EP139: Spatial transcriptomic approaches for characterizing childhood intellectual disability

Abstract

The genetic characterization of childhood intellectual disability (ID) as a form of developmental delay has undergone extensive study. Genome sequencing (GS) and exome sequencing (ES) have emerged as the standard test of choice for diagnostic uses as a result of evidence based studies. The American College of Medical Genetics and Genomics recently issued clinical guidelines where GS/ES was recommended in first-tier testing confirmation of suspected intellectual disability. This abstract proposes the application of spatial transcriptomic methods to reveal gene expression patterns and cellular and tissue environments in diagnosed pediatric patients with intellectual disability towards establishing potential medically actionable findings for these patients. A review will be performed using keywords “intellectual disability”, AND “whole transcriptomic” and “whole exome sequencing” and “whole genome sequencing” AND “intellectual disability” and “signaling pathways” AND “intellectual disability” and “cellular and tissue heterogeneity” AND “intellectual disability” and “gene expression” AND “intellectual disability” as inclusion criteria to propose a set of standards and methods for spatial transcriptomic approaches for revealing tissue and cellular heterogeneity and gene expression patterns for characterizing childhood intellectual disability. “Single cell sequencing” is also included in the search methods. “Epilepsy” and “autism spectrum disorder” were excluded search criteria. ID is a medical disorder characterized by reduction in cognitive and intellectual function and impaired social adaptation, affecting 1-3% of the worldwide population. No pharmacological therapies are currently available. Approximately 1000 genes have been discovered in ID indicating significant genetic heterogeneity. A significant level of genetic heterogeneity has been demonstrated in ID. In a whole transcriptomic analysis using RNA-Seq in consanguineous families with ID, it was found that SHTN1 was down-regulated while FGFR2 gene was upregulated. Gene expression alterations were also observed in genes affecting neuronal and actin cytoskeletal function in ID families. The Rho GTPase signaling pathway was associated with ID being implicated in the actin-rich nature of dendritic spines, reflecting impaired cytoskeleton remodeling and impacting cell processes such as neuronal migration and synaptic plasticity. Variants in the Rho GTPase family are significant in that they are key regulators of actin dynamics and organization. Systems biology approaches such as spatial transcriptomics focus on the overall interconnected network of individual genes and spatial distribution of mRNA molecules and allow for the revealing of cellular heterogeneity in tissues and the subcellular distribution of transcripts in conditions such as childhood ID. Individual cell functioning is only sufficiently explained in the context of identifying their exact locations and spatial transcriptomics methods connect gene expression to the spatial organization of cells. Techniques include fluorescent in situ hybridization, in situ sequencing and in silico approaches and could be applied to understanding more profoundly the cellular and tissue behavior of ID and suggesting a spatially-informed model of the condition. This is particularly significant since the actin cytoskeleton and molecular pathways such as tyrosine kinase pathways and GTPase signaling have been observed in ID. I will describe how these techniques could potentially apply to ID, and propose a set of spatial transcriptomics approaches to generate insight into the aberrant signaling pathways, cellular networks, tissue heterogeneity and gene expression patterns for this condition, and what information could potentially result of as a result of these methods, which may constitute a new contribution to the literature on ID. Spatial transcriptomics gives the ability to researchers to comprehend the spatial component of cell-to-cell signaling networks that are implicated in neurobiological disorders such as ID.