Genomic Basis of Primary Muscle Diseases.CI

• Applicant: Dr. Sebahattin Cirak
• Subject Area: Pediatric and Adolescent Medicine
• Term: from 2020 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 433156347

In the last decade, we have made large progress in the identification of the genetic basis of neuromuscular disorders by Whole Exome Sequencing (WES). However, based on our own preliminary data on a large cohort and of others, we estimate that 40% of inherited neuromuscular cases are genetically unsolved despite extensive genomic workup. Because WEShas also its limitations: intronic mutations are not detected, synonymous changes are often ignored yet may alter ESE or other aspects of mRNA processing and metabolism, and finally, there is about a 10% drop out of exons due to the hybrid capture technologies utilized. Whole Genome Sequencing (WGS) is the ultimate method for mutation detection in the exome-negativecases and has the power to uncover structural rearrangements like inversions and other pathogenic structural variants. It has been estimated that 10% (Weischenfeldt et al., 2013) of Mendelian diseases are caused by CNVs/structural rearrangements, some of those will occur in non-coding regions but will still have pathogenic effects. We have extensively genetically andclinically investigated and recruited over 200 cases(DNAs) with inherited neuromuscular disorders from our own and international centers with elusive underlying mutations till now. We aim to sequence 50 Transcriptomes from muscle biopsies of exome-negative cases and these 50 cases will also undergo a trio-whole genome sequencing (150 genomes). To increasethe power, we aim to whole exome sequencing of 200 cases. The validation of the pathological impact of intronic or structural variants will be facilitated by the integrative approach of combining RNAseq (Transcriptomics) data from primarily affected disease tissues (muscle biopsies) and patient cell lines together with the whole genome sequencing data.Those novel disease-associated gene mutations will serve as hypothesis for the functional research based on biochemical/biophysical recombinant mutant proteins or suitable in-vitro models to develop chemical chaperones and also gain an in-depth understanding of the pathophysiological processes. The functional research is already established in the laboratory of the principal investigator.

• DFG Programme: Research Grants