1. BIOREpository

Understanding repeat expansion dynamics and phenotype variability in myotonic dystrophy type 1 through human studies, nanopore sequencing and cell models

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Primary Data

Project title
Understanding repeat expansion dynamics and phenotype variability in myotonic dystrophy type 1 through human studies, nanopore sequencing and cell models
Code
111-3
Project Coordinator
Participant Organization(s)
 
Status
Completed
Start date
10-01-2022
Expected Completion
09-01-2025
 

Description

Abstract
Unstable expansions of short tandem repeats are uniquely present in the human genome and cause almost 50 incurable neurological diseases, including myotonic dystrophy type 1 (DM1), the most common adult muscular dystrophy. DM1 expansion instability is driven by the number of repeats but other factors, such as repeat interruptions and change in local DNA methylation pattern have a critical impact as well. All these factors result in an extremely variable DM1 clinical presentation and disease progression. Current methods are not suitable for analyzing DM1 expansions, which not only hinders our understanding of the disease but also the prognosis and development of causative treatments. We propose to adapt the Oxford nanopore sequencing technology to solve these challenges. The developed method will be used to define factors shaping repeat instability and its change over time (dynamics) in DM1 patients. Obtained longitudinal patient genetic and epigenetic data will be integrated with longitudinal clinical data to describe phenotype variability and, most importantly, the disease progression. At the molecular level, we will dissect the respective effect of local DNA methylation and repeat interruptions on DM1 expansion instability. This will be achieved by developing specific cell line models using CRISPR-Cas9 genome and epigenome editing and analyzing repeat dynamics. Overall, this project will result in: • An innovative diagnostic procedure for DM1 based on the Oxford nanopore sequencing. All clinically relevant features of DM1 mutation will be included: expansion size and instability, repeat interruptions and DNA methylation • Models of DM1 genotype-phenotype correlation with increased prognostic value • Identifying the role of local DNA methylation on repeat dynamics The READ-DM1 will enable standardization of the genetic method for not only DM1 but other repeat expansion diseases as well, and a personalized approach in treating DM1 patients.
 
Keyword(s)
Myotonic dystrophy;