Abstract
The unprecedented technological advances in nucleic acid analysis methods and platforms of the past two decades have enabled the interrogation not only of the human genome but also of its transcriptome at a high degree of granularity. From the original analysis of short sequences to arrays encompassing all known genes and more recently high-throughput sequencing methodologies, transcriptomics has offered a unique insight into the regulation and translation of human variation from the deoxyribonucleic acid (DNA) level toward protein expression. Combinatorial analyses of DNA and ribonucleic acid (RNA) sequencing have improved genetic diagnostic yield for some phenotypes, due to the opportunity that RNA sequencing (RNA-seq) offers in detecting disease-relevant mechanisms that had remained invisible through DNA analyses alone. Prominent examples involve aberrant and often tissue-specific splicing, differential expression of genes in disease-derived tissues compared to control profiles, and cases of monoallelic expression of disease variants, a phenomenon through which heterozygous DNA variants can mimic a recessive state. Despite the fact that transcriptomic analyses represent a snapshot of cellular biology in time, they offer an orthogonal view into how DNA variant information translates into disease biology. As current transcriptomic limitations such as experimental variability, access to relevant tissues, and assembly of adequate control populations improve, our understanding of rare diseases will also likely broaden. This chapter provides an overview of the methodologies used to study the human transcriptome, reviews the knowledge emerging from recent discoveries that successfully demonstrate the utility of RNA-seq in diagnosing rare disorders, and offers a balanced discussion on the next hurdles that need to be overcome in order to maximize the potential utility of this approach in studying the biology of disease and potentially for molecular diagnostics.
Published Version
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