Transcriptomic characterization of induced pluripotent stem cell-derived neural cells from patients with Williams Syndrome

Authors

• CV da Silva Camargo
• S Detera-Wadleigh
• N Akula
• A Schulmann
• A Elkahloun
• M Gregory
• D Eisenberg
• K Bernan
• F McMahon

Abstract

Williams Syndrome (WS) is a rare neurodevelopmental disorder caused by a hemizygous deletion on chromosome 7q11.23, characterized by mild intellectual disability, specific cognitive traits, distinctive facies, overly social comportment, and other nervous system abnormalities. While WS has a well-defined cognitive/behavioral profile, its cellular and molecular underpinnings have not fully resolved. To model the neurobiological mechanisms involved in neural cell development, we analyzed iPSCs-derived neural progenitor cells (NPCs) and neuronal precursors from induced pluripotent stem cells (iPSCs) from WS patients and their non-carrier siblings. Single cell RNA sequencing (scRNAseq) performed in duplicates on NPCs from an initial sample derived from one non-carrier and three WS patients revealed clusters of cells representing distinct neural differentiation stages. Most cells were captured at an early developmental stage expressing NPC markers. The remaining neural cells showed progression toward neural maturation, as evidenced by expression of genes encoding GABAergic and glutamatergic markers. Most genes localized in the 7q11.23 hemi-deleted region such as GTF2I and LIMK1 were significantly downregulated, as expected. Differentially expressed genes (DEGs) at earlier NPC stages were enriched for terms related to cell cycle and mitotic processes. DEGs in more mature neuronal stages were enriched for various biological processes including ‘nervous system’ and ‘synaptic signaling.’ Future directions include multi-omics analysis from additional individuals. Emergent genetic and molecular profiles will be correlated with extensive neuroimaging and clinical phenotypes available. Further neurobiological and neuromolecular characterization of these samples may help reveal signature pathways that could be targeted in the development of new, more efficacious therapeutics.

Scientific Focus Area: Neuroscience

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