Structural variants impacting peripheral neurodegeneration

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Many Mendelian diseases have benefited from next-generation sequencing (NGS) technologies for gene discovery and the establishment of molecular diagnosis. However, the technical limitations of NGS pose a challenge for identifying mutational mechanisms in genomic regions impenetrable by these technologies. I hypothesize that complex genomic rearrangements called structural variants in these loci can explain a significant proportion of missing heritability in many monogenic diseases. To this end, I propose to investigate the involvement of structural variants in the pathogenesis of Charcot-Marie-Tooth disease (CMT), the most common genetic affliction of the peripheral nervous system. I will utilize long-read Nanopore sequencing in a unique patient cohort to look for potentially disease-causing structural variants. I will then adopt genetic and functional in vitro and in vivo approaches to characterize the identified genomic variants and ascertain the associated functional genes that most likely underlie molecular pathology. The findings of my pioneering study will highlight the contribution of structural variants in peripheral neurodegeneration, discover non-conventional mutational mechanisms long overlooked by state-of-the-art technologies, and deliver in vivo models that might provide clues for therapeutic approaches for peripheral nerve disorders with common etiology.