Speaker
Description
The recent expansion of multi-omic molecular methods, including transcriptomics, proteomics, epigenomics and whole-genome sequencing, has led to huge improvements in the diagnosis and research of rare diseases, such as neurodevelopmental disorders (NDDs). The accuracy of these methods in pathology profiling is in part determined by the closeness of the tested biological sample to the diseased tissue of interest. The norm to avoid the need for invasive biopsy is the sequencing of clinically accessible tissues (CATs), commonly peripheral blood mononuclear cells (PBMCs) or lymphoblastoid cell lines (LCLs) from blood, fibroblasts from skin, or now with increasing frequency Urine-Derived Renal Epithelial Cells (UREC). Previous studies have revealed that only about 60% of topologically associating domains (chromatin features) are conserved between tissues. Similarly, a study in non-CATs reported that 40.2% of genes have splicing that is inadequately represented by at least one CAT with 6.3% of genes having splicing inadequately represented by all assessed CATs.
By combining previous research mapping RNA splicing variations in CATs and 56 different nonaccessible tissues, including foetal and adult cortex (Aicher et al., 2020), with new RNA-sequencing and chromatin confirmation mapping (Hi-C) of neuronal tissues (adult neurons and glia, foetal cortex at different developmental timepoints) and CATs (PBMC, LCLs, and fibroblasts), we have outlined the expression levels and splicing events of 1182 NDD related genes, and 3D chromatin features absent/inadequately represented from commonly used CATs. Initial analysis revealed only 3.53% of NDD genes within adult cortex neurons display adequate expression, 3D structure, and splicing within tested CATs, demonstrating the consideration required for CAT choice in the majority of diagnostic settings. With this list, we can now begin feasibility testing of novel CATs for use in NDD research and diagnostics, based on their ability to adequately represent neurogenomic features lacking in established CAT systems.
| Author(s) | Michael B Vaughan*, Lara Colombo, Esperanza Daal, Aude Beyens, Eva Vanbelleghem, Robbe Derudder, Sebastian Leimbacher, Eva D'haene, Bert Callewaert, Sarah Vergult |
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| Affiliation(s) | "Department of Biomolecular Medicine, Ghent University, Ghent, Belgium, Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium" |
