Genome sequencing as a generic diagnostic strategy for rare disease

Although human genetic diseases are rare by themselves, together they account for an important public health burden. During life, 1 in 17 individuals will be affected by a rare condition at some point. More than 6000 rare diseases have been identified thus far. Diagnostic approaches to detect the underlying genetic causes of these diseases require a broad spectrum of technologies, ranging from traditional to more advanced technologies. Each of these technologies is dedicated to detecting one or multiple variant types. Now, genome sequencing (GS) promises comprehensive variant calling of all variant types from a single experiment, allowing for all types of molecular diagnoses.
Researcher Gaby Schobers and colleagues performed a benchmarking study to show the feasibility of transitioning to a generic ‘GS-first’ diagnostic workflow. The research group, led by Lisenka Vissers from the department of Human Genetics, published their results in Genome Medicine.

Using a cohort of 1,000 individuals previously molecularly diagnosed with a rare genetic disease, representative of the myriad of genetic variant types that were previously identified across 10 different workflows, they found that GS detected >95% of all pathogenic variants in a single sequencing set-up. Subsequently, they modeled the impact of a complete transition to a generic GS workflow for their diagnostic laboratories and concluded that for 68% of diagnostically referred individuals a generic GS-only workflow would be possible, and 3% would need additional testing, suggesting that for 71% of individuals a GS-first strategy would be beneficial. Hence, diagnostic efficacy of the laboratories can be enhanced by reducing the complexity of sample handling and the number of workflows. This will be highly beneficial for the genetic odyssey of patients with rare disease, as in most cases sequential testing will no longer be needed. Additionally, an increase in diagnostic yield might be expected from GS over standard care, enabled by evolving bioinformatic tools, and a greater understanding of non-coding and structural variant interpretation. In conclusion, GS can capture clinically relevant germline variants in a ‘GS-first strategy’ for the majority of clinical indications in a genetics diagnostic lab, and thus appears a suitable generic first tier test to diagnose individuals with rare diseases.