Transcriptomics in the Diagnosis of Genetic Myopathies
Date
2021-09-24
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Abstract
The myopathies are a diverse group of primary muscle disorders that arise for a variety of reasons, including both acquired disease (i.e. autoimmune disorders), or from genetic variation (the genetic myopathies). RNA sequencing is the application of next-generation sequencing technologies to sequence the transcriptomes of cells and tissues, yielding a functional, and regulatory snapshot of a sample. Comparing the transcriptomes of the autoimmune disorder inclusion body myositis, and a variety of genetic myopathies, including samples with mitochondrial, myofibrillar, dystrophic, or otherwise nonspecific pathology, showed an extensive immunological influence on those with myositis. There are more nuanced differences in the transcriptomes of the histologically grouped conditions among this cohort, including the previously described FGF21 upregulation in mitochondrial myopathies. Long non-coding RNAs are a neglected species of RNA with myriad regulatory roles. Several non-coding transcripts were identified among the studied groups, that will serve as candidates for testing their biomarker potential for muscle diseases. We tested the utility of RNAseq at diagnosing the genetic myopathy participants of this cohort, identifying four cases where potentially pathogenic variants were detected by accounting for transcript isoform abundance. Genes with transcriptional findings, and potentially pathogenic variants included FLNC, MYOT, NEB, and SELENON. The approach may not be optimal for diagnosing individuals with presumed mitochondrial disease, where minimal differences were observed in mitochondrial transcripts. Ultimately, RNAseq provides another tool for clinicians to investigate genetic disorders, and assist with differential diagnosis.
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Keywords
myopathy, transcriptomics, lncRNA, variant prioritization, clinical genetics
Citation
Joel, M. M. (2021). Transcriptomics in the Diagnosis of Genetic Myopathies (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.