Up to 350 million people worldwide suffer from a rare disease, and while the individual diseases are rare, in aggregate they represent a substantial challenge to global health systems. The majority of rare disorders are genetic in origin, with children under the age of five disproportionately affected. As these conditions are difficult to identify clinically, genetic and genomic testing have become the backbone of diagnostic testing in this population. In the last 10 years, next-generation sequencing technologies have enabled testing of multiple disease genes simultaneously, ranging from targeted gene panels to exome sequencing (ES) and genome sequencing (GS). GS is quickly becoming a practical first-tier test, as cost decreases and performance improves. A growing number of studies demonstrate that GS can detect an unparalleled range of pathogenic abnormalities in a single laboratory workflow. GS has the potential to deliver unbiased, rapid and accurate molecular diagnoses to patients across diverse clinical indications and complex presentations. In this paper, we discuss clinical indications for testing and historical testing paradigms. Evidence supporting GS as a diagnostic tool is supported by superior genomic coverage, types of pathogenic variants detected, simpler laboratory workflow enabling shorter turnaround times, diagnostic and reanalysis yield, and impact on healthcare.
- clinical genome sequencing
- rare and undiagnosed
- genetic testing
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Contributors DB, MJ, RJT and JB were involved in the planning and developing of the main conceptual ideas. DB and ST conducted the literature searches and provided an initial draft with critical input from MJ, RJT and JB. All authors provided feedback and contributed to the final version of the manuscript.
Competing interests DB: Envision Genomics—stock; Smith Family Clinic LLC—billing for care; Clinical Services Laboratory LLC—fee for clinical analysis; Genomics England—scientific advisory board. MJ: nothing to disclose. ST: current employee and shareholder of Illumina. RJT: current employee and shareholder of Illumina. JB: current employee and shareholder of Illumina.
Provenance and peer review Not commissioned; externally peer reviewed.
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