Identification of tandem repeat expansions in unsolved neurological disorders

• Applicant: Professorin Dr. Christel Depienne, Ph.D.
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Human Genetics
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 458099954

Tandem repeats are unstable and polymorphic variations abundantly present in human genomes. Their expansion is a well-known pathological process involved in ~40 neurological disorders, all identified through family-based (linkage) approaches. However, the contribution of repeat expansions to the missing heritability of neurological disorders remains largely unknown due to methodological difficulties in mapping reads filled with repeats and estimating repeat lengths on both allele using current next generation sequencing technologies. Tandem repeats, which have the highest mutational rate in the genome, have not been systematically assessed in cohorts of patients, and very likely constitute an enormous unexplored reservoir of pathogenic variations. We have recently identified a characterized pentanucleotide repeat expansions in two different genes as a major cause of familial adult myoclonic epilepsy. This work has prompted us to set up experimental conditions and bioinformatics pipelines allowing to detect repeat expansions from short-read and long-read individual genomes. The goal of this project is to take advantage of these tools to systematically assess the contribution of repeat expansions in unsolved patients with neurological disorders. We will search for repeat expansions in 196 patients from four different cohorts: septo-optic dysplasia, Tourette syndrome, and two cohorts of patients with neurodevelopmental and neurodegenerative disorders, for which exome sequencing was unsuccessful. Our strategy will consist in sequentially combining short-read sequencing and long-read Oxford nanopore technologies. We will use state-of-the-art bioinformatic pipelines to perform case-control comparisons and outlier analyses and detect repeat expansions. In addition, RNAseq (from lymphoblasts or fibroblats) will also be performed for 50 selected cases to pinpoint the existence of RNA filled with repeats and abnormally expressed genes. This project should provide new insights into the genetic architecture and missing heritability of unsolved neurological disorders. It will also contribute to the development of tools and methods that should become part of the standard pipelines required for identification of repeat expansions.

• DFG Programme: Research Grants