Abstract
Developmental and Epileptic Encephalopathies (DEEs) are a heterogeneous group of neurodevelopmental disorders characterized by severe seizures and developmental delay, often with a genetic basis. Despite advances in genetic testing, a significant diagnostic gap remains, preventing counseling and effective clinical treatment. In our group, we have generated trio long-read nanopore sequencing data in a cohort that will ultimately include 60 well-phenotyped DEE patients who currently lack a molecular diagnosis. Here, I perform a first-of-its kind trio analysis using native long-read nanopore sequencing and native methylation analysis to investigate imprinting defects in DEE. Additionally, I will perform outlier methylation analysis identifying potential disruptions that lead to DEE in our cohort. Finally, I propose the development of a novel multi-omics framework to detect, annotate, filter, and prioritize structural variants by integrating long-read sequencing, transcriptomics and methylomics. This framework addresses current limitation in interpretation of structural variants often classified as variants of unknown significance (VUS). By leveraging these state-of-the-art improvements, I aim to reclassify VUS identified in our cohort and improve the diagnostic yield for DEE patients. Ultimately, my approach will reduce the diagnostic gap in DEE and pave the way for more targeted therapies.
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