiology are typically rare, owing to the very high number of individual genes that are causative for such conditions, but their aggregate societal impact is dramatic. Among the causative mutated genes, most are involved in two broad functional domains, synaptic processes and chromatin regulation (epigenetic mechanisms). In this proposal we selected five distinct NDDs: Kabuki, Kleefstra, Gabriele-de Vries, Helsmoortel-Van der Aa, and a syndromic type of Autism Spectrum Disorder (ASD) caused, respectively, by mutations in KMT2D, EHMT1, YY1, ADNP and CHD8. The uniquely informative edge of jointly studying these specific NDDs stems from the involvement of the causative genes in inter-related chromatin pathways, both directly and through their associated protein partners, and from the observation of major overlapping clinical features. We thus hypothesize that mutations in these five genes give rise to major transcriptional dysregulation in both common as well as unique gene regulatory networks, thereby generating shared and unique downstream effects in gene transcription and translation. Therefore, the IMPACT collaborative project aims to reveal common molecular and cellular signatures of chromatinopathy gene disruptions. Such converging mechanisms of disease offer an attractive target for the development of knowledge-based therapeutic interventions across individual NDDs that can potentially be useful for designing interventions suitable for multiple related rare neurodevelopmental disorders.

Autism spectrum disorders (ASDs) are a group of heterogeneous conditions characterized by difficulties in establishing social contacts and the manifestation of repetitive behaviors. Genes coding for chromatin-remodelers are frequently mutated in ASD patients and among them, chromodomain helicase DNA binding protein 8 (CHD8) is one of the most frequently mutated and most penetrant. In this study, we used cerebral organoids (miniature brain-like structures grown from human stem cells) and single-cell RNA sequencing to investigate the effects of CHD8 haploinsufficiency (having only one functional copy of the gene) on human cortical development. The findings revealed disruptions in the differentiation of excitatory and inhibitory neurons, leading to altered temporal dynamics during brain development. The analysis identifies specific genes and pathways affected by CHD8 mutations, particularly related to cell cycle regulation, RNA splicing, and neurogenesis. Our research sheded light on the cellular and molecular mechanisms underlying ASD and CHD8-related phenotypes, providing valuable insights into the neurodevelopmental aspects of these disorders.