Exploring the role of structural variants in peripheral neurodegeneration.

Many Mendelian diseases have benefited from next-generation sequencing (NGS) technologies for molecular diagnosis and gene discovery. However, technical limitations of NGS pose a challenge for identification of mutational mechanisms in genomic regions impenetrable by these technologies. I hypothesize that complex genomic rearrangements called structural variants (SVs) in these loci can explain a significant proportion of missing heritability in many diseases. To this end, I propose to explore the involvement of SVs in 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 SVs. 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.

Keywords:CHARCOT-MARIE-TOOTH DISEASE

Disciplines:Genetics, Genomics, Medical genomics, Molecular and cell biology not elsewhere classified, Neurological and neuromuscular diseases