Evidence supports sequencing as first-line rare disease diagnostics

Recently published in nature Magazine genomic medicine, showing that short-read genome sequencing (GS) reduces the time needed to diagnose and treat pediatric patients who may have rare genetic diseases. This evidence supports efforts to make GS the first-line standard of care, particularly for patients in the neonatal intensive care unit (NICU) and other critical care settings.

“Historically, we’ve used a step-by-step approach to diagnosing these conditions, starting with the least comprehensive tests,” said Dr. Ryan Taft, vice president of scientific research at Illumina and an author of the study. If initial efforts fail to produce a diagnosis, then more sophisticated tests are used, and finally genome sequencing is used as a last resort. But this approach wastes time and resources and can be emotionally devastating for families who are left without answers. The evidence shows that in many cases, sequencing is the most effective diagnostic method whenever possible, and we simply make genome sequencing our first stop.

The study was conducted by the Medical Genome Initiative (MGI), a consortium of clinical genome sequencing laboratories dedicated to expanding access to high-quality GS. As their latest manuscript reports, there is significant evidence that genome sequencing performs well as a diagnostic test for rare genetic diseases, but clinical adoption has been unexpectedly slow.

In order to fully evaluate the evidence of GS in rare genetic disease groups, MGI conducted a key literature review and comprehensive analysis. A total of 71 papers published between January 2014 and August 2022 met the criteria, including more than 13,000 patients. The studies were evaluated based on their analysis strategy, including type of variant analyzed, interpretation guidelines, healthcare setting, secondary findings, turnaround time, cohort type, diagnostic yield, and clinical utility.

Overall, the study found that the average diagnostic rate for first-level genome sequencing was 45%, compared with an average of 33% for the group of patients who received early genetic testing and an average of 33% for those who did not receive exome sequencing. The diagnostic rate is 33%. One-third of studies reported clinical utility. Management changes described included outcome efficacy in diagnostic thinking, treatment, patient outcomes, and social impact, and the authors found a wide range (20% to 100%) in reporting rates of management changes because the methods used to assess clinical utility varied across studies. Go to the next item.

Taft said the evidence suggests that in many cases, genome sequencing should be the first line of genetic testing. Pediatric patients with unexplained illness in the intensive care unit should be first in line. Additionally, if the target panel does not include all suspected genes that may contribute to a child’s condition, comprehensive genome sequencing can fill in these gaps.

In addition to providing high diagnostic yield, genome sequencing is also fast. Rapid methods pioneered over the past few years can produce results within days, a capability that is particularly beneficial for critically ill infants in the neonatal intensive care unit. Comprehensive alternatives to GS may waste valuable time and delay much-needed diagnosis.

While this review highlights the many benefits of genome sequencing in critical care settings, more work remains to be done. The authors found few published studies on first-line GS in outpatient and other less urgent settings. More research is needed; however, for many patients, the evidence clearly supports the clinical efficacy of genome sequencing.

Taft said there remains resistance to genome sequencing due to perceptions that the price is too high, but this cannot explain the recent dramatic decline in GS costs and its impact on the downstream continuum of care. Getting precise answers faster, especially for patients with rare genetic diseases, is almost always the most cost-effective approach.

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