Neurogenomics Conference

Unravelling Convergence and Divergence Mechanisms in Neurodevelopmental Disorders Through Single-Cell Transcriptomics

19 May 2025, 18:30

3h

Board: 65

Poster presentation Poster Session

Speaker

Mazen Khaddour (Human Technopole)

Description

Neurodevelopmental disorders (NDDs) encompass a heterogeneous spectrum of conditions that impact the development of the nervous system, leading to impairments in cognitive function, behaviour, and social abilities. The genetic basis of these disorders ranges from highly penetrant monogenic diseases to complex polygenic influences, in addition to a wide array of environmental factors. Despite the heterogeneity of genetic and environmental factors, many NDDs converge at distinct functional impairments. In vitro modelling has emerged as a crucial approach to studying neurodevelopmental physiology, providing a controlled system to investigate disease mechanisms. Among these models, cortical brain organoids have demonstrated transcriptional similarities to fetal tissues, making them a valuable tool for understanding early brain development.
We generated cortical brain organoids from 52 cell lines of 10 NDDs representing anchor points in neurodevelopmental pathology. We profiled with single-cell transcriptomics, whole genome sequencing and Imaged-based phenotyping at three-time points recapitulating transcription changes in fetal cortex at 8 and 12 post-conceptional weeks. Differential expression analysis revealed that transcriptional changes are specific for each disease at an early stage and converge at one particular shared set of genes at later stages. Diseases like Kabuki-Syndrome, GADEVS, and CHD8 Haploinsufficiency converged at all stages in functions related to synaptic activity and excitatory/inhibitory imbalance.
A comprehensive analysis of the mechanisms underlying NDDs facilitates the identification of shared and unique pathways, providing a foundation for future drug discovery and therapeutic interventions.