RNA-Seq and transcriptome-based approaches to aid in the diagnosis and understanding of genetic diseases

Genetic disease studies have been major beneficiaries of the next-generation sequencing era. Since the first reports of new genetic diagnoses arising from exome and genome sequencing little over a decade ago, the volume of diagnostic successes has burgeoned as studies have continued to increase in scale and number. Cohort-based studies of rare genetic disease have reported diagnostic rates of 18 -40% and figures in this range have come to represent something of a status quo in the field. Since 2017, a slow trickle of new publications have emerged espousing the diagnostic benefits of augmenting DNA-based testing with RNA-Seq assays and analyses. These efforts have studied various transcriptomic phenomena including differential expression, alternative splicing, allele-specific expression and less commonly, fusion transcripts. Remarkably, the latter were often considered to be an oncogenic phenomenon and their discovery underlying germline disease raises the question of whether profiling of other recognized oncogenic drivers such as alternative transcription start sites and alternative polyadenylation might further expand diagnostic capabilities in genetic disease studies. Muscular pathologies, mitochondriopathies and other wide ranging phenotypes including multiple exostoses and severe combined immunodeficiency have benefited from this addition of transcriptomic analyses to the analytical toolkit. These reported benefits can only continue to grow as researchers learn of the potential of transcription approaches and begin to utilize them in their own studies.

The goal of this Research Topic is to generate and collate a high quality, varied and comprehensive collection of manuscripts of various forms (case studies, original research, commentaries etc) that demonstrate the utility of RNA-based approaches and analysis in improving the diagnosis and understanding of genetic disease. Wet-lab and computational approaches are of interest, either in isolation or combination and similarly transcriptome-based approaches may occur independently or in unison with genetic, epigenetic or other methodologies. We wish to consider the practical elements of the problem as well as the philosophical as we consider how the next frontier of transcriptome analysis may manifest in the study of genetic disease.

As researchers who have demonstrated true, pioneering expertise in the field, you are invited to submit your original work and be a part of this seminal effort to generate a collection of work exploring this new, fertile and exciting area of genetic disease investigation.