Clinical Utility of Transcriptome Sequencing: Toward a Better Diagnosis for Mendelian Disorders.

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In a recent issue of Science Translational Medicine , Cummings and colleagues have shown for the first time, in a cohort of rare Mendelian disorders, the clinical utility of next-generation sequencing (NGS)2-based transcriptome sequencing (RNA-seq) to increase molecular diagnostic yield (1). In this study, they performed RNA-seq on the target tissue of skeletal muscle biopsies from patients with putative monogenic neuromuscular disorders (NMDs) that were undiagnosed from whole exome sequencing (ES) or genome sequencing (GS) results. The authors could identify pathogenic events focusing on splicing defects and allelic imbalance that resulted in a 34% increased definite molecular diagnosis, thereby demonstrating the promise of RNA-seq as a complementary tool to ES or GS in the clinical setting. These study results are even more promising because as DNA-based NGS analyses continue to produce massive amounts of data, the number of coding and noncoding variants of uncertain significance (VUSs) identified also increases, which in turn creates a medical and financial burden on variant classification, disease association, and follow-up diagnosis and therapy options. As Cummings et al. describe, current in silico approaches in clinical DNA-based genetic testing to classify VUSs have limitations and potentially lead to false-positive prediction of pathogenic splice-site aberrant events. In addition to the high prevalence of VUSs, the diagnostic challenges are further enhanced in cases of genetically and phenotypically heterogeneous rare disorders such as NMDs, in which >200 genes are associated with broad and overlapping phenotypic spectra. To overcome clinical diagnostic challenges, more emphasis is being given using other -omics approaches to analyze the functional consequences of genomic data at the levels of RNA, protein, epigenomics, posttranslational modifications, metabolites, and RNA-seq in particular (2), as recommended by American College of Medical Genetics and Genomics guidelines. Indeed, the clinical utility of RNA-based testing, albeit not using target tissue, has …